ISSN: IJBPAS, March, 2013, 2(3): A ROLE OF MONOCLONAL ANTIBODIES IN TARGETING DRUG DELIVERY OF CANCER THERAPY: A REVIEW

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1 : ISSN: A ROLE OF MONOCLONAL ANTIBODIES IN TARGETING DRUG DELIVERY OF CANCER THERAPY: A REVIEW GAYATHRI DEVI SG*, MUTHUKUMARAN M AND KRISHNAMOORTHY B Montessori Siva Sivani Institute of Science & Technology-College of Pharmacy Mylavaram, Vijayawada-Andhrapradesh *Corresponding Author: E Mail: gayathri.sripathi@yahoo.com ABSTRACT In this review, we discussed about the use of monoclonal antibodies to specifically bind to target cells or proteins and deliver the drug for the treatment of cancer by blocking the growth signals or triggring the immune system or by preventing the formation of new blood vessels. The recent clinical success of anticancer monoclonal antibodies like catumaxomab, brentuximab, denosumab, ipilimumab, tocilizumab are widely used and these are proving of success rate about monoclonal antibodies for different cancer treatment. Monoclonal antibody therapy has emerged as an important therapeutic modality for cancer. These monoclonal antibodies are produced by the preparation of hybridomas i.e. the fusion of B-lymphocytes with mylenoma cells. Catumoxomab, denosumab etc are widely used anticancer drugs used to treat cancer disease. Thus monoclonal antibodies in cancer therapy can confidently predict that progress towards more specific and less toxic therapy for human cancer in our near future. Keywords: Monoclonal Antibody, Targeting Drug Delivery, Cancer Therapy INTRODUCTION Monoclonal antibodies (mab in medical specific nature of antibodies becomes a tool shorthand) are antibodies that are identical, with wide and potentially revolutionary each derived from one type of immune cell applications. In essence, they can be deployed and each a clone of a single parent cell. For to find a single targeted substance, such as an science, that means that the extraordinarily antigen found only on a cancer cell, and make 712

2 it possible to pinpoint the cell and destroy it. In addition to cancer therapies, MAbs are also used in diagnostic tests for everything from pregnancy, to AIDS, to drug screening. Antibody based therapeutics have emerged as important components of therapies for an increasing number of malignancies. Unconjugated mabs directed against the Bcell idiotype [1],against CD20 [2, 3] and against CD22 [4] are useful in treating lymphomas and one anti-cd20 antibody, rituximab has become a widely used, FDAapproved agents with potential applications to other malignancies as well. Radioimmunoconjugates such as ibritumomab, tiuxhochoetan and tositumomab plus directed against CD20 shows substantial anti-tumor activity [5, 6] and have entered standard clinical practice for lymphoma therapy.campth-1h an anti-cd52 antibody that efficiently mediates complements fixation has been approved for chemotherapyrefractory chronic lymphocytic leukemia [7]. An immunoconjugate containing an anti CD33 antibody and calicheamicin has been approved for use in refractory acute-myeloid leukemia [8]. Immunotoxins consisting of recombinant antibody fragments conjugated to catalytic toxins demonstrates anti-tumor activity as well [9]. Trastuzumab, an unconjugated anti-her2/neu antibody, is widely used alone and in combination with chemotherapy agents in breast cancer [10-12]. Antibidies directed against the extracellular domain of the EGFR show activity in advanced cancer and one has been approved for use in patients with colorectal cancer [13, 14]. Antibodies that inhibit T- cell activation by blocking the function of the cytotoxic lymphocyte-associated antigen 4 co-receptor on Tcell show preclinical promise [15] and are undergoing clinical evaluation with promising preliminary results [16]. Here we provide an overview of mab therapy of cancer, emphasizing recent advances that have clarified the utility of maab to treat common malignancies such as breast cancer, colorectal cancer and lymphoma, these successes have energized and informed the development of many new antibodies that target previously tested and new targets for cancer therapy. Production of mab Monoclonal antibodies are artificially produced antibodies. The technique of cell fusion followed by selection is widely used in the production of monoclonal antibodies. Body cells can be cultured from a single cell in a controlled medium. The chromosomes involved are large and easily visible as a result of staining (coloring), so individual chromosomes and their arrangements are 713

3 identifiable. Modern techniques allow fusing the cells in a way that two nuclei function in one cell, which leads to the transfer of DNA into growing culture cells. Several somaticcell genetic techniques involve the fusion of two cells in such way that the nuclei from both parents are brought within one joint cytoplasm. Spontaneous fusion of animal and human cells in culture occurs infrequently, but the rate increases substantially when certain viruses that have lipoprotein envelopes similar to the plasma membranes of animal cells are present. Cell fusion can also be accelerated by the addition of polyethylene glycol, which causes cell plasma membranes to adhere to those of any surrounding cells. In most fused animal cells the nuclei eventually also fuse, producing the desired cells that contain chromosomes from both parents. Hybrids between cultured cells from different mammals also have been widely used. Early production of monoclonal antibodies was fraught with obstacles. At least four monoclonal now on the market in the U.S. are chimerics, including a drug called Reo Pro, which binds to platelets to prevent blood clots. Another approach has been a grafting process that produces what are known as humanized MAbs, wherein some 95 percent of the resulting molecule is human in origin. This technique is employed in such drugs as Herceptin, a monoclonal antibody used to target breast cancer (Figure 1). Mechanism of Monoclonal Antibody CDC is cell killing method that can be directed by antibodies. As with ADDC, the different subclasses of antibodies have varying abilities to elict CDC responses. Although IgM is the most effective isotope for compliment activation, it is not widely used in clinical oncology because IgM does not readily extravasate from vascular structures. IgM and IgG3 are both very effective at directing CDC [17] via the classical compliment activation pathway. In this cascade,the formation of antigen antibody complexes results in the uncloaking of multiple C1q binding sites in close proximity on the CH2 domains of participating IgG molecules. These uncloaked C1q binding sites convert the previously low affinity C1q-IgG interaction to one of high avidity, which triggers a cascade of events including a series of other compliment proteins and leads to the proteolytic release of the effector cell activating agents C3a and C5a.The anti-cd20 mab rituximab has been found that depend on CDC for its in vivo efficacy [18]. Rituximab was shown to cure 100% of immunocompetent mice challenged with murine lymphoma EL4 cells stabily 714

4 transfected with CD20. However its protective properties were completely abolished when the same study was done in syngeneic knockout mice lackn C1q. it is accepted that CDC plays a significant role in the in vivo efficacy of rituximab. The most direct evidence supporting this comes under in vivo studies [19]. Although CDC is not believed to dominate the antitumor effects elicted by most mabs, it generates various factors that can enhance ADCC. The release of the activating agent results in a gradient that draws effector cells, such as NK cells, in to the tumor. Molecules of the complement C3 activation product Ic3b deposited on the surface of tumor cells activate complement receptors 3 on the surface of effector cells and induce CR3- dependent cellular cytotoxicity in the presence of yeast cell-wall providing a potential means of activating a cytotoxic mechanism typically reserved for yeast and fungi [20]. Monoclonal Antibodies Use For Cancer Treatment Monoclonal antibody therapy is the use of monoclonal antibodies (or mab) to specifically bind to target cells or proteins. This may then stimulate the patient's immune system to attack those cells. It is possible to create a mab specific to almost any extracellular/ cell surface target, and thus there is a large amount of research and development currently being undergone to create monoclonal for numerous serious diseases (such as rheumatoid arthritis, multiple sclerosis and different types of cancers).one possible treatment for cancer involves monoclonal antibodies that bind only to cancer cell-specific antigens and induce an immunological response against the target cancer cell (Figure 2). Targeted Conditions Anti-cancer monoclonal antibodies can be targeted against malignant cells by several mechanisms. Radio immunotherapy (RIT) involves the use of radioactively conjugated murine antibodies against cellular antigens. Most research currently involved their application to lymphomas, as these are highly radiosensitive malignancies. To limit radiation exposure, murine antibodies were especially chosen, as their high immunogenicity promotes rapid clearance from the body. Tositumomab is an exemplarily used for non-hodgkins lymphoma. Immunoliposomes are antibodyconjugated liposomes can carry drugs or therapeutic nucleotides and when conjugated with monoclonal 715

5 antibodies, may be directed against malignant cells. Although this technique is still in its infancy, significant advances have been made. Immunoliposomes have been successfully used in vivo to achieve targeted delivery of tumor-suppressing genes into tumors, using an antibody fragment against the human transferrin receptor. Tissue-specific gene delivery using immune liposomes has also been achieved in brain, and breast cancer tissue. Cancer Treatment with Monoclonal Antibodies Monoclonal antibody drugs are used to combat various types of cancer. Unfortunately, some monoclonal antibody drugs have severe side effects. But it is also clear that these medications have a bright future because they enhance already existing body defenses, and can be improved dramatically as the new drug-production technologies evolve. There have been many failures (scientists have not had tremendous success in general with regard to cancer treatment), but the prospects are still bright and many scientists are working with mabs for cancer. Route of Antibody Administration MAbs for cancer treatment are usually injected to the bloodstream with a carrier although some clinical studies have involved the use of intraperitoneal administration of mab where the treatment solution is injected to body cavities. Studies in experimental animals and in humans show that direct cavity injection targets smaller peritoneal tumors more efficiently than intravenous antibody treatment. Larger tumor masses are targeted more efficiently by the intravenous method, leading some researchers to hypothesize that the optimal situation will involve both delivery systems concurrently. Using Antibodies To Deliver Drugs Treatment with mabs often uses them like missiles delivering a warhead. The warhead is the drug intended for the cancerous cell or defective areas of the body; the specificity of the antibodies makes this a truly targeted treatment. Several toxins have been coupled to mabs and have been analyzed. Treatment regimens either involve the induction of antibody by the body or the use of antibodies acting in conjunction with the complement system and/or effector cells (i.e., antibodydirected cell-mediated immunity). Types of Monoclonal Antibodies Used In Cancer Therapy Two types of monoclonal antibodies are used in cancer treatments 716

6 Naked monoclonal Antibodies are those without any drug or radioactive material attached to them. Conjugated monoclonal Antibodies are those joined to a chemotherapy drug, radioactive particle, or a toxin (a substance that poisons cells). Naked Monoclonal Antibodies Naked MAbs are the most commonly used MAbs. Although they all work by attaching themselves to specific antigens, they can be helpful in different ways. Markers For Destruction Some naked MAbs attach to cancer cells to act as a marker for the body's immune system to destroy them. Antibodies now in use in this group include: Rituximab (Rituxan) Rituximab is used to treat B-cell non- Hodgkin lymphoma and some other diseases. It is a monoclonal antibody against the CD20 antigen, found on B cells. It works, in part, by labeling cells so that the immune system can attack them. Ofatumumab (Arzerra): Ofatumumab is another antibody against the CD20 antigen. It is used mainly to treat chronic lymphocytic leukemia when other treatments are no longer effective. Alemtuzumab (Campath) Alemtuzumab is an antibody against the CD52 antigen, which is found on both B cells and T cells. It is used to treat some patients with B-cell chronic lymphocytic leukemia. Activation Blockers Some naked MAbs don't really interact with a person's own immune system. Their effects come from their ability to attach to the specific antigens that are working parts of cancer cells or other cells that help cancer cells grow, and stop them from working. These MAbs are also referred to as targeted therapies. Trastuzumab (Herceptin) Trastuzumab is an antibody against the HER2/neu protein. A large amount of this protein is present on tumor cells in some cancers. When HER2/neu is activated, it helps these cells grow. Trastuzumab stops these proteins from becoming active. It is used to treat breast cancers that have large amounts of this protein. Cetuximab (Erbitux) Cetuximab is an antibody against the EGFR protein, which is present in large amounts on some tumor cells 717

7 and helps them grow and divide. Cetuximab blocks the activation of EGFR. It is used to treat some advanced colorectal cancers as well as some head and neck cancers. Panitumumab (Vectibix) This MAb also targets the EGFR antigen. It is used to treat some cases of advanced colorectal cancer. Bevacizumab (Avastin) Bevacizumab targets the VEGF protein, which is normally made by tumor cells to attract new blood vessels to feed their growth. Bevacizumab attaches to VEGF, which blocks it from signaling for new blood vessels to form. This MAb is used along with chemotherapy to treat some colorectal, lung, breast, and kidney cancers, as well as glioblastomas (a type of brain tumor). It is being studied for use against other cancers. Some of these antibodies have been used for many years. At first they were used mostly after other treatments had stopped working. But more studies have been done and continue to be done. Now, these antibodies are being used earlier in the course of cancer treatment. Side Effects Monoclonal antibodies are given intravenously (injected into a vein). Compared with side effects of chemotherapy, the side effects of naked MAbs are usually fairly mild and are often more like an allergic reaction. If they do occur, it is most often while the drug is first being given. Possible side effects can include: Fever Chills Weakness Headache Nausea Vomiting Diarrhea Low blood pressure Rashes Some MAbs also have effects that are specific to the antigens they target. For instance, like most chemotherapy drugs, some can affect the bone marrow. This can cause lower levels of blood cells, which can increase the risk of bleeding and infection in some people. Conjugated Monoclonal Antibodies Conjugated MAbs are monoclonal antibodies that are attached to drugs, toxins, or radioactive substances. The MAbs are used as homing devices to take these substances directly to the cancer cells. The MAb 718

8 circulates in the body until it can find and hook onto the target antigen. It then delivers the toxic substance where it is needed most. This lessens the damage to normal cells in other parts of the body. Conjugated antibodies may pack more of a punch than naked MAbs, but for this reason they often cause more side effects, too. The side effects depend on which type of substance they're attached to. Conjugated MAbs are also sometimes referred to as tagged, labeled, or loaded antibodies. They can be divided into groups depending on what they are linked to. MAbs with radioactive particles attached are referred to as radio-labeled, and therapy with this type of antibody is known as radio-immunotherapy (RIT). MAbs with chemotherapy drugs attached are often referred to as chemolabeled. MAbs attached to toxins are called immunotoxins. Evolving New Approaches Conjugates of cytotoxic drugs and antibodies are targeted to achieve the direct killing of tumor cells. By contrast, antibody-cytokine fusion proteins exert their therapeutic effect predominantly by directing the host s immune response towards the tumor. However, as the underlying mechanism of oncogenic transformation are deciphered with increasing speed and the general knowledge of biological processing is steadily expanding new approaches to fight cancer. Several of the use these mab to enhance tumor specificity and these attempts are based either on disrupting aberrant signaling in the tumor cell or enhancing processes enabling the eradication of tumor. Apoptosis-this is a programmed cell death-is one of the mechanisms that is dysregulated in most cancer, apoptosis can be initiated by the triggering of death receptors through extrinsic factors. As many tumor cells have an altered threshold but are still able to undergo apoptosis, direct induction of programmed cell death is believed to be a powerful strategy for treating cancer. In this regard, the feasibility of Fas ligation for cancer therapy has been demonstrated. However, systemic treatment with Fas agonist such as anti-fas antibodies causes several systemic toxicities. In addition, homo-dimeric soluble Fas are biologically inactive and have activity only when aggregated secondarily for example, by crosslinking antibodies. Samel and colleagues presented a solution to this problem by targeting sfasl to the tumor with a tumor specific single chain antibody upon binding to the respective cell-surface molecule several trimeric sfasl molecules aggregate and there by mimic the activity of membrane bound FasL. 719

9 Figure 1: Diagram Shows the Stages of Monoclonal Antibody Production 720

10 CONCLUSION The monoclonal Antibodies (mabs) have emerged as important therapeutic agents for several different malignancies they have proved to be well tolerated and effective for the treatment of different cancers, and were consequently approved by FDA.Besides their role on cancer therapeutics on their own, their ability to target tumors also enables them to improve the selectivity of other types of anti cancer agents, some of which cannot be applied alone. The stroma is the interface between tumor and host, and accordingly, mabs against stromal antigens may make it more resistant to the onslaught of tumor cells. At first glance, the clinical efficacy of mabs may be attributed to target-specific effects. By binding to their target, mabs neutralize an important factor or receptor that drives cell proliferation and tumor growth. However, the therapeutic activity of mabs may go beyond these target-related effects. Currently available mabs are IgG antibodies, and consequently, they have the potential to activate immune-mediated effector functions, including ADCC and CDC. ADCC occurs when target-bound antibodies mobilize effector cells via interaction of their Fc domain with FcRs on the surface of immune cells. Recent research has demonstrated the wide variety of agents that can be targeted to tumors by mabs. Moreover, preclinical testing of tumor targeted therapies generated improved results. The clinical value for cancer therapy for most of these approaches however, yet to be confirmed. A major task will be to define for each tumor entity the suitable combination of antibody effective agent and adjuvant therapy. REFERENCES [1] Miller et al., Teatment of B-cell Lymphoma with Monoclonal antiidoitype antibody, Medicial Intelligence, 306, 1982, [2] McLaughlin et al., Rituximab chimeric anti-cd20 monoclonal antibody therapy for relapsed indolent lymphoma:half of patients respond to four-dose treatment program, J. Clin. oncol., 16, 1998, [3] Coiffier B et al., CHOP chemotherapy plus rituximab compared wiith CHOP alone in elderly patients with diffuse large B-cell lymphoma, N. Engl. J. Med., 346, 2002, [4] Leonard JP et al., Link, B. K. Immunoyherapy of non-hodgkins lymphoma with hll2 and HU1D10 Semin, oncol., 29, 2002, [5] Witzig TE et al., Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan 721

11 radioimmunotherapy versus rituximab immunotherapy with patients with relapsed or refractory low-grade, follicular, or transformed B-cell non- Hodgkins lymphoma, J. Clin. oncol., 20, 2002, [6] Kaminski MS et al., radio immunotherapy with iodine (131) tositumamab for relapsed or refarctory B-cell non-hodkin lympoma;updated results and long term follow up of the university of Michigan experience, Blood, 96, 2000, [7] Lundin J et al., phase 2 trial of subcutaneous anti-cd52 monoclonal antibody alemtuzumab as first-line treatment for patients with B-cell chronic leukemia (B-CLL), Blood, 100, 2002, [8] Sievers EL et al., Selective ablation of acute myeloid leukemia using antibody targeted chemotherapy: a phase1 study of an anti-cd33 calicheamicin immunoconjugate, Blood, 93, 1999, [9] Kreitma RJ et al., Efficacy of the anti- CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairycell leukemia, N. Engl. J. Med., 345, 2001, [10] Cobleigh MA et al., Multinational study of the efficacy and safety of humanized anti-her2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease, J. Clin. oncol., 17, 1999, [11] Vogel CL et al., Efficacy and safety to trastuzumab as a single agent in first -line treatment of HER2- overexpressing metastatic breast cancer, J. Clin. oncol., 20, 2002, [12] Slamon DJ et al., Use of chemotherapy plus monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2, N. Engl. J. Med., 344, 2001, [13] Robert F et al., phase1 study of antiepidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer, J. Clin. Oncol., 19, 2001, [14] Foon KA et al., Preclinical and clinical evaluations of ABX-EGF,a fully human anti-epidermal growth factor receptor antibody, Int. J. 722

12 Radiat. oncol. Biol. Phys., 58, 2004, [15] Egen JG et al., New insights in to its biological function and use in tumor immunotherapy, Nat. Immunol., 3, 2002, [16] Sanderson K et al., Autoimmunity in a phase1 trial of a fully human anticytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages 3 and 4 melanoma, J. LClin. oncol., 23, 2005, [17] Janey C et al., Immunobiology, Vol. 3, Current Biology, London, [18] Di Gaetano N et al., Complement activation determines the therapeutic activity of rituximab in vivo, J. Immunol., 171, 2001, [19] Golay et al., CD20 levels determine the invitro susceptibility to rituximab and complement of B-cell chronic lymphocytic leukemia :further regulation by CD55 and CD59, blood, 98, 2001, [20] Gelderman KA et al., Compement function in mab-mediated cancer Immunotherapy, Trends Immunol., 25, 2000,