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Past, present and future of monolonal antibodies Monoclonal antibodies: the discovery In 1975, Köhler and Millsteindiscovered how to prepare hybridoma's: a new cell type, resulting from the fusion of B-lymphocytes (immune cells of a mouse) with a myeloma (cancer) cell. The hybridoma combines two characteristics of the parent cells: immortality of the cancer cell and specific antibody production of the B-lymphocyte. Since all hybridoma cells derived of this fusion product make the same cell antibody type, these antibodies are called monoclonal (coming from one clone) antibodies.   Optimism and hype about usefulness The monoclonal antibody technology was quickly adopted by scientists in both industry and academia and led to a hype in industry and academia about the almost unlimited usefulness of monoclonal antibodies. Their usefulness in research and diagnostics has by now been proven: it is difficult to find a research laboratory where monoclonal antibodies are not generated for research purposes, in particular for selection of compounds. Industrially, they are used to recognize proteins from a culture broth and thereby assist in purification processes. In diagnostics, numerous test kits are on the market featuring monoclonal antibodies that specifically recognize certain molecules. Among the over the counter products featuring monoclonal antibodies, easy-to-use pregnancy or fertility tests are best known among the public. This widespread use of monoclonal antibodies was based on such inherent characteristics as safety, a broad range of potential targets, high selectivity, high affinity and ease of preparation (easy to generate).   Therapeutic disappointments in the 1980s In the early 1980s, the hype about monoclonal antibodies extended to the field of therapeutics. The concept of the 'magic bullet' was born: a combination of a specific drug or toxin, bound to a monoclonal antibody that specifically zeroes in on its target and delivers the drug or toxin there where it is needed. However, in the mid and late 1980s the development of therapeutic monoclonal antibodies suffered a number of serious disappointments, which reduced faith in the therapeutic applicability of monoclonal antibodies considerably. These disappointments were caused by the need for high therapeutic doses; low immunogenicity; poor penetration in solid tumours; potential cross reactivity with other tumours; high production costs; potential viral safety problems; technical difficulties in large scale productions; and relatively poor patent protection. In addition, all monoclonal antibodies were derived from rodent cells, and these rodent-derived monoclonal antibodies suffered from a very short half life; poor recognition of the rodent IgG-C region by human effector functions; HAMA response.   Strategies to overcome drawbacks All these drawbacks led to technological developments, primary consisting of strategies to generate human(ized) monoclonal antibodies (mab's). There are 5 such strategies: generation of true human mab's (but these are instable and have only a limited number of targets); chimerization (the resulting monoclonal antibodies are 60-70% human); humanization (the resulting monoclonal antibodies are 90-95% human); use of phage display (resulting in fully human monoclonal antibodies); use of transgenics (resulting in fully human monoclonal antibodies).   Monoclonal antibodies in development These technological developments have led to a whole series of new projects in industry, resulting in many monoclonal antibodies in clinical trials. Below we list these monoclonal antibodies, the developing company and the potential application. Company Product Application ImClone Systems/Merck BEC2 Anti/idiotypic for small cell lung cancer and melanoma ImClone Systems/Merck C225 Blocks EGF (HER-1) receptor for cancer treatment LeukoSite LDP-01 Inflammation following stroke and transplantation LDP-02 Crohn's disease, inflammatory bowles disease, ulcerative colitis LDP-03 (campath) Chronic lymphocytic leukemia Abgenix ABX-IL-8 Human è-Interleukin-8 for RA and psoriasis ABX-CBL GVD ABX-EGF Blocks EGF-anticancer Techniclone TNT Malignant glioma Oncolym Non-Hodgkin's lymphoma Coulter Pharmaceuticals Bexxar Mab linked to I-131 bind on mature B-cell; Non-Hodgkin's lymphoma PDL è-CD3 Transplantation. autoimmunediseases M195 Acute myeloid leukemia Ostavir è-hepatitis B Ixys Inc Vitaxin Antibody to a-v b-3 integrin, inhibitis angiogenesis in cancer XTL Biopharmaceuticals XTL001 è-hepatitis B (2 monoclonals) Immunomedics LI2 Mab conjugated with rec-ribonucleases-cancee LymphoCide Mab Y90 conjugate Non-Hodgkins CEA-Cide Mab Y90 conjugate - CAE expressing solid tumours Xoma/Genentech Hu1124 è-CD11 psoriasis Medarex MDX-CD4 è-CD4 autoimmune diseases Medarex/Centeon MDX-33 Down regulation of effector cells -idiopathic thrombocithopenia purpura Medarex MDX-44 MDX-33 Ricin A conjugate - psoriasis CAT-BASF D2E7 è-TNFè - RA IDEC-SKB IDEC-151/ BB-217969 RA Genentech/Novartis E25 è-IgE - allergy Celltech CDP 870 RA Celltech/Schering Plough CDP 835 Severe asthma Celltech Norasept Crohn's disease CAT è-TGFß Proliferative vitreo retinopathy IDEC Y2B8 Lymphoma's     Occasional disappointing clinical trials Occasionally, the clinical trials with the 'new generation' monoclonal antibodies give disappointing results. Often, these are caused by insufficient characterization of the product and its performance in vitro, inadequate preclinical testing or unrealistic expectations of clinical performance, leading to inadequately designed clinical trials. In particular patient populations should be better subdivided.   Monoclonals approved for therapeutic use In total, since 1986, 9 mab's have been approved for therapeutic use. The table below gives a listing. Approved monoclonal antibodies for therapeutic use Trade name Company Target Source Year Indication Orthoclone J&J CD-3 all rodent 1986 transplantation rejection Panorex Glaxo Wellcome EGP-2 all rodent 1994 colon carcinoma ReoPro Centocor/Lilly GPIIb, IIIa chimeric 1994 High risk angioplasty Rituxan IDEC/Genentech CD20 chimeric 1994 Non-Hodgkin's lymphoma Remicade TNF-è chimeric 1998 Crohn's disease Simulect Novartis CD25 chimeric 1998 Transplantation rejection Synagis Medimmune RSV F Protein humanized 1998 RSV infection Zenapax PDL/Roche CD25 humanized 1997 Transplantation rejection Herceptin Genentech HER-2 humanized 1998 Breast cancer   Sales improving The sales prospects of these approved mab's are good, ranging between 120 and 1300 million USD for 1999: Product 1998 (million USD) 1999 (million USD) Remicade 27.5 1302 ReoPro 360 445 Rituxan 52.1 245 Herceptin 30.5 120 Synagis 109.7 228.3   Foundation for optimism Currently, there is a much better climate for the development of monoclonal antibodies. This has been brought about by:   the availability of human(ized) mab's; demonstrable financial success; more experience in the selection of good targets; improvements in manufacturing (cheaper, larger scale); well established registration procedures; decreasing success rate for other biotech projects, such as cytokines.
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