Drug Discovery. Michael Palazzolo and William Boyle. December 11, 2014
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1 Drug Discovery Michael Palazzolo and William Boyle December 11, 2014
2 Reminders Questions Webinar participants: chat box In house: microphone Survey questions Course evaluation
3 Overview High Level Objectives Learn more about this fastest growing class of new medicines Review of approved mabs and target classes being prosecuted in the clinic How therapeutic mabs are generated Technologies currently in play and next generation methods PK/PD of monoclonal antibodies
4 THERAPEUTIC ANTIBODIES AND TARGET CLASSES
5 36 Approved Monoclonal Antibodies International non-proprietary name Trade name Type Indication first approved First EU (US) approval year Muromonab-CD3 Orthoclone Okt3 Anti-CD3; Murine IgG2a Reversal of kidney transplant rejection 1986* (1986#) Abciximab Reopro Anti-GPIIb/IIIa; Chimeric IgG1 Fab Prevention of blood clots in angioplasty 1995* (1994) Rituximab MabThera, Rituxan Anti-CD20; Chimeric IgG1 Non-Hodgkin's lymphoma 1998 (1997) Basiliximab Simulect Anti-IL2R; Chimeric IgG1 Prevention of kidney transplant rejection 1998 (1998) Daclizumab Zenapax Anti-IL2R; Humanized IgG1 Prevention of kidney transplant rejection 1999 (1997); # Palivizumab Synagis Anti-RSV; Humanized IgG1 Prevention of respiratory syncytial virus infection 1999 (1998) Infliximab Remicade Anti-TNF; Chimeric IgG1 Crohn disease 1999 (1998) Trastuzumab Herceptin Anti-HER2; Humanized IgG1 Breast cancer 2000 (1998) Gemtuzumab ozogamicin Mylotarg Anti-CD33; Humanized IgG4 Acute myeloid leukemia NA (2000#) Alemtuzumab MabCampath, Campath-1H Anti-CD52; Humanized IgG1 Chronic myeloid leukemia 2001 (2001) Adalimumab Humira Anti-TNF; Human IgG1 Rheumatoid arthritis 2003 (2002) Tositumomab-I131 Bexxar Anti-CD20; Murine IgG2a Non-Hodgkin lymphoma NA (2003) Efalizumab Raptiva Anti-CD11a; Humanized IgG1 Psoriasis 2004 (2003); # Cetuximab Erbitux Anti-EGFR; Chimeric IgG1 Colorectal cancer 2004 (2004) Ibritumomab tiuxetan Zevalin Anti-CD20; Murine IgG1 Non-Hodgkin's lymphoma 2004 (2002) Omalizumab Xolair Anti-IgE; Humanized IgG1 Asthma 2005 (2003) Bevacizumab Avastin Anti-VEGF; Humanized IgG1 Colorectal cancer 2005 (2004) Natalizumab Tysabri Anti-a4 integrin; Humanized IgG4 Multiple sclerosis 2006 (2004) Ranibizumab Lucentis Anti-VEGF; Humanized IgG1 Fab Macular degeneration 2007 (2006) Panitumumab Vectibix Anti-EGFR; Human IgG2 Colorectal cancer 2007 (2006) Eculizumab Soliris Anti-C5; Humanized IgG2/4 Paroxysmal nocturnal hemoglobinuria 2007 (2007) Certolizumab pegol Cimzia Anti-TNF; Humanized Fab, pegylated Crohn disease 2009 (2008) Golimumab Simponi Anti-TNF; Human IgG1 Rheumatoid and psoriatic arthritis, ankylosing spondylitis 2009 (2009) Canakinumab Ilaris Anti-IL1b; Human IgG1 Muckle-Wells syndrome 2009 (2009) Catumaxomab Removab Anti-EPCAM/CD3;Rat/mouse bispecific mab Malignant ascites 2009 (NA) Ustekinumab Stelara Anti-IL12/23; Human IgG1 Psoriasis 2009 (2009) Tocilizumab RoActemra, Actemra Anti-IL6R; Humanized IgG1 Rheumatoid arthritis 2009 (2010) Ofatumumab Arzerra Anti-CD20; Human IgG1 Chronic lymphocytic leukemia 2010 (2009) Denosumab Prolia/Xgeva Anti-RANK-L; Human IgG2 Bone Loss 2010 (2010) Belimumab Benlysta Anti-BLyS; Human IgG1 Systemic lupus erythematosus 2011 (2011) Ipilimumab Yervoy Anti-CTLA-4; Human IgG1 Metastatic melanoma 2011 (2011) Brentuximab vedotin Adcetris Anti-CD30; Chimeric IgG1; immunoconjugate Hodgkin lymphoma 2012 (2011) Pertuzumab Perjeta Anti-HER2; humanized IgG1 Breast Cancer 2013 (2012) Raxibacumab (Pending) Anti-B. anthrasis PA; Human IgG1 Anthrax infection NA (2012) Trastuzumab emtansine Kadcyla Anti-HER2; humanized IgG1; immunoconjugate Breast cancer In review (2013) Vedolizumab (Pending) Anti-alpha4beta7 integrin; humanized IgG1 Ulcerative colitis, Crohn disease In review (NA) BLyS, B lymphocyte stimulator; C5, complement 5; CD, cluster of differentiation; CTLA-4, cytotoxic T lymphocyte antigen 4; EGFR, epidermal growth factor receptor; EPCAM, epithelial cell adhesion molecule; GP, glycoprotein; IL, interleukin; NA, not approved; PA, protective antigen; RANK-L, receptor activator of NFkb ligand; RSV, respiratory syncytial virus; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor. Source: Janice M. Reichert, Editor-in-Chief, mabs.
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7 Target Classes for Therapeutic Antibodies Target Class MOA Examples Cytokines Primarily neutralization TNFa, IL-6, BlyS, RANKL, INF-g, IL-23, L- 17 Cytokine Receptors Immune Modulators and CD s Receptor antagonist, agonist, blocking and internalization Receptor antagonist, ADCC, ADC, neutralization of viral entry IL-1r, DR-4, DR-5, CD40, IL-6R, TPOR CD28, CTLA-4, CD52, CD33, B7RP-1, PD-1 Growth Factors Primarily neutralization VEGF, HGF, ANG1/2, NGF, CSF-1 Growth Factor Receptors ADCC, ADC, blocking HER, HER2, IGFR-1, CSFR-1, TrkA Cell Adhesion Molecules Blocking counter receptor binding Gp IIb/Iia, CD11 (LFA), a4b1, a4b7, ICAM GPCR s Extracellular Matrix/Mucins/Amyloid Neutralization, ADCC, antagonist, antagonist Blocking, dissolution of aggregated plaque Glucagon receptor, CXCR 2-5, Calcitonin R Sclerostin, MUC1, b-amyloid Compliment Pathway Blocking, protease neutralization C5a, tissue factor, factor VIII, VWF Ig and FcR Class Neutralization and blocking IgE, FceR1, Fc receptor giiib Enzymes and Serum Proteins Blocking Carbonic anhydrase, oxidized LDL, PSCK9 Gated Voltage Channels Blocking ion flux K= channel, TRPV1, PN3, SDF-1 Infectious Disease Antigens Neutralization and opsinization RSV, HIV, MRSA, HCV, Influenza Ca 2010; non-redundant target list ~ 110 targets
8 MOA of Therapeutic Antibodies Neutralization of growth factors and cytokines Blocking receptors and adhesion molecules Cell killing and clearing via Effector functions Interference of Pathogen Entry and Pathology Interference of Enzymatic Activity
9 What are Therapeutic Antibodies? IgG-Fab: Antigen Binding Hinge Oligosaccharide IgG-Fc: Fc Receptor Binding Fc Receptors & Complement Binding FcRn Binding Antigen Binding Generally Humanized Recombinant Immunoglobulins (IgG1, 2, 4) Heavy and Light Chain Linked via Cys Bonds Constant Regions Including Fc Domain Hypervariable Regions, CDR s, Involved in Antigen Binding Ig Repitoire Capable of Generating 10E+09 Diversity Recombination of Germline Variable Regions Somatic Hypermutation to Increase Affinity and Specificity
10 Antibody Modalities in the Clinic Variety of platforms allow for the isolation and optimization of all antibody modalities; full length and fragments to produce best-in-class therapeutics Full-length product formats Hyphenated product formats Major Industry Focus Full length bivalent, fully human
11 GENERATION OF THERAPEUTIC ANTIBODIES - TECHNOLOGY
12 Recombination Creates Initial Antibody Diversity
13 How are Antibodies Formed? Recombination Somatic Hypermutation Antibody specificity and affinity are selected following these two critical events
14 Antibody Diversity Generation Recent Advances in Understanding Somatic Hypermutation SHM is initiated by Activation Induced Cytidine Deaminase (AID) ** * * Natural process of mutagenesis that occurs in B cells during the selection and maturation of antibodies Key in vivo process for formation of antibodies with potent characteristics Follows an optimized design template created during Ig recombination Mutations are often non-obvious and hence difficult to recapitulate by in vitro mutagenesis
15 Generation of Therapeutic Antibodies Antibody humanization is the fundamental breakthrough that allowed antibodies to become a major therapeutic class CDR grafting most approved MAbs developed this way Queen IP estate - PDL, Genentech Transgenic mice fully human antibodies from mice Abgenix/Amgen (Cell Genesys) Medarex/BMS (GenPharm) Phage display Abbott s Humira anti-tnf CAT, Morphosys, Dyax Yeast Display Abbott, Adimab, Alder Alternative Routes to Humanization Morphotek Kalabios Xencor AnaptysBio BioAtla
16 Antibody Discovery Platform Overview: Several Advantages Library Based Technologies In Vivo Immunization Cell Based Technologies CAT Dyax Morphosys Abgenix Medarex Kirin Morphotek Humabs AIMM Companies Domantis Glycofi Xoma Hematech Regeneron Ablexis Theraclone Chiome 4-Antibody Adimab Sea Lane F-Star Kymab Ablynx Silverlake Vivalis AnaptysBio BioAtla Key Limitations Rely on partial antibody formats for discovery and format conversion Accumulate mutations in the framework due engineering and requires germ lining/humanizing Lack of critical read-outs (expression levels, affinity) In vivo bias against homologous targets Further germlining required Limited selectivity of target epitope(s) Search for rare events in a disease state Further optimization is often required can lead to loss of activity Often identify key epitopes rather than product leads Key Industry Advantages Requirements Select full length human mab; save time and avoid loss due to format conversions Ability to screen large libraries with several different types of antigens in different formats Retain avidity and affinity from both V H and V L binding Ability to measure simultaneously affinity and expression levels Fast cycle times Acquired or Encumbered Recent Start-up (2010) Established with Partnerships Other
17 Industry Needs New, powerful Ab discovery and protein optimization approaches Mouse immunization (e.g., XenoMouse, HuMab-Mouse & wt mice) Static library approaches (e.g., antibody phage display) Example technical limitation Body does not always generate useful Abs to desired site on target Antibody that meets design goals not always present in library How industry mitigates risk Large pharma example (AstraZeneca): Owns/access multiple platforms incl., CAT/phage lib., Dyax/Phage lib., Amgen/XenoMouse, REGN/VelocImmune, Xencor/XmAb, MEDI/humanization, other Industry adopts redundant, resource and time intensive approaches to address technical limitations of other platforms
18 Antibodies in the Clinic 120 Number of Known Antibodies Humanized Transgenic Mouse Phage Display Approved Phase III Phase II Phase I Despite emergence of phage display and transgenic mouse platforms, majority of industry continues to utilize humanized antibodies 15 Stage of Development 20
19 Humanization: Part I Begin with Mouse Immunization & Mab Production Process is well understood Immunization techniques are important Route, duration, antigen selection and formulation Screening techniques key for antibody selection From our perspective, two starting points; immunization or existing sequence Immunizied spleen cells Fusion and Hybridoma Formation High Through-Put Hybridoma Screening ELISA Hybridoma Selection & Antibody Production and Bioassay Myeloma cell Clone and generate H&L chain sequences
20 Humanization Part II: Process and Goal Splicing of CDR sequences obtained from a rodent (mouse) immunoglobulin onto a human immunoglobulin scaffold; i.e., CDR Grafting Goal is seamless integration of mouse and human sequences using the smallest amount of mouse sequences in the final product Ordinary Mouse Chimeric Humanized Human 100% Mouse Protein (>60%) ~30% mouse protein (25-30%) 5-10% mouse protein (1-8%) No mouse protein (~1%) Antibody humanization is the fundamental breakthrough that allowed antibodies to become a major therapeutic class
21 Humanization: Herceptin Example Herceptin example (~1% immunogenicity) Back mutations introducing mouse sequences needed in this case SHM technology should bypass this need and give rise to more humanlike product candidates HEAVY B 35A B 52A C 82B 82A C 100B 100A * g4d5 E V Q L V E S G G G L V Q P G G S L R L S C A A S G F N I K D T Y I H W V R Q A P G K G L E W V A R I Y P T N G Y T R Y A D S V K G R F T I S A D T S K N T A Y L Q M N S L R A E D T A V Y Y C S R W G G D G F Y A M D Y W G Q G T L V T V S S * * * * * * * * * CDR1 CDR2 CDR3 human E V Q L V E S G G G L V Q P G G S L R L S C A A S G F T F S S Y A M S W V R Q A P G K G L E W V S V I S G K T D G G S T Y Y A D S V K G R F T I S R D N S K N T L Y L Q M N S L R A E D T A V Y Y C A R G R X G X S L S G X Y W G Q G T L V T V S S KD without back-mutations: KD with back-mutations: 25nM 0.3nM Mouse residue back-mutations Humanized mabs can be very close to fully human mabs depending on the complexity of the engineering process used
22 Humanization Process wet approach Random Mutagenesis and/or PDL Technology (Queen method) Mouse Immunization Murine Antibody CDR Grafting (Winter method. MRC) CDR-Grafted Antibody Dry approach Published Mouse Ab Sequence and immediate grafting and affinity maturation Murine Mabs still to be the largest source of new antibody medicines in the future Traditional methods use both Winter and Queen patents to humanize murine monoclonal antibodies for therapeutic uses Winter IP is close to expiration Queen Patent still in force and an issue for humanization Alternative methods for affinity improvement
23 Immunogenicity of Therapeutic Antibody Types EU and FDA guidelines acknowledge the immunogenic potential of monoclonal antibodies Product Name Indication Ig Modality Reported Immunogenicity OKT3 Acute rejection of organ transplants Murine 80% Rituxan Herceptin B-cell lymphoma Metastatic breast cancer Chimeric 1.1% Humanized >1% Humira RA/Crohn s Human Phage display 15% Panitumumab Colorectal cancer Human Transgenic 4% Remicade RA/Crohn s Chimeric 45% Zenapax Acute rejection of organ transplants Humanized 34% Tysabri MS Humanized 10% Avastin Colorectal cancer Humanized >1% Source: Product labels and patient information leaflets Ig isotype, route of administration, method of optimization and human V gene scaffold usage are important determinants in HAHA formation may impact PK/PD No major safety issues, but efficacy can be compromised Fully human antibodies remain the ideal choice, but depending on the methods used, humanized abs are as good as fully human antibodies wrt immunogenicity
24 Technology Timelines: Comparison of processes XenoMouse 3 mon. XenoMouse + optimization Humanization * 3 mon. * Paper starting point Humanization ** Phage Display 3 mon. 3 mon. ** Wet Lab starting point Antibody Discovery Antibody Engineering/ or SHM Optimization Cell Line Development Manufacturing Scale-up
25 Enhancing Efficacy Loss of patent exclusivity and the emergence of non-antibody scaffolds is driving a need for product differentiation, ideally via improved efficacy Glycosylation Strategies defucosylation to increase affinity to the FcgRIIIa receptor, enhancing ADCC (Antigen Dependent Cellular Cytotoxicity) GlycoFi acquired by Merck Glycart acquired by Roche BioWa multiple partnerships Fc Region Engineering ADCC enhancement, half-life extension, Genentech Xencor multiple partnerships Macrogenics Lilly deal Also, antibody-drug conjugates, ADC s Seattle Genetics, Immunogen, CovX
26 Antibody Drug Conjugates Adcetris and Kadcyla Pave the wave Improvements in linker technology, payload characteristics and ability for site-directed conjugation have enabled this new class of antibody drugs
27 Pharmacology of Recombinant Antibodies
28 Relationship between Antibody Affinity and Dose Critical Concepts: Unique Features of Antibodies; High specificity for target antigen Efficacy and safety generally correlated with the extent of interaction with the target antigen Adequate affinity is required to: Achieve the maximum therapeutic benefit With the intended route of administration At a dose associated with an acceptable cost of goods Will facilitate patient compliance
29 Binding Affinity Design Considerations Target Antigen Concentration Fraction of Antigen bound Antigen Turnover Rate Antibody PK and Biodistribution Properties Recruitment of any Effector Function Impact of Administration Route
30 Impact of Target Antigen Concentration When antigen conc is less than antibody affinity: i.e. Ag <<K D Binding is governed by the affinity of the antibody for the antigen (Region 1) Therefore an improvement in affinity leads to an improvement in potency
31
32 Impact of Target Antigen Concentration When antigen conc is greater than antibody affinity: i.e. Ag > K D and when affinity is reduced to approx. 1/10 th of antigen conc A potency ceiling is reached (Region 2) Therefore further improvements in affinity do not lead to significant improvements in potency
33 AMG 162 vs. AMG 0007 in Cynods Serum Concentration (ng/ml) Mean (±SD) PK Profiles 1 mg/kg SC Urinary N-Tx/UCRT % Change from Baseline Mean (±SD) Urinary N Tx % Change from 60 Baseline 1 mg/kg SC Time (day) Time (day)
34 Take Away Points Therapeutic Mabs are the largest growing area of human therapeutics Diverse targets with preference to specific classes some classes are relatively intractable Multiple modality opinions; naked and ADC s PK/PD is critical for design goals Other properties TBD manufacturability, IP and Integration of Target Biology and Drug Concept
35 Acknowledgements UCLA Pharmacology UCLA CTSI UC BRAID CAI NCAI (UC, Harvard, Ohio) NHLBI Upcoming Webinar: Archived Webinars: UC CAI I-Corps Stephanie Marrus Friday, January 23, 11 AM PST
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