Kythera going for $2.1 billion

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1 AUGUST 2015 : VOLUME 11 : NUMBER 8 PHARMA, BIOTECH & LIFE SCIENCE PUBLISHED SINCE WHAT S INSIDE DISCOVERY 6 RESEARCH & DEVELOPMENT 12 PRECLINICAL 17 CLINICAL TRIALS 26 DIAGNOSTICS 30 BUSINESS & GOVERNMENT POLICY 33 TOOLS & TECHNOLOGY Expanding the search for disease-causing genes...8 NuGEN sampling effort could accelerate cancer research...16 MSKCC selects Ascentos software for preclinical research...20 On the cutting edge...34 FINANCE/MARKETS 3 EDITORIAL/COMMENTARY 10 PRODUCTS & SERVICES 37 Q&A 38 STEM CELL SPECIAL REPORT: Germlines and gene editing After engineering SuperRat, is Superman far behind? 21 Kythera going for $2.1 billion Allergan looks to bolster existing facial aesthetics business with acquisition BY JEFFREY BOULEY DUBLIN It was in mid-june that Irish pharma Allergan plc announced that it would acquire Westlake Village, Calif.-based Kythera Biopharmaceuticals Inc., a biopharmaceutical company focused on the discovery, development and commercialization of novel prescription products for the aesthetic medicine market. More recently, near the end of July, the companies announced that the U.S. Federal Trade Commission had granted early termination of the waiting period under the Hart- Scott-Rodino Antitrust Improvements Act of 1976 with respect to the pending acquisition. The early termination of the waiting period under the act satisfies one of the conditions to the closing of the pending acquisition, which remains subject to other customary closing conditions, including receipt of approval by Kythera s stockholders. Allergan sees the California company as The acquisition of Kythera is a strategic investment that strengthens our leading global position in aesthetics and continues to position us for long-term growth, says Brent Saunders, CEO and president of Allergan. Kybella is an exciting new product that offers patients the first and only clinically proven, non-surgical treatment for submental fullness (excess fat under the chin). As a leader in aesthetics, we know our customers are looking to offer their patients new options beyond traditional facial aesthetics. Kybella will do that while complementing our market-leading facial aesthetics portfolio. complementary to its existing position in facial aesthetics and expects the acquisition will enhance its long-term growth profile. A notably attractive part of the acquisition for Allergan is that Kythera s lead product, KYTHERA CONTINUED ON PAGE 35 Dialing up diagnostic efforts QIAGEN kicks off a trio of diagnosticfocused partnerships in June and July BY KELSEY KAUSTINEN TOKYO & HILDEN, Germany No moss has been growing on QIAGEN N.V. lately, as the diagnostics company announced three deals in as many weeks focused on molecular diagnostics and companion diagnostics. Among those, QIAGEN has struck a long-term strategic collaboration with Hitachi High-Technologies Corp. focused on initiatives to advance molecular testing. Initially, the companies will focus on developing new automation systems based on polymerase chain reaction (PCR) and next-generation sequencing (NGS) technologies. Though no financial details were disclosed, Hitachi High-Technologies and QIAGEN agreed that the collaboration could be expanded in the future to include co-commercialization of products in certain geographic markets. Hitachi High- Technologies will be bringing its expertise in industrialized instrument development and manufacturing technologies to the deal, with QIAGEN bringing leadership in molecular sample to insight solutions. QIAGEN signed three deals in as many weeks in June and July focused on molecular diagnostics and companion diagnostics. This new strategic partnership with Hitachi High-Technologies will form a very powerful platform to create new molecular testing solutions. Hitachi High-Technologies is a recognized leader in industrial automation and has a proven track record of innovation as well as a significant presence in the Asia-Pacific region, said Thierry Bernard, senior vice president, head of the Molecular Diagnostics Business Area and a member of the Executive Committee of QIAGEN. Combining the NGS-related CREDIT: QIAGEN and other molecular know-how of QIA- GEN with the instrumentation expertise of Hitachi High-Technologies will enable us to bring innovative automation solutions to customers all over the world and across the continuum from basic research through to routine molecular diagnostics. That s not the only Eastern partnership for QIAGEN in the past few months, as the company also announced a collaboration with Seegene Inc. The Seoul, South Koreabased firm will develop a menu of multiplex assay panels for QIAGEN s QIAsymphony RGQ MDx automation platform. In the first project, the focus will be the development of comprehensive panels for profiling infectious diseases, with QIAGEN validating the new tests to run on the aforementioned platform and marketing them worldwide as QIAGEN-branded assays, beginning in Asia and Europe. QIAGEN s QIAsymphony is an innovative, easy-to-use modular system that can integrate a molecular laboratory s workflow from initial biological sample processing to final insights. QIAsymphony RGQ MDx consists of QIAsymphony SP for sample preparation, QIAsymphony AS for assay setup and QIAGEN s real-time PCR detection platform Rotor-Gene Q MDx. QIAGEN CONTINUED ON PAGE 32

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3 For more information, visit FINANCE AUGUST 2015 DDNEWS 3 Oncobiologics secures $31M to advance BioSymphony platform and monoclonal antibody biosimilars pipeline CRANBURY, N.J. Oncobiologics Inc. in July announced the closing of a $31-million financing. Proceeds will be used to support continued development and expansion of the company s proprietary BioSymphony biosimilar platform and advancement of its preclinical and clinical programs. The investment round was led by new investor Perceptive Advisors. Participating new investors included Cormorant Global Healthcare Master Fund, Longwood Capital Partners and venbio Select Fund. Other investors included Proximare Lifesciences Fund, OSSB Pharma Fund and MIH Fund. Citigroup and Jefferies LLC advised Oncobiologics on the transaction. Biosimilars are rapidly becoming a major growth sector for the life-sciences industry, and our proprietary BioSymphony platform is uniquely designed to develop and manufacture high-quality, cost-effective monoclonal Castle Biosciences closes $11.7M tranche FRIENDSWOOD, Texas Castle Biosciences Inc. today announced it has closed the first tranche of a $20-million Series F financing, raising $11.7 million. The funding will be used to accelerate the growth in clinical adoption of the company s gene test for identifying metastatic risk in early-stage cutaneous melanoma, Decision- Dx-Melanoma and its other tests designed to improve cancer care. We are excited to support the continued growth of Castle Biosciences clinically important molecular diagnostic tests, building on the commercial success of its uveal melanoma test, and continuing the fast pace of adoption of its cutaneous melanoma test, said Victor Hwang of Industry Ventures. We initially invested in Castle Biosciences through a secondary transaction and have been impressed by management s strategic build-out of its infrastructure, including the recruitment of accomplished executives and board members from the genomics industry, expansion of its sales and marketing efforts and the continued development and commercialization of important new diagnostic tools for underserved cancers. Castle Biosciences tests are designed to go beyond traditional staging methods to provide tumor-specific information to help determine the best treatment approach in patients with uveal melanoma, cutaneous melanoma, esophageal cancer, mesothelioma and other underserved cancers. We re extremely pleased to have Industry Ventures lead this financing round, and to have the continued support of our current investors including HealthQuest Capital and Mountain Group Partners, said Derek Maetzold, Castle Biosciences president and CEO. The funding enables us to expand our efforts to reach physicians and payers, and ultimately increase the number of patients who can benefit from improved cancer staging and better treatment decisions enabled by our molecular diagnostic tests. antibodies in a timely manner, said Dr. Pankaj Mohan, founder and CEO of Oncobiologics. We highly value the significant interest, confidence and financial support of such a successful group of life-science investors, which enables us to further our objective of bringing critical care therapeutics to patients in a cost-effective manner. Joseph Edelman, CEO and portfolio manager of Perceptive Advisors, said, We look for life-science technologies, products and a team with scientific competence that has the potential to generate significant returns to our fund. Oncobiologics has an advanced and deepening biosimilar pipeline emerging from a fully integrated technology platform that will differentiate the company in a growing and potentially competitive biosimilar market. We look forward to contributing to the company s growth in this important segment of the biotechnology industry. Oncobiologics is focused on developing and commercializing monoclonal antibody biosimilar therapeutics. It is advancing its pipeline of 11 biosimilar products, two of which are currently in clinical development. Searching for a complete system for expansion of human ips cells? S T E M C E L L R E S E A R C H Cellartis DEF-CS Culture System Feeder-free culture with virtually no background differentiation Simplified single-cell passaging Stable, reproducible expansion Includes defined media, additives, and coating compound Request your sample today at or call Scan to find out more Clontech Laboratories, Inc. 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4 4 DDNEWS AUGUST 2015 MARKETS For more information, visit Coastal cities dominate list of top life-sciences clusters Rank Outlook Report (current) Greater Boston Area (no change) 2 Raleigh-Durham (+2) 3 San Francisco Bay Area (-1) CHICAGO U.S. biopharmaceutical innovation is thriving, with areas like Boston, Raleigh-Durham and San Francisco dominating life-sciences activity in the United States. However, a scarcity of laboratory space is pushing biopharmaceutical companies to seek locations in suburban markets where space is available or can be constructed, while still providing proximity to talent and resources. These trends, along with a ranking of the top U.S. life-sciences cities and the global industry landscape, are revealed in JLL s fourth annual Life Sciences Outlook Report that was released in late July. In their U.S. operations, biopharmaceutical companies are being squeezed by rising costs for highly trained talent, more expensive real estate markets and a shrinking supply of available laboratory space, said Roger Humphrey, executive managing director and leader of JLL s Life Sciences group. Many are willing to pay a premium for proximity to the leading research institutions and 2014 Outlook Report Year-Over-Year Trends Greater Boston San Francisco Bay Area San Diego 4 San Diego (-1) Raleigh-Durham 5 New York City (n/a) New Jersey/NYC/ Westchester) 6 7 Los Angeles/Orange County (No Change) Philadelphia (No Change) 8 Long Island (n/a) 9 Minneapolis (No Change) Los Angeles/Orange County Philadelphia 10 Seattle (No change) Seattle Suburban Maryland/ Metro Washington DC Minneapolis/St. Paul Source: JLL 2015 Global Life Sciences Outlook Report Boston remains the clear leader. The San Francisco Bay Area continues to lead the nation in life-sciences patents, with 1,652 total in 2013, the most recent year for which data is available. Small- and mid-size companies continue to drive most facility development and leasing transactions. The Raleigh-Durham area has experienced a strong uptick in life-sciences start-ups and employment stemming from the region s well-regarded research institutions. Long Island, New York City and New Jersey each boast unique cluster activity and varying real estate demand, warranting separate rankings this time around. scientists, but the lack of space is compelling companies to look at secondary sites that are a little less conveniently located. High-volume mergers and acquisitions continue to reshape the biopharmaceutical sector as global pharmaceutical giants seek greater operating efficiencies through consolidation. Investment in start-ups and mid-sized companies developing new products is also playing a key role in industry dynamics. The report found that this burgeoning innovation has driven a space crunch for laboratories in cities such as Boston, Los Angeles and the San Francisco Bay Area. In addition to the above information, the report also tracks other geographic shifts in life-sciences innovation, operations and facilities investments, including analysis of countries and cities most actively investing in their life-sciences sectors. It includes a ranking of the top U.S. life-sciences clusters and a look at top global cities to watch, as well as analyses of global trends. PHARMACEUTICAL AND BIOTECH MARKET INDICES Pharmaceutical Index /Aug 12/Sep 17/Oct 14/Nov 12/Dec 16/Jan 13/Feb 13/Mar 17/Apr 15/May 17/Jun 16/Jul SOURCE: NYSE ARCA SOURCE: NYSE ARCA Mini-pharma and Mini-biotech Indices /Aug 12/Sep 17/Oct 14/Nov 12/Dec 16/Jan 13/Feb 13/Mar 17/Apr 15/May 17/Jun 16/Jul Biotechnology Index SOURCE: NYSE ARCA MINI-BIOTECH MINI-PHARMA /Aug 12/Sep 17/Oct 14/Nov 12/Dec 16/Jan 13/Feb 13/Mar 17/Apr 15/May 17/Jun 16/Jul P U B L I C C O M P A N Y N E W S Genticel provides Q2 update PARIS Genticel s second-quarter financial update showed cash and cash equivalents and liquid investments of 25.2 million (about $27.9 million) as of June 30, 2015, which was reportedly in line with company expectations. The company also reported promising pharmacology with in-vivo results of GTL001 (ProCervix) presented at AACR Annual Meeting 2015, positive proof-of-concept results for GTL002, Genticel s multivalent HPV therapeutic vaccine candidate based on proprietary Vaxiclase platform and FDA clearance of an IND application for a U.S.-based Phase 1 clinical trial of GTL001. Tenax announces Q4 and FY2015 results MORRISVILLE, N.C. Tenax Therapeutics Inc., a specialty pharmaceutical company developing and commercializing a portfolio of products for the critical care market, recently announced financial results for the fourth quarter and fiscal year 2015 ended April 30, 2015, and provided a corporate update. We continue to be encouraged by the significant progress and expansion of our levosimendan development program, said John Kelley, CEO of Tenax. We now have 51 sites activated in our Phase 3 LEVO-CTS trial in low cardiac output syndrome, with 35 having enrolled at least one patient, and we expect to eventually have at least 70 total hospitals participating in the trial. With 130 patients enrolled thus far, we expect these additional sites to increase enrollment, and we now expect to report results from the LEVO-CTS trial in calendar year He also noted that with a strong cash position that will enable us to complete LEVO-CTS in 2016 while opportunistically supporting the LeoPARDS study, we are well equipped to execute on our development plan as we continue building Tenax into a fully integrated critical care company. Adocia reports on first half of 2015 LYON, France Adocia recently announced its financial results for the first six months of the fiscal year ended June 30, The results are characterized by, in part, a solid financial position resulting from the 32-million ($35.4 million) increase in capital realized in March 2015 from a private placement of nearly 10 percent of its share capital from healthcare specialist investors, allowing a cash position as of June 30, 2015 of 72.8 million ($80.5 million). The cash needed to finance operations amounted to 7.1 million ($7.9 million) in the first six months of The results also show a positive net result of 6.7 million ($7.4 million) over the first half of 2015 compared to a 5.5 million ($6.1 million) loss for the first half of 2014.

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6 6 DDNEWS AUGUST 2015 For more information, visit DISCOVERY BRIEFS LDC, Johnson & Johnson Innovation ink two-year deal DORTMUND, Germany A recently announced collaboration between the Lead Discovery Center GmbH (LDC) and Johnson & Johnson Innovation Ltd. will focus on the identification and acceleration of innovative drug candidates for the treatment and prevention of diseases with high unmet medical needs. The organizations will collaborate to identify translational research opportunities sourced from LDC s academic network, which Johnson & Johnson Innovation will evaluate for the purpose of establishing drug discovery collaborations with LDC in selected projects. A collaboration agreement will be negotiated for the joint development of each project Johnson & Johnson Innovation selects, up to the next mutually agreed-upon milestone, with financial and research details established on a project-by-project basis. Any revenue that results will be shared with the inventors and collaborating institutions. HemoShear announces name change CHARLOTTESVILLE, Va. HemoShear has announced that it will be changing its name to HemoShear Therapeutics to reflect its new concentration on drug discovery, with its initial focus on developing therapies for nonalcoholic steatohepatitis (NASH) and organic acidemias, a group of rare genetic metabolic disorders. The company will be leveraging REVEAL-Tx, its proprietary platform, which offers the ability to characterize metabolic disorders by revealing complex human pathophysiological pathways. In late 2014, we established a collaboration with Children s National Medical Center to discover drugs for children with rare metabolic diseases, Vincent Aurentz, president of HemoShear Therapeutics, commented in a statement. HemoShear Therapeutics is focusing on a family of rare disorders responsible for chemical imbalances in the body that result in life-threatening health complications at an early age. Tragically, these young patients rarely live past their teens and no drugs exist to treat their diseases. IN THIS SECTION Alzheimer s disease One step at a time against Alzheimer s... 6 Collaborative research LDC, Johnson & Johnson Innovation ink two-year deal... 6 We are the world... 6 Exome sequencing Metabolic disorders HemoShear announces name change... 6 Oncology An initial partnership for Invenra... 8 Ubiquitous ubiquitins?... 6 One step at a time against Alzheimer s Brain inflammation targeted in first drug discovery project from Dementia Consortium BY LLOYD DUNLAP LONDON Funding worth nearly half a million pounds (about $780,000) will unite academics at the University of Southampton with drug discovery experts at the medical research charity MRC Technology to target the immune system in the hunt for new treatments for Alzheimer s disease. The work is the first to be funded by the Dementia Consortium, a discovery collaboration between Alzheimer s Research UK, MRC Technology and the pharmaceutical companies Eisai and Eli Lilly. By uniting expertise, this focused cash injection is intended to be an initial step in bridging the gap between academic research and the pharmaceutical industry in the search for new drugs to slow the development of Alzheimer s. According to Steve Suchting, business development manager at MRC Technology, the consortium was the result of the fact that no new development to treat brain inflammation, including Alzheimer s, had been introduced in many years, and new models for drug discovery were required. MRC will bring its drug discovery resources to bear and provide project management. Dr. Justin Bryans, director of drug discovery at MRC Technology, added, Our Centre for Therapeutics Discovery has proven capability in drug discovery and, as a charity, we are ideally placed between academia and pharma to translate promising science into effective treatments for patients. DEMENTIA CONTINUED ON PAGE 7 In addition to a drug discovery pact with Genentech related to ubiquitins, Almac Group recently announced a new facility in Singapore. Pictured here are Jim Murphy, president and managing director of Almac Clinical Technologies, and Dr. Robert Dunlop, president and managing director of Almac Clinical Services. UBIQUITOUS UBIQUITINS? Almac Discovery and Genentech partner on ubiquitin-related target for potential cancer drugs BY ILENE SCHNEIDER CRAIGAVON, U.K. Almac Discovery, a biopharmaceutical company focused on identifying and developing innovative therapeutics for the treatment of cancer, and Genentech, a member of the Roche Group, recently inked a research and licensing agreement designed to discover and develop small-molecule inhibitors of a ubiquitin-specific protease (USP) target. According to the National Center for Biotechnology Information, Ubiquitin-specific proteases are deubiquitinating CREDIT: ALMAC GROUP The Dementia Consortium has funded its first project, which is focused on immune system protein CSF1R as a possible lead for effective Alzheimer s disease therapeutics. We are the world Open Innovation Drug Discovery program expands to bring academia, scientists, researchers, biotechs together across the globe BY LORI LESKO INDIANAPOLIS Aimed at boosting the discovery of effective treatments for difficult-to-treat diseases and creating a worldwide network of problem-solvers, Eli Lilly has expanded the scope of its Open Innovation Drug Discovery (OIDD) program from investigators at qualified universities to also include researchers of institutes and small biotech firms. Currently, we have 567 global researchers from 24 countries around the world and 286 institutions, spokesperson David Polk tells DDNews. Of the 286 institutions, 44 are biotechs and 242 are academic institutions. We have seen success in two critical ways, Polk says. First, our network of potential collaborators has expanded. We ve found an effective and efficient way to work with small biotechs and academic institutions. What s most exciting is that we are working with scientists whom we might not have prior to the OIDD program. Second, we now have access to new ideas and compounds unavailable anywhere else. For example, we have two new collaborators who have discovered chemical scaffolds that target a key cardiometabolic protein. Lilly now has formal collaborations with these institutions so that together, we can study the potential of these small molecules. Jimmy Wu, an associate professor of chemistry at Dartmouth College, has been a driving force in this effort. Wu secured a $1.5-million grant from the National Institutes of Health as a result of his work in Open Innovation Drug Discovery. Wu USP CONTINUED ON PAGE 8 OIDD CONTINUED ON PAGE 9

7 For more information, visit DISCOVERY AUGUST 2015 DDNEWS 7 DEMENTIA CONTINUED FROM PAGE 6 Suchting notes that the consortium is in the pre-competitive stage and that new partners may be added. Ultimately as much as 3 million in funding may be made available. The project is milestone-driven, he states, and all partners participate in meetings. The endpoint of the project is to prove that the target can be modulated. On the academic side, Dr. Diego Gomez-Nicola and colleagues at the University of Southampton will build on their current finding that a protein in the immune system called CSF1R could be the key to an effective new drug for Alzheimer s disease. Together with drug discovery experts at MRC Technology, they will seek to develop novel therapeutics to target the immune system a double-edged sword in the brain s response to nerve cell death. Researchers now believe that Alzheimer s disturbs the brain s inflammatory response, causing the damage associated with the disease. According to Gomez-Nicola, Inflammation is the body s response to damage and something we ve all experienced, but sometimes these mechanisms to defend the body go awry. In Alzheimer s disease, specialized immune cells called microglia are a little too eager to clear damage. Their ranks swell and activity increases, with damaging consequences for surrounding nerve cells. CSF1R is a key player in regulating the brain s immune response. In their previous studies in mice, the University of Southampton team found that blocking CSF1R can dampen the inflammatory response to nerve cell death and improve symptoms in other neurodegenerative diseases. However, the compounds currently available to block CSF1R are not ideal to take into the clinic, due to unwanted effects and difficulties crossing the blood-brain barrier. This investment via the Dementia Consortium will allow the researchers to explore other, more targeted approaches to block CSF1R important groundwork before any new treatment can go into the clinic. This project will allow us to find the best way to interfere with the biological cascade that leads to an increase in microglia numbers. We know that targeting CSF1R is being explored as a potential treatment for cancer and inflammatory conditions, and we hope that by fine-tuning compounds to act specifically in the brain, this approach could be tested for benefits in Alzheimer s, too. This crucial drug discovery work in cells and mice should act as stepping stone to develop new treatments that can halt damaging brain inflammation and nerve cell death, Gomez-Nicola states. Dr. Eric Karran, director of research at Alzheimer s Research UK, adds, It s been fascinating to see the academic community dissect the role of inflammation in Alzheimer s disease and learn more about the friendly fire that takes place during the course of the disease. But now we need to translate this interesting biology into tangible benefits for the 500,000 people in this country living with Alzheimer s. It s a long road from research in the laboratory to Patented Hybrid Technology with independent filter and monochromatorbased optics for sensitivity and flexibility Variable bandwidth selection for optimized fluorophore sensitivity Live cell options: atmospheric control and direct bottom plate detection The Dementia Consortium is still in the precompetitive stage, says Steve Suchting, business development manager at MRC Technology, and other partners may yet be added along with MRC, Alzheimer s Research UK, Eisai and Eli Lilly. treatments in the clinic, but investment to boost the number of new drug targets is critical if we are to face this huge medical challenge. Neuroinflammation is emerging Ultra-fast plate processing speeds with multiple PMT detectors as a key contributing factor in driving Alzheimer s disease pathology, notes Dr. Andy Takle, Eisai s senior director of Open Innovation, UK. The biological mechanisms that underpin this process are incredibly complex, and our understanding relies heavily on information originating from the academic community. For this reason, we recognize that collaboration is key in identifying new opportunities to intervene. As a Dementia Consortium partner on this exciting project, we look forward to bridging academic expertise with a focused drug discovery effort to develop new medicines for this devastating disease. Michael Hutton, chief scientific officer for neurodegeneration at Eli Lilly, echoed those sentiments by saying, Lilly is delighted to support this exciting program as part of the Dementia Consortium, which offers a new model for public-private partnership to support drug development in Alzheimer s disease. EDITCONNECT: E There can only be one Highest-Performance reader. And it s BioTek s Synergy Neo2, the most advanced, high-performance, high-speed plate reader on the market today. 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8 8 DDNEWS AUGUST 2015 DISCOVERY For more information, visit An initial partnership for Invenra Biopharmaceutical company strikes mab deal with Oxford BioTherapeutics BY KELSEY KAUSTINEN MADISON, Wis. & OXFORD, U.K. Invenra Inc., which specializes in next-generation therapeutic human antibodies and antibody derivatives, is stepping into the partnering sphere with a collaboration announcement involving Oxford BioTherapeutics (OBT) as its first partner. The agreement is for the identification and characterization of a panel of fully human therapeutic monoclonal antibodies (mabs) against a novel cancer target identified by OBT through its OGAP discovery platform. The terms of the deal stipulate that OBT will make an initial payment to Invenra upon receiving a panel of novel mabs confirmed to meet mutually agreed-upon design goals and specifications. After that point, OBT will assume responsibility for further development of the therapeutic product candidates. Should they be successfully developed, Invenra stands to receive additional milestone payments and royalties on net sales of the therapeutic and diagnostic products. OBT will also gain diagnostic product rights from Invenra as well as the option of developing diagnostic products. Specific financial details were not disclosed. OBT is passionate about developing targeted cancer therapies for patients, and we are excited to be working with Invenra on a new approach to pursue mab-based therapies, Keith Wilson, chief scientific officer at OBT, remarked in a press release. This collaboration leverages the complementary expertise of our two companies in identifying optimal mabs against targets differentially expressed in cancer. Invenra s platform, which is based on ultra-high-throughput technology to synthesize hundreds of thousands of full-length antibodies via cell-free expression and release them into nanowells, enables quick, direct interrogation against cells in a multiplexed fashion. Mark Kubik, Invenra s vice president of business development, notes that the two main approaches to developing antibodies are in-vitro-based approaches like Invenra s, which focus on libraries, and animal- or in-vivo-based approaches using either a traditional mouse to generate a mouse monoclonal antibody that then gets humanized, or any number of different transgenic animals that have had human immunoglobulin genes inserted into them to in theory create human monoclonal antibodies coming out of a mouse system. Invenra works with its library and will then move into full IgG [Immunoglobulin G] molecules using a cell-free expression technology that we use, and then we analyze these very large panels of full IgGs directly in phenotypic assays. Because we re an in-vitro system, we re not driven by the immunodominance of a particular target antigen...our platform technology, in contrast, because it s an in-vitro approach, it s completely agnostic to the immunodominance of any given target antigen, Kubik tells DDNews. So rather than an antibody response that s being driven against a very specific immunodominant element of that target antigen, our antibodies are going to be binding all over that target antigen... so one of the compelling differentiation hypotheses for the Invenra technology is that we re going to find the antibodies that bind all over that target antigen, in different epitopes, and then you can choose which antibody is the one that does exactly what you want it to do. Roland Green, CEO and president of Invenra, added that, This collaboration is a major milestone for Invenra as a company and a validation of our innovative technology. We are delighted to be collaborating with Oxford BioTherapeutics to identify best-in-class antibodies against their novel oncology target. In addition, this collaboration with OBT fits well within our business model, whereby we are making our technology available to a select group of companies while continuing to develop our own internal proprietary pipeline of therapeutic product candidates. Given Invenra s approach and OBT s focus on oncology and a core competency centered on target discovery that has produced a variety of very interesting targets, Kubik says the U.K.-based company was a nice fit for them as a partner. We definitely believe that this is just the beginning of a hopefully long and fruitful relationship, so I think it could definitely add a lot of value for both us and OBT in the sense that there are additional programs that we can work on together, says Kubik. EDITCONNECT: Expanding the search for diseasecausing genes TOOLS & TECHNOLOGY SANTA CLARA, Calif. Noting that its SureSelect targetenrichment product family has already enabled researchers to identify more than 50 Mendelian diseasecausing genes, Agilent Technologies Inc. announced in July additions to that family: the SureSelect Human All Exon V6, V6+UTR and V6+COSMIC. All are designed to address the current limitations of exome sequencing, Agilent says, giving researchers better coverage of hard-to-capture regions and providing deep coverage of relevant regions, with minimal sequencing enabling those researchers to delve deeper into both constitutional diseases and cancers. The SureSelect exome has been widely adopted in both clinical and translational research, and it has greatly enabled discovery of diseasecausing genes, said Jacob Thaysen, president of Agilent s Diagnostics and Genomics Group. The Human All Exon V6 is an important addition to our strong NGS portfolio for constitutional disease research. It targets hardto-capture and multi-mapping regions that had proven challenging for current exome products on the market. Along with Sure- SelectQXT, Agilent now provides the fastest hybridizationbased enrichment solution, which will add great value in any research setting, enabling the identification of more variants with greatly reduced turnaround time and at lower sequencing cost. Thaysen noted that the new products cover more regions (including previously recognized gaps), increase the sensitivity of variant calling and minimize false negative calls. SureSelect Human All Exon V6+UTR adds untranslated regions of the exome for translational research, while V6+COSMIC adds data from the cancer research database known as the Catalogue Of Somatic Mutations In Cancer. This latest design, optimized to cover targeted regions in greater detail, can also be blended with any custom capture design, enabling an exome tailored for specific applications, Thaysen said. USP CONTINUED FROM PAGE 6 enzymes involved in the removal of ubiquitin from specific protein substrates resulting in protein salvage from proteasome degradation, regulation of protein localization or activation. DNA alteration and overexpression in different cancer types, as well as involvement in many cancerassociated pathways, make ubiquitin-specific proteases attractive for the cancer drug discovery purposes. While ubiquitin-specific proteases are emerging as potential targets in cancer and other diseases, inhibitors of USPs have been difficult to identify, in spite of the efforts of pharmaceutical and biotech companies. According to Tim Harrison, vice president of drug discovery at Almac Discovery, Ubiquitinspecific proteases have been shown to play an important role in a number of key oncogenic pathways, and the identification of potent, selective inhibitors provides an exciting opportunity to fully exploit this novel biology, as well as further demonstrating the chemical tractability of this important target class. Under the terms of the agreement, Almac Discovery will receive an upfront payment of $14.5 million and be eligible to receive up to $349 million in payments based on achievement of certain predetermined milestones, as well as escalating tiered royalties on potential commercial sales of multiple products to the target by Genentech. Almac Discovery s novel, Ubiquitin-specific proteases have been shown to play an important role in a number of key oncogenic pathways. Tim Harrison, vice president of drug discovery at Almac Discovery potent and selective smallmolecule inhibitors will be the starting point for a two-year joint research program funded by Genentech, which will be responsible for all preclinical and clinical development, as well as commercialization of products coming out of the collaboration. The partnership is designed to translate Almac Discovery s medicinal chemistry and biology into the clinic. According to James Sabry, senior vice president and global head of Genentech Partnering, We re pleased to initiate this collaboration with Almac Discovery, where we hope to discover and develop therapies targeting an important USP that can potentially advance the standard of care for patients with cancer. The Almac Group, which provides a full range of contract services from biomarker and discovery services to active pharmaceutical ingredient development and manufacturing as well as pharmaceutical development, clinical trial material supply and commercial-scale drug substance and drug product manufacturing also recently announced an agreement with OncoMed Pharmaceuticals Inc. to develop a companion diagnostic test to help predict a patient s likelihood of responding to OncoMed s novel therapeutic that targets R-Spondin 3 (RSPO3). Anti- RSPO3 (OMP-13R10) has demonstrated activity in preclinical models against a variety of tumor types, including colon, lung and ovarian cancers. Almac and OncoMed are developing a gene-expression RSPO3 CLIA assay that can be used to prospectively select patients in the clinical development of anti-rspo3. In addition, in July the Almac Group announced an expanded Asia Pacific presence with a new regional headquarters and clinical trial supply facility in Singapore. Asia Pacific is a vital region for us, as currently 23 percent of global clinical trials for new pharmaceutical products are being conducted here. By basing our regional headquarters and operations in Singapore, we are better equipped to support our Asia-based clients in their own time zone and languages, said Dr. Robert Dunlop, president and managing director of Almac s Clinical Services business unit. With the opening of our new Singapore facility, we are directly supporting studies run by regional and global pharmaceutical firms by providing critical manufacturing, packaging, supply chain management and interactive response technology support services in Asia Pacific. EDITCONNECT:

9 For more information, visit DISCOVERY AUGUST 2015 DDNEWS 9 challenges posed by alignment of business and scientific objectives, sharing of intellectual property and the high risk and long-time horizon for converting basic science into clinical outcomes. The bottom line is, a mutual desire to advance innovative science and create medicines to help patients brought industry and academic partners together, he says, and all of OIDD s offerings have the same path to potential collaboration. Once you are a member, you can use design tools to create your own molecules, submit compounds for screening in Lilly s biological assay modules, have your scaffolds considered for inclusion in the Lilly internal collection, synthesize compounds remotely through the Lilly Automated Synthesis Laboratory and connect with global partners toward discovering medicines for neglected and tropical diseases, Palkowitz says. EDITCONNECT: E R DSC XP2_3.375x10_Layout 1 5/2/14 9:34 AM Page 1 Pipet-Aid Eli Lilly s Open Innovation Drug Discovery program looks to bring together industry and academia and offer resources to often-struggling researchers, while also providing potential opportunities for Lilly s own pipeline expansion. XP2 OIDD CONTINUED FROM PAGE 6 worked independently (without a Lilly collaboration agreement) and by leveraging the program data, he was able to obtain a patent. Says Polk, Using the data generated by the Lilly OIDD program, Dr. Wu secured a grant for synthesizing compounds that can be used to stimulate production of GLP-1 or inhibit the CGRP receptor. Academic institutions are all eligible, Polk explains. For biotechs, we want to ensure that we re supporting the companies that will benefit the most. For example, the biotechs must be legally established and have lab facilities. However, we use market cap to limit the scope to smaller companies. Polk touts the wide array of drug discovery technologies available through Eli Lilly in both Indianapolis (where the company is headquartered) and San Diego, including high-throughput in-vitro screening technology and sophisticated mode-of-action assays. In San Diego Lilly s West Coast site we have structural biology, he adds. Depending on the collaboration, technologies from both facilities can be employed. In fact, it s the same capabilities available to our own internal scientists. By default, researchers keep the IP rights to everything they submit, Polk says. If Lilly and the researcher or institution create a formal collaboration agreement, we negotiate the terms together. The greatest benefit that Lilly receives from the OIDD program is developing a relationship with talented researchers, Polk says. If the data generated reveals something of interest to Lilly, we have the first option to negotiate a collaboration agreement to study the compound further. Once you are a member, you can use design tools to create your own molecules, submit compounds for screening in Lilly s biological assay modules, have your scaffolds considered for inclusion in the Lilly internal collection, synthesize compounds remotely through the Lilly Automated Synthesis Laboratory and connect with global partners toward discovering medicines for neglected and tropical diseases. Alan Palkowitz of Eli Lilly All the biological data is generated internally at Lilly, Polk says, then published on the OIDD platform and displayed within 24 hours of it being available. Alan Palkowitz, vice president of Discovery Chemistry and Research Technologies at Eli Lilly, wrote an executive summary in the OIDD brochure, noting, We realize it s important to bring together through partnership and collaboration, diverse scientific talent and capabilities to find the best possible outcomes for the people we serve. And, unlike other programs, Lilly s OIDD creates a broad playing field since it is open to any scientist at eligible research universities, research institutes and small biotechnology companies. The idea, he says, is to provide a spirit of cooperation under which Lilly provides access to the company s cutting-edge research by giving participants the tools and data that can help advance their own scientific work, while allowing access to Lilly s intellectual property rights and input once a collaborative agreement is signed. All of this is necessary because the present environment for drug discovery is complicated by many challenges, Palkowitz noted, including rising costs of R&D, poor productivity as measured by a declining number of new drug approvals per dollar investment, patent expirations and increasing regulatory restrictions. Ironically, this environment follows on the heels of two decades of transformational breakthroughs in the understanding of disease biology, Palkowitz says. Furthermore, the demand for new therapies has never been higher, fueled by unmet medical need, an aging population that will live longer and the growth of emerging markets such as China. Pharmaceutical companies have taken varied approaches to address these challenges, ranging from in-licensing of development-stage molecules, consolidation through mergers and acquisitions and aggressive cost-cutting measures such as outsourcing of work to low-cost providers, Palkowitz says. While these approaches have merit, they provide only short-term benefits if they are not supported by scientific innovation that can be translated into clinical opportunities, he says. One area that has historically been a fertile ground for innovation is the interface between industry and academia. There are, likewise, examples of clinical success stories that trace their origins to a direct collaborative interaction between industry and academia on specific molecules, he says. These relationships successfully negotiated the Advanced Ergonomics for Working on a Bench Comfort The most comfortable pipettor you ever laid a hand on Convenience Uninterrupted extended operation Control Quiet precision pump responds instantly to the touch of the button Drummond Pipet-Aids have set the standard for making pipetting in the laboratory safer, easier, and more convenient. The Pipet-Aid XP2 delivers more. More comfort more convenience better control. From the Developers of the Original Pipet-Aid MADE For a copy of our catalog or more information on the Pipet-Aid XP2 visit IN USA 500 Parkway, Box 700 Broomall, PA 19008

10 EDITORIAL 10 DDNEWS AUGUST 2015 For more information, visit Dog days of summer. Dog years of oncology? BY JEFFREY BOULEY Of minimum wage and cancer drugs PETER T. KISSINGER DEMANDS TO RAISE the minimum wage and lower the cost of cancer drugs have engendered considerable public noise all summer. How can I possibly relate them? A politician has also suggested that university tuition be free to all. Oncologists are anxious about cancer drugs at Ferrari prices. Others decry that you can t support a family of four at the federal minimum wage. We ve thrived, relatively speaking, in a system where we want to be paid more and our employers see reasons to not comply. We ve thrived when customers want to pay less and manufacturers want to charge more. In every case, given some time, we arrive at a compromise. When we value the product more than we pay for it, we buy it. When our employer values our efforts more than not having us at all, she pays us. Whether we are earning a living or buying a product or service, we have choices. We can work elsewhere or buy elsewhere and should exercise that right. The expectation of a good living from a fast-food job should suggest becoming the manager or owning a series of restaurants, not throwing in the towel on learning more. Yes, you can. Entitlement to the latest cancer drugs is likewise an attractive, but equally false, notion. As a scientist and engineer, I like the idea of stress-testing both systems and ideas. For Peter T. Kissinger Jeffrey Bouley, DDNews Chief Editor AS THE HEAT and humidity fully roll in to announce we re deep into summer, I don t really have any opinions. Y know, except that the first half of spring and most of the season of fall are the only two times in the year I feel really comfy. However, the fact I m light on opinions right now related to pharma, biotech and life sciences doesn t mean I have nothing to share. Got something in my inbox from some folks at MIT that piqued my interest, so let s let it shine here. According to a study newly published and coauthored by MIT economists, pharmaceutical firms underinvest in long-term research to develop new cancer-fighting drugs due to the greater time and cost required to conduct such research. I know, I re thinking: All those hundreds of millions billions even of R&D dollars and trying to get approval if you make it past clinical trials, and there s underinvestment? Here s the thing, according to the MIT economists: specifically, drugs to treat late-stage cancers are less costly to develop than drugs for earlier-stage cancers, partly because the late-stage drugs extend people s lives for shorter durations of time. This means that the clinical trials for such drugs get wrapped up more quickly, too, as well as provide drug manufacturers more time to control patented drugs in the marketplace. There is a pattern where we get more investment in drugs that take a short time to complete, and less investment in drugs that take a longer time to complete, says MIT economist Heidi Williams, co-author of a new paper in the American Economic Review that details the findings of the study. She is the Class of 1957 Career Development Assistant Professor in MIT s Department of Economics, and her co-authors are Eric Budish, an economist at the University of Chicago s Booth School of Business, and Benjamin Roin, an assistant professor at the MIT Sloan School of Management. The social cost is significant, the researchers say, estimating that the lack of investment in longer-term drugs resulted in a loss of 890,000 life-years among people diagnosed with cancer in the year 2003 alone. The paper also suggests three policy adjustments that might produce more long-term research on anticancer drugs. The finding doesn t mean that the private firms are doing anything wrong, Williams adds, given the incentives they face. However, she observes, The public sector is more willing to invest in these long-term projects than is the private sector, suggesting that new policies could produce more types of drugs for patients. By examining the historical data, Budish, Roin and Williams found that in some cases where surrogate endpoints are allowed in cancer research clinical trials including many types of leukemias there were relatively more trials and money poured into research, other things being equal. When you have good surrogate endpoints, you see a dramatic increase in R&D investment, which means lives saved, Roin says. All well and good, but they did say there were three possible solutions, right? What are they? The first, they say, coming off the point just made, is the continued use of surrogate endpoints or at least, initially, more research to find out if wider use of surrogate endpoints for additional cancers is valid. A second possible policy change is more public funding of research and development for anticancer drugs, since such funding is free of shortterm, private-sector shareholder pressure to produce returns. There are only six cancer drugs in existence that are preventative in nature and all six have been developed because of public funding, or relied on surrogate endpoints. These first two points are related, Williams emphasizes, noting, No individual private firm wants to come in and provide all of the evidence that you need to validate a surrogate endpoint, because once one is validated, that s going to be used by all of the firms on the market. A third potential new policy, suggest the researchers, would be changing the terms of drug patents, which typically run from the time of patent filing, to run from the time when the drug hits the market. That said, the FDA can currently grant exemptions that lengthen drug patents to account for the time R&D takes. The researchers admit they aren t trying to be medical or healthcare professionals they aren t life scientists and they know it. And, similarly, I m not an economist. But it sounds to me like they have some good places to start, and the sooner we get started on better ways of carrying out cancer research, the sooner we can get to a plethora of cures and maybe stop hearing the conspiracy theories about how Big Pharma is hiding the cure for cancer. example, we could do the thought experiment of demanding that fast food wages rise to $100/ hour; after all, this is only 10 percent of the fee schedule of many reputable corporate lawyers. With respect to cancer (throw in hepatitis C as well), a stress test would be an upper level of $100/ dose. It is immediately evident we d be in deep trouble, so let s back down on fast food to $25/hour and up on cancer to $400/dose. We could go further to $1.25/hour (the minimum wage I enjoyed in my high school years) and up to $100,000/ dose for cancer treatment. Under the latter rules, no one would work at fast food until the pay went up and very few patients would get treated until the price came down. What works very well is the invisible hand of free markets ascribed to Adam Smith in the 18th century (The Wealth of Nations, 1776, a banner year for free markets). A challenge with the invisible hand is that it is indeed invisible to many scientists and physicians. Politicians derive much of their power from denying its existence. That minimum wages or price controls provide any real benefit is an illusion. It s best to eliminate them. On the other hand, all the yapping about fast-food wages has caused them to go up. All the noise about drug prices stimulates them to go down as competitive forces come into play. We now have more transparency with disease-free and progression-free survival data. That helps, too. Discussions about paying for outcome vs. treatment reflect that drug responses are variable. That debate is good; it s another component of the invisible hand at work. The minute the debate presses for a controlling rule, the invisible hand stops working. The legions of complaining oncologists likely have a good deal of their 401k assets in biopharma companies. Their kids are expecting R&D jobs in San Diego for more than a minimum wage. Scientists from a prestigious institute in Europe recently asked to know to what extent drug prices were the result of innovation vs. satisfying shareholders. They apparently do not appreciate that without satisfying shareholders, innovation will stop. Do cancer patients and their caregivers think about such a consequence? Do they ask about the notorious medical device tax? Do they also realize that income from oncology funds research on Alzheimer s disease should they survive their cancer? Know the hand! Nothing has ever worked better. Gleevec and the rest will be generic, but not soon enough for some. That s the problem. There is no alternative to accepting the natural time constant of 20 years. Let life-science innovation stay free from price controls, but encourage open debate and stay tuned to Peter T. Kissinger (who can be reached at is professor of chemistry at Purdue University, chairman emeritus of BASi and a director of Chembio Diagnostics, Phlebotics and Prosolia. PUBLISHER Bruce Poorman ASSOCIATE PUBLISHER Laurence Doyle EDITORIAL Jeffrey Bouley, Chief Editor Lloyd Dunlap, Managing Editor Kelsey Kaustinen, Senior Editor FEATURES EDITOR Randall C Willis CONTRIBUTING EDITORS Zack Anchors, Jim Cirigliano, Lori Lesko, Ilene Schneider, Mel J. Yeates ADVERTISING NORTHEAST Michael Stack 1127 Kristin Drive, Suite 100 Libertyville, IL TEL MIDWEST/MIDATLANTIC Ryan King 1900 N. Hudson, #D Chicago, IL TEL NORTHWEST/SOUTHWEST Kayte Miller 8124 Cantershire Way Granite Bay, CA TEL EUROPE, AFRICA, ASIA Stephanie Painter Painter-Lowe Communications TEL FAX MARKETING Laurence Doyle TEL FAX PRODUCTION John O Brien TEL OPERATIONS Margaret Gorsline, Manager TEL FAX REPRINTS Chris West READER SERVICES ICN, Inc New Rodgers Road, Bristol, PA TEL Old Detroit Road #203 Rocky River, OH TEL FAX PRESIDENT Bruce Poorman EXECUTIVE VICE PRESIDENT Laurence Doyle Bio-Ohio Membership Application to Mail at Periodicals Postage Rates is at Cleveland, OH

11 For more information, visit EDITORIAL AUGUST 2015 DDNEWS 11 COMMENTARY: An industrywide call for greater antibody information BY ROUMEN BOGOEV OF BIO-RAD LABORATORIES INC. FEW PEOPLE HAVE battled antibody unreliability to the extent of Steven Elliott, formerly one of Amgen s scientific executive directors. In 2001, Amgen received approval for an advanced erythropoietin-stimulating agent (ESA). As the drug became widely available, Elliott and researchers worldwide began to investigate whether the erythropoietin receptors (Epo-R) it targeted were widely expressed. After many years spent studying the receptor, Elliott was convinced they were only found in significant levels on erythroid progenitor cells. However, other researchers arrived at a different conclusion. The problem was the antibodies they used to survey different cell types for the receptor also bound to off-target proteins, generating a signal that the scientists wrongly identified as Epo-R. Elliott, having identified the antibody issue, spent years talking and writing to these scientists to explain what was happening, but few listened. Recalling how scientific literature and preclinical and clinical trials became contaminated with the incorrect notion that Epo-R is widely expressed, Elliott says, All of it started because of these flawed antibodies that were improperly validated. It just spun out of control until it became the prevailing opinion. In reality, the scientists were using an antibody that detected a common heat shock protein (HSP70) and ascribed that band on the western blot to Epo-R. Researchers were building off the data supplied in peerreviewed papers, with the expectation that if the reagents had been published, they were proven and validated for that use. This particular antibody has been used in 38 publications, according to CiteAb. However, all those studies failed to include a negative control cell type to detect false-positive data and used improper positive controls. The true Epo-R band showed up as a faint line below the HSP70 band often cropped out of the submitted image. The anti-epo-r antibody is still marketed and used today. Building awareness Many powerful commentary pieces in the last few years have highlighted unreliability and irreproducibility at every level of science research, adding up to an estimated $28 billion wasted each year in irreproducible preclinical research in the United States alone. In 2014, the director of the National Institutes of Health (NIH), Francis Collins, called for action in a Nature article. The recent evidence showing the irreproducibility of significant numbers of biomedical-research publications demands immediate and substantive action, wrote Collins. Arguably the greatest need for change lies in the field of commercial antibodies. As the case study above shows, endemic quality-control Roumen Bogoev of Bio-Rad Laboratories issues including non-specific binding are propagated throughout academia, facilitated by a lack of supplementary data and scientific rigor. In 2012, C. Glenn Begley wrote a landmark paper that analyzed 53 preclinical studies that relied heavily on antibodies. His team found they could replicate only six of them. Collins cites many complex reasons for the status quo, including a lack of researcher training and an academic system that incentivizes provocative statements. Another chief concern of his is the lack of data transparency demanded by peer-reviewed publications. Due to the minimal information required by journals, it can be hard to determine if studies, such as those using antibodies, involved the necessary controls. Industry leaders are calling for change. Though proposed solutions differ considerably, a common theme has emerged: the need for greater transparency, from data in peerreviewed journals to antibody vendors to the antibodies themselves. Journal transparency Buying antibodies is not an easy task, and one that frequently lacks sufficient scientific rigor. Busy researchers often have little time to select antibodies for a study, so many follow precedent, selecting products colleagues have recommended or ones cited in a peerreviewed journal. To help streamline the process, several third-party websites are gaining traction as independent databases for antibody citations. For a researcher purchasing perhaps a dozen different antibodies for an experiment, having a central source for this information can save significant time. CiteAb is a popular example, with more than 1.8 million antibodies listed and 15,000 unique visitors per month. The website was founded by Dr. Andrew Chalmers on the back of his own frustrations dealing with unreliable antibodies. Along with collating and ranking antibodies by number of citations, Chalmers says the goal is to publish more comprehensive antibody data. To ensure that information is available for CiteAb to post, Chalmers says journals need to begin demanding many more details about the type of antibody used, including the name of the antibody provider, the catalog and batch number and what in-house validation the researchers performed. He s not alone in his views. As Collins noted in his Nature article: Journals should be encouraged to devote more space to research conducted in an exemplary manner that reports negative findings, and should make room for papers that correct earlier work. With the advent of online peer-reviewed publications, it is now possible to include this information as supplementary data with any submitted paper. However, even if this avenue is maximized, the practice of relying on citations will continue to have limitations. The Epo-R case study underscores this point. As a result, Chalmers believes researchers always need to screen the reagents themselves and, where possible, use positive and negative controls. Once you ve chosen an antibody, it s very important to validate it and check that it s behaving as you expect in your own lab. There is no getting away from that, he says. Authors also could help give context to their findings by providing details of their validation studies. Doing so would address, at least partially, the problem of publication bias. Then, readers might understand that when a picture-perfect western blot is published, it doesn t mean the study and the antibody are of the highest quality. It means the best blot was chosen, and potentially cropped, to highlight the bands of interest. Vendor transparency Some degree of change is surely in the antibody pipeline. What can vendors do in the interim? The first step toward restoring scientists trust in commercial antibodies is weeding out products that simply don t perform. Only antibodies that detect endogenous proteins should be sold for studies using direct immunodetection methodology (i.e., without prior enrichment using techniques such as immunoprecipitation pull-down). If an antibody has been screened on overexpressed protein samples, that should be made abundantly clear it might mean the reagent is not suitable for direct detection of the target in naturally occurring sample concentrations. For some targets, enrichment may be required prior to immunodetection. In all cases, vendors need to be clear what kind of proof of performance is being shown. Vendors should share the complete data generated with this antibody (for example, the full western blot when testing for westerns not simply the lane or segment of the membrane that shows the positive band). Just because the signal was weak or missing in a certain sample doesn t mean the information is not valuable. Rather, it may offer valuable clues as to how the reagent performs, increasing users chances of success. Alongside the push for more information, researchers need to recognize antibodies inherent limitations. Science needs to move beyond the idea that antibodies can be given a blanket pass or fail grade as they re streamed through a vendor s quality-control process. Antibody transparency In a recent Nature commentary piece, Andrew Bradbury, a Los Alamos National Laboratory scientist, and Andreas Plückthun of the University of Zurich called for radical action far beyond greater product clarity. They believe that, given the severity of the waste and the damage to science, the antibody industry must be overhauled in two key ways. First, vendors must move from manufacturing and selling polyclonal antibodies to recombinant antibodies. Second, for all recombinant antibodies entering the market place, vendors should also make available the specifics of the product s gene sequence. This gene-based paradigm, Bradbury says, is the only way to ensure antibodies from different companies are recognizing the same target and binding to the same site. The scientists also believe accompanying validation data should be lot-specific; vendors should not use historical data in data sheets as they may not relate to the batch being sold. If everybody is using the same antibody, you can be sure results can be directly comparable, he says. The move would also counter the familiar issue of lot-to-lot variability. With the status quo, the potential to accurately replicate an antibody study dies with the rabbit that generated those polyclonals. However, Bradbury s proposed actions face many hurdles, perhaps the strongest being the industry s reliance on proprietary sequences to fund research. Individual companies are reluctant to release antibody sequence information that they perceive to be vital to their competitive advantage. Additional issues to consider are that changes to product performance may occur due to differences in the manufacturing process that can affect activity, purity and stability. This means that a recombinant antibody produced by several different companies may not perform identically, even though the same DNA sequence was used. That said, there is little doubt this would lead to far greater reproducibility than the present use of animal-derived antibodies. Conclusion Multiple parties are doing their part to improve things, including Bio-Rad Laboratories itself, where we are attempting to deliver a product that better meets researchers needs. After acquiring AbDSerotec in late 2013, our team has been undertaking market research, listening to researchers pain points and gathering feedback from experts in this space also, combining the antibody experience in AbDSerotec and the western blotting expertise in Bio-Rad to launch the PrecisionAb antibody product line this June. The need for industry-wide changes in the way antibodies are manufactured, sold, validated, used and reported is now well established. As awareness of antibody unreliability and its consequences grows, many groups are lobbying to find a better way. This has become an epidemic, Elliott says about the propagation of flawed scientific work. In some cases the experiments are trivial or irrelevant, but in other cases it s very troubling because there are antibody data that are published around important biological questions and if the antibody is wrong, or non-specific, or the data is misinterpreted, then it creates a huge impact on the scientific community. While a total shift to recombinant proteins may not yet be feasible, transparency is achievable today. Antibody users should be fully informed the integrity of science depends on it. Roumen Bogoev is the antibody content manager at Bio-Rad Laboratories. You can learn about Bio-Rad s PrecisionAb antibodies at The opinions expressed in guest commentaries do not necessarily represent those of DDNews and/or its owners, editors or other staff.

12 12 DDNEWS AUGUST 2015 For more information, visit RESEARCH & DEVELOPMENT BRIEFS ips-based cell lines focus of new Horizon deal CAMBRIDGE, U.K. Horizon Discovery Group plc has begun a collaboration with DefiniGEN Ltd. for the development of a range of unique, geneengineered induced pluripotent stem (ips)-based cell lines for use in research. Per the agreement, Horizon will conduct genome engineering on the ips cells, which DefiniGEN will then differentiate. The initial focus will be on the generation of 10 ips-based cell lines for research in areas with a lack of high-quality disease models. DefiniGEN will culture, differentiate and quality control the resulting cell lines, alongside an isogenic control, and the cell line reagents will be made available through DefiniGEN and co-marketed by Horizon. Dr. Marcus Yeo, DefiniGEN s CEO, noted that These next-generation ips cell products will help to improve the efficiency and economics of drug development and enable the underlying mechanisms of disease to be elucidated in a manner that has previously not been possible. Partners offer FUT8 knockout CHO DG44 cell line services MORGAN HILL, Calif. Aragen Bioscience Inc. and Transposagen Biopharmaceuticals Inc. have developed a FUT8 knockout CHO DG44 host cell line, with Aragen to offer protein expression and cell line development services with this cell line for products to be used for research purposes. The launch of this cell line is expected in the second half of Transposagen is offering custom gene-editing services using the FUT8 knockout CHO DG44 host cell line, and will offer gene-editing kits with the cell line and its unique technologies, including Footprint-Free Gene Editing, to create disease-specific cell lines and XTNTM TALEN or NextGEN CRISPRs to create additional gene knockouts and knock-ins. Dr. Oren Beske, chief operating officer of Aragen, said Easy access to this unique service further broadens our portfolio and positions Aragen Bioscience as a value-added partner to the biopharmaceutical industry. IN THIS SECTION Cell lines ips-based cell lines focus of new Horizon deal Partners offer FUT8 knockout CHO DG44 cell line services Compound libraries UK companies pair on libraries targeting ubiquitin system Oncology Casting off with CD From the ground up with upar NuGEN sampling effort could accelerate cancer research Predicting survival Casting off with CD206 BIND and Macrophage to explore possibility of Manocept-linked Accurins to target disease-associated macrophages BY KELSEY KAUSTINEN CAMBRIDGE, Mass. BIND Therapeutics Inc. and Dublin, Ohio-based Macrophage Therapeutics, a subsidiary of Navidea Biopharmaceuticals Inc., have launched a research collaboration to engineer Accurins using the Manocept targeting platform, which allows for selective, efficient binding to CD206-positive disease-associated macrophages. Should the partners achieve proof of concept, they expect to expand the collaboration to develop Manocept-linked Accurins as a novel approach of impacting the tumor microenvironment. We are pleased to work with BIND Therapeutics to explore the therapeutic potential of our two complementary technology platforms, said Dr. Michael M. Goldberg, CEO of Macrophage and director of Navidea. The Manocept platform is the basis for the FDA-approved CD206- targeted sentinel lymph node detection agent Lymphoseek injection. Coupled with BIND s specifically engineered Accurins that concentrate therapeutic payloads to extracellular and intracellular compartments... we are optimistic that we can create a wide range of therapeutic applications. BIND s Accurins are targeted nanoparticles that offer prolonged circulation, controlled and tunable release and selective targeting of a therapeutic payload to diseased tissue or CD206 CONTINUED ON PAGE 13 From the ground up with upar Cancer Research UK invests in startup company s novel cancer treatment BY ZACK ANCHORS LONDON The world s largest independent cancer research charity, Cancer Research UK, is placing a bet on a biopharma startup s experimental cancer treatment. The organization has reached an agreement with Monopar Therapeutics to finance and coordinate preclinical development of an antibody that targets the cell surface protein upar. This target, upar, is overexpressed in some of the most deadly cancers, such as pancreatic, ovarian and glioblastoma, Cancer Research UK is putting money down to advance an experimental cancer treatment from Monopar Therapeutics that targets the cell surface protein upar. Chandler Robinson, Monopar co-founder and CEO, tells DDNews. The orthotopic models we ve done seem to show Accurins are polymeric nanoparticles that incorporate a therapeutic payload and are designed to have prolonged circulation within the bloodstream, enable targeting of diseased tissue or cells and provide for the controlled and timely release of a therapeutic payload. UK companies pair on libraries targeting the ubiquitin system Agreement combines Ubiquigent biology expertise with Cyclofluidic chemistry platform to identify smallmolecule libraries BY LORI LESKO DUNDEE, Scotland Targeted toward discovering therapies in such areas as cancer, cardiovascular, metabolic, neurological, musculoskeletal, infection and immunity, Ubiquigent Ltd., a Scottish biotech specializing in ubiquitin cell-signaling system drug discovery, and Cyclofluidic Corp., a London-area medicinal chemistry company, have struck an agreement to develop novel libraries that specifically target the ubiquitin system. The selective degradation of many short-lived proteins in eukaryotic cells is carried out by the ubiquitin system, according to the National Center for Biotechnology Information. In this pathway, proteins are targeted for degradation by covalent UPAR CONTINUED ON PAGE 14 UBIQUITIN CONTINUED ON PAGE 16 CREDIT: BIND THERAPEUTICS

13 For more information, visit RESEARCH & DEVELOPMENT AUGUST 2015 DDNEWS 13 CD206 CONTINUED FROM PAGE 12 cells while avoiding the issues of immune surveillance detection and systemic toxicities. The Manocept platform is a proprietary mannosecontaining, receptor-directed technology platform that can engineer novel, synthetic receptor-targeted imaging agents and therapeutics. Specifically, its properties make it possible to engineer novel immunoconstructs that can selectively bind to the mannose receptor CD206, as well as other C-type Lectins found on activated, disease-associated macrophages and tumor-associated macrophages. Disease-associated macrophages are known to play a primarily pro-tumoral role, in addition to being immunosuppressive. Tumor-activated or diseaseassociated macrophages are immune cells that play part of the role in the body s defense against pathogens and tumor cells. They engulf unwanted cells and kill them Coupled with BIND s specifically engineered Accurins that concentrate therapeutic payloads to extracellular and intracellular compartments... we are optimistic that we can create a wide range of therapeutic applications. Dr. Michael M. Goldberg, CEO of Macrophage per the direction of the immune system, but a lot of times in cancer, for instance those cells don t do that; they actually confer protection of the tumor cells against the macrophages, explains Andrew Hirsch, president and CEO of BIND Therapeutics. And so we thought it was a very, very attractive cancer target to be able to target these activated macrophages. And then there s a number of therapeutic approaches we can take once we target them, so this is really an idea of Can we use their targeting platform and our Accurins to create a new therapeutic approach? It s a bit of a departure for us from our traditional product development focus. Hirsch tells DDNews that Macrophage Therapeutics will provide the potential ligands for the deal while BIND provides its nanoparticle technology, adding that Jointly we re evaluating whether or not the Accurins actually target these activated macrophages by targeting CD206 and actually how do they target it: do the particles get inside, is it because they re engulfed by the macrophages or is it because the actual ligand is pulling the particle into the cell by targeting CD206? It is well established that macrophages play an important role in many disease states, but it has proven difficult to selectively target and alter macrophages that play a key role in disease progression, Dr. Hagop Youssoufian, chief medical officer at BIND Therapeutics, commented. By coupling Accurins with Macrophage s well-credentialed CD206 targeting ligand, we may be able to treat macrophage-mediated diseases through increased uptake and concentration of targeted therapeutic payloads in the tumor microenvironment. BIND s Medicinal Nanoengineering platform is able to combine multiple molecular components into a targeted, long-circulating Accurin. An Accurin nanoparticle that binds to CD206-positive macrophages could be a valuable asset in the armament against multiple cancers and disease states. EDITCONNECT: E Do You Suffer from Panel Envy? 6Ckine, Adiponectin, Adpisin, A-FABP, AFP, Aggrecan, Ang-1, Ang-2, Angiogenin, ANGPTL3, ANGPTL4, APP, AREG, ATIII, Autotaxin, β2m, B7-H1, BAFF, BCMA, BDNF, BLC, BMP-2, BMP-4, BMP-9, BRAK, C5a, CA125, CA15-3, Calbindin D, CCL14, CD14, CD27, CD30, CD40, CD40L, CD44, CD93, CD163, Chemerin, CINC-2, CINC-3, Clusterin, COL4A1, C-Peptide, Cripto-1, CRP, CTACK, ctni, CXCL16, Cystatin C, DcR3, Dkk-1, DPPIV, DR3, EGF, EMMPRIN, ENA-78, Endoglin, Endostatin, Eotaxin, Eotaxin-2, Eotaxin-3, EphA2, Epo, ESAM, E-Selectin, ET-1, Fas, FasL, Fetuin A, FGF acidic, FGF basic, FGF-21, FLRG, Flt-3L, FST, Gal-3, Gal-3BP, Gal-9, GCP-2, G-CSF, GDF-15, GDNF, Glucagon, GM-CSF, gp130, GRO-α, HB-EGF, Her2, H-FABP, HGF, hgh, ICAM-1, IFN-γ, IFN-γ R1, IGFBP-1, IGFBP-3, IGFBP-rp1, IL-1 ra, IL-1 RI, IL-1 RII, IL-1α, IL-1β, IL-2, IL-2 Rα, IL-3, IL-4, IL-5, IL-6, IL-6 Rα, IL-7, IL-8, IL-9, IL-10, IL-12 p70, IL-13, IL-15, IL-17A, IL-17F, IL-18 BPa, IL-19, IL-22, IL-23, IL-25, IL-27, IL-28A, IL-31, IL-33, IL-34, IL-36β, IGF-I, Insulin, IP-10, I-TAC, ITIH4, KC KIM-1, KLK5, Leptin, L-FABP, LIF, L-Selectin, MIP-2, LIX, Lumican, MCP-1, MCP-2, MCP-3, MCP-4, M-CSF, MDC, MFG-E8, MICA, MICB, MIF, MIG, MIP-1α, MIP-1β, MIP- 3α, MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-12, MMP-13, MPO, MSP, Myoglobin, NCAM-1, Nephrin, NGAL, NRG1-β1, NT-4, NT-Pro-ANP, OPN, OSM, PAI-1, PAPP-A, PARC, PCSK9, PDGF-AA, PDGF-BB, Periostin, PF4, PlGF, PGRN, Prolactin, Protein C, PRTN3, PSA, P-Selectin, PTX3, RAGE, RANK L, RANTES, RBP4, Renin, Resistin, ROBO4, S100A8, S100A9, S100B, SCF, SDF-1α, SHBG, SOST, SPARC, SP-D, ST2, TACI, TARC, Tenascin C, TFF3, TFPI, TfR, TGF-β1, TGF-β2, TGF-β3, THBS2, THBS4, Tie-1, Tie-2, TIMP-1, TIMP-2, TIMP-3, TIMP-4, TNF-α, TNF RI, TNF RII, Tpo, TRAIL, TRAIL R2, TRAIL R3, ULBP-1, ULBP-2/5/6, ULBP-3, ULBP-4, upa, upar, Uteroglobin, VAP-1, VCAM-1, VEGF, VEGF-C, VEGF-D, VEGF R2, VEGF R3, Visfatin, Vit DBP, vwf-a2, YKL-40 analytes in 1 Luminex Leaders and researchers at BIND Therapeutics hope that by combining their Accurins with Macrophage s CD206 targeting platform, they might be able to treat macrophage-mediated diseases thanks to increased uptake and concentration of therapeutic payloads. assay. EXPLORE NOW #PanelEnvy #100Plex CREDIT: BIND THERAPEUTICS

14 14 DDNEWS AUGUST 2015 RESEARCH & DEVELOPMENT For more information, visit PREDICTING SURVIVAL patients with high ERCC1 levels (10 UCSD researchers months). They also found that 29 use biomarkers to patients had low TS levels and significantly longer average survival gauge response to times (36 months) than patients chemotherapy with high TS levels (15 months). BY ILENE SCHNEIDER SAN DIEGO Colorectal cancer (CRC), the third-deadliest cancer in the United States, is projected to have 132,700 new cases and cause 49,700 deaths in New cytotoxic and targeted agents for patients with metastatic CRC have improved overall survival rates, but scientists at the University of California, San Diego (UCSD) wanted to do a bit better. According to researchers at the UCSD School of Medicine, who published their findings in the June 17 issue of PLOS ONE, In patients Twenty-two of the 41 patients had low levels of both ERCC1 and TS, and 20 of them responded to oxaliplatin, suggesting that this should be the first treatment choice for patients with low ERCC1 and TS. Patients responded to irinotecan at the same rate, whether they had low or high levels of these genes, implying that physicians might want to select irinotecan as the first-choice chemotherapy for patients with high ERCC1 or TS levels. These results are consistent with other studies evaluating the roles of ERCC1 and TS in metastatic colorectal cancer. with metastatic colon cancer, Our study is small, retrospective and all of the patients were located at a response to first-line chemotherapy single medical center, but it demonstrates that it s possible to use According to senior author Dr. is a strong predictor of overall survival. Currently, oncologists lack respond to a given treatment. Given this proof of principle, it s our hope fessor of medicine and oncolo- molecular diagnostics to identify subgroups of patients more likely to Paul Fanta, assistant clinical pro- diagnostic tests to determine which that molecular biomarkers will be included in future prospective clinical gist at UCSD s Moores Cancer chemotherapy regimen offers the trials in metastatic colorectal cancer, says Dr. John Paul Shen of UCSD. Center, Several large trials compared oxaliplatin and irinotecan Pictured here is the university s Atkinson Hall. greatest chance for response in an individual patient. The researchers conducted a proof-of-principle study with a small group of metastatic colorectal cancer patients. The results revealed two genes, ERCC1 and TS, that could help physicians make more informed treatment decisions for patients with this disease. Their analysis of the results for 41 patients with de-novo metastatic colon cancer diagnosed between July 2008 and August 2013 at UCSD was designed to determine the potential clinical utility of measuring ERCC1 and TS expression in managing patients with metastatic colorectal cancer. The researchers used a commercially available test to analyze levels of the genes ERCC1 and TS that encode proteins involved in building and repairing DNA. They found that 33 of their 41 patients had low ERCC1 levels. Those patients had much longer average survival times (36 months) compared to head-to-head and concluded that the response rate is about equal. How an oncologist bases his or her treatment decision can be based on experience, comfort level prescribing and the patient s health. But in reality, the two drugs are very different. For any individual patient, one might be better than the other. EDITCONNECT: E CREDIT: UCSD As an oncologist, how do I know which is better for my patient? That s where this study comes in. Co-first author Dr. John Paul Shen, a senior clinical fellow and postdoctoral fellow, added, Our study is small, retrospective and all of the patients were located at a single medical center, but it demonstrates that it s possible to use molecular diagnostics to identify subgroups of patients more likely to respond to a given treatment. Given this proof of principle, it s our hope that molecular biomarkers will be included in future prospective clinical trials in metastatic colorectal cancer. Co-authors of this study also include Michel B. Choueiri, Andrew M. Gross, Justin K. Huang and Trey Ideker, all of UCSD. This research was funded, in part, by Arthur Athans in the name of his wife, Barbara Mae Athans, the National Institutes of Health (grants R01 ES and U24 CA184427), Marsha Rivkin Center for Ovarian Cancer Research and Conquer Cancer Foundation of ASCO. Overall, these findings suggest that measurement of ERCC1 and TS expression has potential clinical utility in managing patients with metastatic colorectal cancer, the report concluded. UPAR CONTINUED FROM PAGE 12 that our antibody is as effective as currently available treatments, but what s really intriguing are the very synergistic possibilities for it to be used in combination with other treatment for some of these extremely deadly cancers. The antibody to be developed, HuATN-658, was discovered by Monopar Chief Scientific Officer Andrew Mazar, an expert on the upar pathway. Promising findings from numerous studies of HuATN- 658 led to the founding of Monopar in 2014 with a focus on the antibody s development. When you see a drug with antitumor effectiveness in one or two mouse models, it can still be difficult to predict its potential, says Robinson. But when we started seeing effectiveness in five or more models not just in Andrew s hands, but also at leading labs we began to realize that we might have a drug that could be quite impactful. The terms of the agreement call for Cancer Research UK s Centre for Drug Development (CDD) to finance Phase 1 clinical trials of the experimental antibody in cancer patients with advanced solid tumors. The main goal of the trial will be to gauge the safety of the antibody, although the effectiveness of the drug will also be evaluated. The trials will be managed and run by the CDD through the Experimental Cancer Medicine Centre (ECMC) network, a United Kingdom-wide initiative funded by Cancer Research UK, the National Institute for Health Research in England and the Departments of Health for Scotland, Wales and Northern Ireland. Once the trials are over, Monopar will have the right to acquire the clinical data produced. If Monopar declines that option, Cancer Research Technology (CRT), a wholly owned subsidiary of Cancer Research UK, may continue the development and commercialization of HuATN-658 in exchange for giving Monopar a share of any future revenues that result from the drug. CRT is a specialist commercialization and development company focused on developing new cancer treatments. Researchers have previously tested other approaches to targeting upar, the cell surface protein, but Robinson says that HuATN- 658 offers a novel approach. In the past, people have tried targeting upar and upa, but that s only one ligand interaction and it s only half the story, he tells DDNews. So Andrew invented this antibody that hits a completely different domain on upar and seems to be affecting multiple of the ligand interactions and through them to have even more effective anticancer effects than previous approaches at targeting upar. Robinson says that the agreement will provide financing for the development of the antibody that would be difficult for an emerging company like Monopar to otherwise access. While these are still the early days of the company, we have created a very strong team and development strategy, he says. The development partnership with Cancer Research UK allows Monopar to leverage a strong platform for the clinical advancement of this compound as it brings longestablished clinical, regulatory and manufacturing expertise and resources that would be difficult for an emerging company to amass quickly. Nigel Blackburn, Cancer Research UK s director of drug development, says that the partnership represents the latest collaboration through its Clinical Development Partnerships program, which aims to help progress promising The brain cancer glioblastoma is one in which the cell surface protein upar is overexpressed, as is also the case in ovarian and pancreatic cancers, and all three are on the radar of Cancer Research UK and Monopar as they team up to advance an experimental antibody therapeutic. treatments from drug company pipelines and bring them into early-phase trials sooner. Thanks to this, six new treatments are now in clinical trials that may otherwise never have moved beyond the lab, he says. EDITCONNECT: E081509

15 Discovery. Applied. Identifying meaningful biological variants is what you do. Genetic analysis is how you get there. Robust chemistries, reliable instruments, and scalable informatics your research demands nothing less. And it all must work together. Seamlessly and consistently. Because when the right tools are applied, discovery is not far behind. Explore your path to discovery at For Research Use Only. Not for use in diagnostic procedures Thermo Fisher Scientific Inc. All rights reserved. All trademarks are the property of Thermo Fisher Scientific and its subsidiaries unless otherwise specified. CO

16 16 DDNEWS AUGUST 2015 RESEARCH & DEVELOPMENT For more information, visit NuGEN sampling effort could accelerate cancer research SAN CARLOS, Calif. Scientists at NuGEN Technologies Inc. have simultaneously surveyed the RNA of more than 400 targeted genes in a single assay, using next-generation sequencing (NGS) to detect fusions known to be key drivers of tumor growth in several cancer types. The scientists, who employed an innovative method of targeted sequence library preparation, also discovered low-frequency fusions that had not previously been reported. The new method based on NuGEN s Single Primer Enrichment Technology (SPET), which allows the simultaneous interrogation of multiple, specific genes for RNA sequencing is said to significantly simplify fusion detection when compared with standard RNA sequencing approaches. The method can greatly enhance scientists ability to understand the underlying oncogenic impact of a variety of genomic disruptions, according to Elizabeth Hutt, NuGEN s CEO. Applications based on this TOOLS & TECHNOLOGY exciting new technology promise to speed up cancer research and lead to more effective diagnoses and treatments. As described in the June 1, 2015, issue of PLOS ONE, in a paper titled An efficient method for identifying gene fusions by targeted RNA sequencing from fresh frozen and FFPE samples, the scientists used the new method to prepare cancerous and normal tissue samples for targeted RNA sequencing. The goal was to detect the presence of genes that had joined together or fused, resulting in disruption of regulatory mechanisms. Through NGS, the scientists were able to identify multiple known and previously unreported fusions from fresh-frozen and formalin-fixed paraffin-embedded (FFPE) tissue. By targeting specific RNAs for sequencing, the scientists report, they were able to reduce the number of sequencing reads and increase the sensitivity of gene fusion detection when compared with standard RNA-Seq methods. Traditional methods require a much larger number of sequencing reads in order to detect fusion events in a background of some 20,000 transcripts. Other focused methods cannot survey the entire repertoire of previously recognized fusions; they are limited to detection of small numbers of potential events. Douglas Amorese, vice president of research and development for NuGEN Traditional methods require a much larger number of sequencing reads in order to detect fusion events in a background of some 20,000 transcripts, said Douglas Amorese, NuGEN s vice president of research and development. Other focused methods cannot survey the entire repertoire of previously recognized fusions; they are limited to detection of small numbers of potential events. Reportedly, the assay is fully customizable to target any gene or set of genes in any genome; it will be the foundation for a suite of sample preparation products provided by NuGEN. Offered in easy-to-use reagent kits, the new method will initially be employed to discover the role of gene fusions in many more types of cancer. It will ultimately be used in molecular diagnostic products to guide treatment. UBIQUITIN CONTINUED FROM PAGE 12 Some months prior to sealing its collaboration deal with Cyclofluidic, Ubiquigent had announced a similar type of deal with the Drug Discovery Unit of the University of Dundee to develop and market new ubiquitin system-targeted compound libraries. ligation to ubiquitin, a highly conserved small protein. Ubiquitin-mediated degradation of regulatory proteins plays important roles in the control of numerous processes, including cell-cycle progression, signal transduction, transcriptional regulation, receptor down-regulation and endocytosis. The ubiquitin system has been implicated in the immune response, development and programmed cell death. In this collaboration, Ubiquigent comes to the table with its biology expertise, while Cyclofluidic displays its chemistry platform to develop the comprehensive library, according to a June 3 news release. Key to the collaboration is Cyclofluidic s CyclOps platform, which integrates flow chemistry, purification, screening and drug design, utilizing machine-learning algorithms to allow drug lead molecules to be assayed in minutes, rather than weeks, after they are designed. The team has shown that use of the platform reduces timelines for hitto-lead optimization by 50 percent, allowing molecules to progress into preclinical studies faster. We are very pleased to be entering into this relationship with Cyclofluidic, as we believe that our combined approach will uncover many exciting opportunities in this rapidly developing field, Jason Brown, managing director of Ubiquigent, stated in a news release. This latest collaboration further supports Ubiquigent s goal of being the first ubiquitin system-focused, fully integrated provider of biology, assays, small-molecule libraries and compound profiling services. Jason Mundin, commercial director of Ubiquigent, tells DDNews: The ubiquitin system offers many new drug discovery target opportunities across multiple therapeutic areas. Involving the modification of proteins through the attachment of the protein ubiquitin, or ubiquitin-like proteins (Ubls), ubiquitylation and related Ubl modifications are key to the control of cellular protein homeostasis as well as signaling, akin to the critical role played by phosphorylation approximately 30 percent of commercial drug discovery programs target phosphorylation enzymes and holds similar potential for clinical utility. The goal of the collaboration is to build novel ubiquitin system-targeted compound libraries that will represent start-points for ubiquitin-focused drug discovery programs, Mundin adds. The output of the collaboration will be jointly commercialized by the companies. Furthermore, the collaboration is openended and will continue as long as it s successful, Mundin says, adding, One of the challenges with the ubiquitin field is the chemistry. This is similar to the situation in the kinase field a number of years ago. As with the kinase area, we are convinced that the chemistry is possible and that it will open up many new opportunities for points of therapeutic intervention across multiple therapeutic areas. Part of our strategy at Ubiquigent is to collaborate with groups that we feel have the potential to tackle this challenge so we can combine their chemistry with our biology, thus our collaboration with Cyclofluidic. Mundin anticipates they will be able to start screening compounds later this year. Currently we don t have any particular CREDIT: UNIVERSITY OF DUNDEE therapeutic focus, but as and when compounds start to emerge, we will be looking to take them into therapeutically relevant assay systems and models either prior to or part of our commercialization strategy, he notes. Dave Parry, chief operating officer of Cyclofluidic, states: We are excited by the opportunity to demonstrate the advantages of our CyclOps platform in accelerating discovery to this rapidly evolving area of biology, which has been made possible through access to Ubiquigent s leading expertise in the field. The main focus for the collaboration is to generate new chemistry libraries for ubiquitin targets which will aid the research community in providing tools and leads to continue to develop this important emerging area of disease biology, Parry says. In October 2008, Cyclofluidic, a breakthrough technology company, was established with the aim of significantly accelerating the drug discovery process by allowing researchers to test a greater range of potential new medicines in a shorter time. The UK government s Innovate UK agency, then called the Technology Strategy Board, helped facilitate this innovative arrangement between Pfizer and UCB and will continue to support Cyclofluidic by co-funding its R&D. The aim of Cyclofluidic is to develop technologies that automate and integrate processes known as flow chemistry and flow biology to help pharmaceutical companies shorten timelines in drug development. In late 2014, Ubiquigent struck a deal not unlike the one with Cyclofluidic with the Drug Discovery Unit (DDU) of the University of Dundee to develop and market new ubiquitin system-targeted compound libraries aimed at discovering potent and selective therapeutics across such areas as cancer, cardiovascular and metabolic, neurological and musculoskeletal and infection and immunity. Under the terms of the agreement, Ubiquigent and the DDU will design, develop and characterize small-molecule compound libraries targeting the intracellular proteins of the ubiquitin system to provide a valuable source of novel targeted libraries to unlock new medicinal chemistry opportunities. EDITCONNECT: E081510

17 For more information, visit AUGUST 2015 DDNEWS 17 PRECLINICAL BRIEFS PEP-Therapy teams with CleveXel for peptide development PARIS & MAISONS-ALFORT, France PEP-Therapy and CleveXel Pharma have begun co-developing a peptide as a targeted therapy for the treatment of cancers with high medical need. PEP-Therapy and CleveXel Pharma will take the product through to clinical proof of concept, with the regulatory preclinical phase scheduled for the end of this year and clinical trials expected to begin by the end of PEP-Therapy will also continue developing companion biomarkers to accompany the product. For CleveXel Pharma, this partnership paves the way for real innovation in oncology. CleveXel Pharma s know-how and expertise in development add value to this project. We have also been attracted by the involvement of biological and clinical researchers from Inserm, Pierre & Marie Curie University and Institut Curie, Christian Bloy, CEO of CleveXel Pharma, noted in a statement. RX selected for NCL preclinical program ROCKVILLE, Md. The National Cancer Institute s Nanotechnology Characterization Laboratory (NCL) has selected Rexahn Pharmaceuticals Inc. s RX-21101, a polymer conjugated form of docetaxel containing a signaling moiety that directs it into tumors, for its preclinical characterization program to help advance the drug candidate toward human clinical trials. The NCL will conduct several preclinical studies of RX including physiochemical characterization, in-vitro cytotoxicity/ hematology/immunology and in-vivo rodent pharmacokinetic studies that will, along with other work by Rexahn, be the basis of filing an IND application to begin Phase 1 clinical testing. The NCL was established to aid in translating promising nanotechnology-based therapeutics for the treatment of cancer, together with the National Institute of Standards and Technology and the U.S. Food and Drug Administration. IN THIS SECTION Data reproducibility Waste not, want not HPV/Vaccination Early-stage immunotherapy Headache/Migraine/ Chronic pain Going right to the head Oncology MSKCC selects Ascentos software for preclinical research PEP-Therapy teams with CleveXel for peptide development RX selected for NCL preclinical program Ophthalmology/Oncology Two for the price of one WASTE NOT, WANT NOT GBSI survey says U.S. squanders $28 billion annually on flawed preclinical research, stalling discovery of new therapies BY LORI LESKO WASHINGTON, D.C. Aimed at accelerating the discovery of lifesaving diagnostics, therapies and cures, while saving time, money and precious resources, three economists writing in PLOS Biology contend that in the United States alone, an estimated $28 billion annually is spent on preclinical research that is not reproducible. Published June 9, The Economics of Reproducibility in Preclinical Research, authored by Global Biological Standards Institute (GBSI) President Leonard P. Freedman and leading economists Iain M. Cockburn and Going right to the head TNX-201 demonstrates significant analgesic effects in animal models of migraine and chronic pain BY LLOYD DUNLAP NEW YORK It s rare, perhaps, but sometimes an old standby can be repurposed with good effect which is true of Tonix Pharmaceuticals Holding Corp. s Phase 2 drug for tension headaches. Tonix, a clinical-stage company developing next-generation medicines for fibromyalgia, post-traumatic stress disorder and episodic tension-type headache, presented nonclinical data from its TNX-201 (dexisometheptene mucate) program in two posters at the 57th Annual scientific meeting of the American Headache Society in Washington, D.C. Tonix is currently evaluating TNX-201 in a Phase Errors in biological reagents and reference materials along with faulty study design, data analysis and reporting and laboratory protocols may account for as much as $28 billion of waste in U.S. life-sciences spending, due to irreproducibility of preclinical data results. Timothy S. Simcoe, is the result of a yearlong study to examine the causes of irreproducibility in life-sciences research and quantify the cumulative cost. The solution to the dilemma, the authors write, is to design a framework for new best practices guidelines aimed at improving preclinical research quality that would ultimately lead to WASTE CONTINUED ON PAGE 19 Two for the price of one Elsalys Biotech nets rights for anti- CD160 antibody with anti-angiogenic, immunomodulatory effects BY KELSEY KAUSTINEN LYON, France Biopharmaceutical company Elsalys Biotech has boosted its portfolio with the acquisition of development and marketing rights for an anti-cd160 antibody from Mablife that thus far has been developed in ophthalmology. Elsalys, which specializes in the development of first-in-class therapeutic antibodies against cancer and inflammatory diseases, has begun preclinical evaluation of different humanized versions of the antibody in age-related macular degeneration, with results expected in the first half of next year. No financial details were released. The antibody was identified and characterized by Dr. Armand Bensussan of the Skin Research Center and Dr. Philippe le Bouteiller of the Centre de Physiopathologie Toulouse-Purpan. The acquisition of anti-cd160 is obviously a great opportunity for a company like ours, said Dr. Christine Guillen, CEO and co-founder of Elsalys. With this antibody we not only strengthen our position in antibody immunotherapy, but we reach a stage of maturity that allows us to envisage more rapid development and thus reinforce the commitment of our investors. In addition, TONIX CONTINUED ON PAGE 18 The active ingredient in TNX-201 contains (R)-isometheptene, or (R)-IMH, a single optical isomer of isometheptene. Dr. Seth Lederman, chairman and CEO at Tonix, points out that the R-isomer is more than seven times as potent as the old racemic IMH that has been widely used for various indications, including tension-type headache. ELSALYS CONTINUED ON PAGE 20

18 18 DDNEWS AUGUST 2015 PRECLINICAL For more information, visit Early-stage immunotherapy Genticel announces proof of concept for HPV therapeutic vaccine BY ILENE SCHNEIDER PARIS & BRUSSELS Of the 300 million women infected with HPV, 500,000 new cases of cervical cancer are identified annually, and 275,000 women succumb to the disease. Seventy percent of cervical cancer cases are caused by two HPV types, and Genticel a French biotechnology company and developer of innovative immunotherapies to prevent cancers caused by the human papillomavirus (HPV) aims to eliminate them at an early stage. Genticel recently announced positive preclinical in-vivo proofof-concept results of GTL002, its multivalent HPV therapeutic vaccine candidate based on the company s Vaxiclase platform. No treatment options are available for women infected with oncogenic HPV types but who have not yet developed high-grade lesions or cervical cancer: GTL002 seeks to eradicate the six most oncogenic HPV types affecting 158 million women worldwide. GTL001, Genticel s first-in-class therapeutic vaccine candidate currently in Phase 2 in Europe, already targets the two most oncogenic HPV types. With GTL001 and GTL002, Genticel is the first company that has established a staged pipeline of HPV therapeutic vaccines for the large female population burdened by this unmet medical need, according to the company. The proof-of-concept data of GTL002 demonstrated that an invivo immune response was induced against each of the six HPV-derived proteins present in the therapeutic vaccine. In addition, in-vivo therapeutic efficacy was shown by tumor eradication in the most widely used and broadly accepted reference model. In 2002, Genticel licensed from Institut Pasteur a modified adenylate cyclase from Bordetella pertussis to be used as an antigen delivery vector able to induce a specific immune response against a pathogen carrying the delivered antigen. The company chose to target HPVinduced diseases to develop its first therapeutic vaccine candidate, GTL001, because the most aggressive forms of HPV induce cancers and thus represent a major health issue, according to Martin Koch, Genticel recently announced positive preclinical in-vivo proof-of-concept results of GTL002, its multivalent HPV therapeutic vaccine candidate; as yet, no treatment options are available for women infected with oncogenic HPV types but who have not yet developed high-grade lesions or cervical cancer. CEO of Genticel. He added, Other reasons we chose it are that the virus is present at the onset of the disease and thus represents an ideal biomarker and allows for a possible therapeutic approach with an immunotherapy at an early stage of the disease; the virus is a foreign agent and it is easier to trigger an immune response against a non-self antigen; and HPV testing is widely available and increasingly used in first-line cervical cancer screening, making it possible to identify patients at risk of developing cancer. When HPV molecular testing began to emerge as the first-line recommended screening for cervical cancer, Genticel decided to develop a therapeutic option for the population of infected women who had not yet developed highgrade lesions. Previously, screening was based only on regular Pap smear tests. HPV molecular testing unveils a wide population of women who are infected with HPV but who have yet to develop cervi- HPV CONTINUED ON PAGE 20 TONIX CONTINUED FROM PAGE 17 2 proof-of-concept (POC) study in episodic tension-type headache. The active ingredient in TNX-201, dexisometheptene mucate, contains (R)-isometheptene, or (R)-IMH, a single optical isomer of isometheptene. Racemic IMH, a mixture of both the (R) and (S) isomers, had been widely used as a single-agent prescription medicine and as a component of combination drug products (e.g., Midrin) for many decades in the U.S. for various indications including tension-type headache. IMH was introduced as a pharmaceutical prior to 1962, and no products containing IMH are currently approved by the U.S. Food and Drug Administration (FDA) for any indication. TNX-201 is being developed as a new chemical entity for the treatment of episodic tension-type headache, based on current FDA drug registration requirements. Dr. Seth Lederman, chairman and CEO at Tonix, points out that the R-isomer is more than seven times as potent as the old racemic mixture. Along with TNK-201, Tonix has two other drugs in the clinic focused on war-related PTSD and fibromyalgia, Lederman points out. The points made in the poster presentations at the Headache Society Our findings that TNX-201 selectively modulates a receptor in the central nervous system that appears to regulate pain perception and responses, together with positive data in two rodent models representative of migraine, support the development of TNX-201 as a therapeutic for headache and potentially other pain indications and one that may be differentiated from currently approved products. Dr. Bruce Daugherty, chief scientific officer of Tonix meeting, including data from receptor binding studies, taken together with the recent description of a decreased pain threshold in imidazoline-1 receptor (I1R) knockout mice, suggest that I1R may be the primary site of action for racemic IMH s analgesic effects. Since (R)-IMH, the active ingredient in TNX-201, binds I1R with approximately 60-fold greater affinity than (S)-IMH, TNX- 201 may be responsible for the therapeutic effect of racemic IMH. In anesthetized rats, treatment with (S)-IMH resulted in dosedependent and statistically significant blood pressure increases that were higher relative to those produced by the (R)-isomer. In the second abstract (PS58), the effects of (R)-IMH and (S)-IMH were evaluated in two rat models of trigeminal pain which feature aspects of chronic migraine: the inflammatory soup (IS) model and the spontaneous trigeminal allodynia (STA) model. These models had been developed to allow for the testing of therapeutic compounds for migraine. Both of these models experience similar symptoms to human migraine patients such as episodic or chronic trigeminal hypersensitivity, phonophobia, responsiveness to abortive and prophylactic headache treatments and sensitivity to migraine triggers. In the IS model, treatment with 30 mg/ kg of (R)-IMH mucate significantly increased trigeminal thresholds at each of the 0.5 hour (hr) (2.3-fold, p<0.01), 1.5 hr (3.0-fold, p<0.01), 2.5 hr (2.9-fold, p<0.001) and 3.5 hr (1.7-fold, p<0.05) time points. In the STA model, treatment with 30 mg/kg of (R)-IMH mucate significantly increased trigeminal thresholds at the 0.5 hr (7.8-fold, p<0.01), 1.5 hr (4.3-fold, p<0.05), 2.5 hr (4.5-fold, p<0.01), 3.5 hr (8.5-fold, p<0.01) and 24 hr (8.2-fold, p<0.01) time points. Treatment with 30 mg/kg of (S)- IMH mucate had no effect on trigeminal sensitivity in either the IS or STA models. Our findings that TNX-201 selectively modulates a receptor in the central nervous system that appears to regulate pain perception and responses, together with positive data in two rodent models representative of migraine, support the development of TNX-201 as a therapeutic for headache and potentially other pain indications and one that may be differentiated from currently approved products, said Dr. Bruce Daugherty, Tonix s chief scientific officer. We look forward to reporting the results of our Phase 2 POC study in episodic tension-type headache in the fourth quarter of this year. Episodic tension-type headache is the most common type of headache. It is estimated that approximately 30 percent of U.S. adults experience frequent episodic tension-type headaches (one to 15 headaches per month over a three-month period). Tension-type headache pain is often described as a constant pressure on both sides of the head, and typically lasts for several hours. All of the FDA-approved prescription options for tensiontype headache contain barbiturates. Tonix Pharmaceuticals is focused on the development of next-generation medicines for common yet challenging disorders of the central nervous system, characterized by chronic disability, inadequate treatment options, high utilization of healthcare services and significant economic burden. Tonix s Tonmya is currently being evaluated in the Phase 3 AFFIRM study in fibromyalgia. TNX-102 SL, the same proprietary product candidate as Tonmya, is currently being evaluated in the Phase 2 AtEase study in post-traumatic stress disorder. A Phase 2 proof-ofconcept study of TNX-201 in episodic tension-type headache is ongoing. TNX-102 SL and TNX-201 are Investigational New Drugs and have not been approved for any indications. EDITCONNECT: E081513

19 For more information, visit PRECLINICAL AUGUST 2015 DDNEWS 19 WASTE CONTINUED FROM PAGE 17 improved reproducibility rates and faster discovery of effective therapies. This new, adopted protocol in life-sciences research would include a close scrutiny of funding requests before any agency or institution opens its proverbial wallet. Best practices are those steps, refined over years of research experience, that experts agree should be routinely observed throughout the research cycle from the idea for the study all the way through to publication, Freedman says. In preclinical research, there are only two formal ANSI/ISO approved standards (one for cell authentication and one for anthrax) and no community-recognized best practices, he adds. In the larger picture, about $115 billion in the United States is estimated to be spent annually on life-sciences research, about half of which is spent on preclinical work, Freedman says. Of that preclinical research, a conservative estimate is that 50 percent of such research is not reproducible. Major sources of this waste are errors in biological reagents and reference materials, followed by faulty study design, data analysis and reporting and laboratory protocols, the PLOS study states. We are calling for a fundamental shift from acceptance of an avoidable problem to the adoption of compelling best practices that support better research and better outcomes, Freedman states. Critics of the PLOS article claim the costs cited are exaggerated, but Freedman, Cockburn and Simcoe stand behind their numbers. Our primary goal here is not to pinpoint the exact reproducibility rate, but rather to identify root causes of the problem and develop a framework to address the highest priorities, Freedman says. Based on exam- While false positives are an inevitable part of scientific research, our study shows that the current level of irreproducibility in preclinical research is very costly. By categorizing the root causes of irreproducibility and estimating their relative importance, we can prioritize potential solutions and ultimately, increase the overall return on public and private investments in research and development. Economist Timothy S. Simcoe To develop our estimate of the current reproducibility rate for preclinical research, we reviewed publicly available data from government sources, industry and analyst reports and scientific articles, says economist Iain M. Cockburn. Science Week Leading in Europe 2015 Sept Congress Center Basel Switzerland KeyNote Speakers KeyNotes Posters Industry Symposia Dr. Jean-Paul Clozel CEO and Co-Founder, Actelion Dr. John Reed Head of Pharma Research & Early Development (pred), Roche Prof. Dr. med. Kushru Asadullah Professor, Charité Medical Center, and former Bayer Healthcare Vice-President & Global Head of Biomarkers Peter Thiel Thiel Capital Our primary goal here is not to pinpoint the exact reproducibility rate, but rather to identify root causes of the problem and develop a framework to address the highest priorities. Based on examples from within the life sciences, application of economic theory and review of lessons learned from other industries, we conclude that community-developed best practices and standards must play a central role in improving reproducibility going forward. Leonard P. Freedman, president of GBSI ples from within the life sciences, application of economic theory and review of lessons learned from other industries, we conclude that community-developed best practices and standards must play a central role in improving reproducibility going forward. Cockburn adds, The problem of reproducibility has been widely discussed. To develop our estimate of the current reproducibility rate for preclinical research, we reviewed publicly available data from government sources, industry and analyst reports and scientific articles. As Simcoe notes, While false positives are an inevitable part of scientific research, our study shows that the current level of irreproducibility in preclinical research is very costly. By categorizing the root causes of irreproducibility and estimating their relative importance, we can prioritize potential solutions and, ultimately, increase the overall return on public and private investments in research and development. The PLOS article authors have aligned with 21st Century Cures, a congressional initiative to update laws to support finding new and improved medicines and diagnostics to keep America competitive in healthcare and biotech. Freedman told DDNews that the impetus for researching reproducibility has come from greater awareness on pressures from researchers. There is also a greater public awareness to the issue, he says. While individual, flashy and fraudulent papers have gotten a lot of media attention, scientific misconduct is actually very rare. The issues around irreproducibility poorly validated reagents, flawed statistical analyses, for example are more mundane, but ultimately incredibly serious. Feedback received from the PLOS article has been varied, ranging from very supportive of the understanding that reproducibility is a cornerstone of scientific research to you are exaggerating the numbers, Freedman says. Ultimately, the hope is that the dollar values calculated in the study will help focus attention on areas where improvements will Forums Courses, Workshops & Awards Facts and Figures The International Life Science Exhibition 2015 Sept Courses, Workshops & Awards Almost attendees in 2014 More than 100 international speakers More than 100 posters More than 100 exhibitors Perfect networking opportunities Networking Events Welcome Reception Interactive Poster Session yield a big bang for the buck. Modest investments in standards and best practices, for example as they relate to biological reagents such as validated cell lines and antibodies, will yield more reproducible results in published studies and, in turn, substantial returns on funding investments, Freedman says. Already, he notes, more than 450 cell biologists have completed their Cell Culture and Authentication Survey to help gain better understanding of and overcome barriers to cell authentication and issues with irreproducibility. With more than 100 stakeholders already signed on, our authenticate campaign is raising awareness among researchers about the importance of cell authentication and the easy and low cost tests that are available and the GBSI is working on ways to incentivize routine cell authentication practice, he says. To help improve the proficiency of researchers, Freedman says plans include an online community to provide coaching and mentoring, as well as online courses with the most up-to-date information in quality research practice. EDITCONNECT: E Online Registration free of charge Scientific Forums Aging and Drug Discovery Digital Health Drug Discovery Sciences GPCR Infectious Diseases Jumpstarting Innovation Medicinal Chemistry Next Generation Sequencing Peptide Therapeutics Signaling and Drug Resistance in Cancer Stem Cells in Biomedicine Synergy Translational Medicine For detailed information please visit: Follow us on Facebook and Twitter #BLSW International Life Science Exhibition Don t miss the opportunity to visit over 100 Life Science exhibitors Basel Tourismus MipTec_Inserat_178x124.indd :39

20 20 DDNEWS AUGUST 2015 PRECLINICAL For more information, visit MSKCC selects Ascentos software for preclinical research MT. ARLINGTON, N.J. PDS Life Sciences, a leading global provider of intuitive data management software and solutions for life-sciences research, announced recently that Memorial Sloan Kettering Cancer Center (MSKCC) has opted to use PDS Ascentos software suite to manage and analyze data that will be generated in its new GLP-compliant preclinical research laboratories. Ascentos software includes toxicology, clinical pathology, reproductive toxicology and pathology modules that are intended to streamline data management from study setup to final reporting. Ascentos is said by PDS to be a complete FDA SEND-ready preclinical solution, because it captures data required by current and future versions of the CDISC SEND data standard. After a rigorous, competitive assessment, according to PDS, MSKCC selected Ascentos because of its intuitive processes, rapid implementation and ability to automate fundamental laboratory workflows. We develop software that works like TOOLS & TECHNOLOGY scientists think, said Sayed Badrawi, CEO of PDS. As innovative companies and research institutions continue to choose PDS Ascentos over the alternatives, it s become clear that building software for the user not just the data being compiled is a key driver of value in the market. For more than 30 years, PDS has provided intuitive data management software and solutions for life-sciences research and development programs worldwide, and the company says most of the world s top 10 pharma companies rely on PDS software, as do industryleading contract research organizations, chemical companies, universities and regulatory agencies. The PDS software lineup is centered on Ascentos, an integrated preclinical software solution that is purpose-built to support toxicology, clinical pathology, reproductive toxicology and anatomic pathology. PDS also offers TranSEND, a complete FDA SEND submission management solution, as well as bioinformatics analysis and other services. ELSALYS CONTINUED FROM PAGE 17 The anti-angiogenic effect of anti-cd160 is really new. Unlike other drugs of its class, anti- CD160 does not deprive the new blood vessels of growth factor to hinder their development, but induces their death while preserving the existing vessels. Dr. Philippe le Bouteiller of the Centre de Physiopathologie Toulouse-Purpan it demonstrates once again that the expertise and experience of our team make a difference when it comes to identifying gems with very strong therapeutic potential. The CD160 receptor is highly expressed on the surface of the activated endothelial cells that line the blood vessels found in most tumors as well as being associated with the vascular anarchic proliferation found in eye diseases such as macular degeneration and diabetic retinopathy. CD160 helps to regulate uncontrolled vascularization because once it binds to its natural ligand, it activates and triggers the death of activated endothelial cells in new vessels; existing vessels are not affected since they don t express CD160 on their surface. The agonist antibody reproduces and amplifies the action of the ligand to trigger the death of new vessels as it stabilizes existing ones. In a mouse model of retinopathy, treatment with anti-cd160 restored vascular circulation in the diseased retina, and in models of melanoma and fibrosarcoma, anti-cd160 together with chemotherapy led to a significant reduction in tumor burden and prolonged survival, benefits associated with a decrease in intratumoral blood vessels, stabilization of existing vessels and stimulation of natural killer cell activity. It is also found on the surface of circulating immune cells, such as some natural killer and T cells, and early studies have demonstrated that anti-cd160 prevents tumor escape through the activation of natural killer cells. When combined with other immunity checkpoint inhibitors such as anti-pd1 antibodies, it also helps prevent T cell exhaustion. Given its anti-angiogenesis and immunomodulatory effects, Elsalys has developed two versions of the antibody one that takes advantage of the anti-angiogenic effect for the treatment of vascular eye diseases, and another that combines both effects to target cancer. For the ophthalmologic approach, Elsalys notes on its website that the goal is to provide a new therapeutic option with better specificity and lower administration frequency than current treatments (one injection every three months versus once a month for Avastin). In terms of cancer, the company commented that the anti-cd160 antibody shows a competitive profile in oncology, notably in B-cell chronic lymphocytic leukemia. The anti-angiogenic effect of anti-cd160 is really new. Unlike other drugs of its class, anti-cd160 does not deprive the new blood vessels of growth factor to hinder their development, but induces their death while preserving the existing vessels, le Bouteiller said in a press release. With this antibody, we are thus able to reduce new retinal vessels in mice eyes with retinopathy. This antibody offers a potential new approach to anti-angiogenesis treatments, as most therapeutics in that category target VEGF. Additionally, preliminary data has found that the anti-cd160 antibody has a synergistic effect with anti-angiogenics targeting VEGF. EDITCONNECT: E DRUG DISCOVERY 15 TELFORD INTERNATIONAL CONFERENCE CENTRE 2 ND - 3 RD SEPTEMBER 2015 World Class scientific programme & exhibition FREE to attend Register NOW HPV CONTINUED FROM PAGE 18 cal dysplasia or cancer. This population represents over 90 million women worldwide for the two HPV types responsible for 70 percent of cervical cancer cases, HPV 16 and HPV 18. For these women, Genticel began to develop GTL001. Vaxiclase has the same mode of action as the CyaA technology, licensed from Institut Pasteur, according to Marie-Christine Bissery, chief scientific officer of Genticel. While CyaA is a valuable antigen delivery vector, it can only accommodate small antigens. Thus, Genticel reengineered the original adenylate cyclase from B. pertussis, enabling it to host several or large antigens as well as antigens with acidic domains. This new proprietary vector, Vaxiclase, is the basis for Genticel s follow-on candidate, GTL002, a multivalent HPV therapeutic vaccine targeting the six most relevant HPV types responsible for 85 percent of cervical cancer worldwide. GTL001 is in Phase 2 in Europe and will be tested in the United States in a Phase 1 study this year. GTL002 could enter a Phase 1 trial in Genticel estimates a market potential of more than $1 billion per year for GTL001 and $2 billion for GTL002. EDITCONNECT: E081515

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