Monoclonal antibodies (1)

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Since the 1980s, genetic engineering has enabled the production of proteins of therapeutic interest, such as insulin, growth hormone and anti-haemophilic factors. The controlled production of these products prevents the risks of microbiological contamination inherent in the use of proteins derived from blood donor plasma.

Monoclonal antibody production was invented by G. Köhler and C. Milstein in 1975. This was a spectacular breakthrough, providing defined reagents that could be used to identify and purify all kinds of biological molecules, provided they were antigenic. In medicine, they have become diagnostic and finally therapeutic tools. The principle of their initial production (fusion of immunized B lymphocytes and immortal myeloma B lymphocytes, followed by a selection and cloning process) was recalled. The ability of such antibodies to act through phagocytosis, antibody-dependent cytotoxicity, complement-dependent lysis of target cells, neutralization of target substances and membrane molecule blockade offers a wide range of functions of therapeutic interest, such as cancer cell destruction, immunomodulation or treatment of infectious diseases. From 1975 to the present day, monoclonal antibody production technology has made great strides: the first antibodies, derived from mouse cells, had a short lifespan in humans, limited biological function and, above all, induced an inactivating immune response and the risk of hypersensitivity accidents. This led to the successive development, using DNA engineering techniques, of "human/mouse" hybrid monoclonal antibodies in which only the part of the antibody involved in antigen recognition comes from the murine molecule. This fraction was further reduced in a subsequent generation of so-called humanized antibodies, before antibodies of 100% human origin could be produced, helping to increase therapeutic efficacy and considerably reduce the risk of hypersensitivity accidents to less than 1% of patients treated. It was against this backdrop that the therapeutic use of monoclonal antibodies exploded in the late 1990s. More than 30 antibodies have been granted drug status and are now used in medicine, notably for transplants, the treatment of autoimmune diseases and, more recently, cancer. The case of the anti-TNF antibody(tumor-necrotizing factor, a major inflammation cytokine) is particularly illustrative. Such antibodies represent a "market" worth some $25 billion a year. They were initially developed for the treatment of rheumatoid arthritis (RA), a disabling inflammatory disease that affects 4 out of every 1,000 people. Experimental work in animal models of rheumatoid arthritis has shown that, of all the pro-inflammatory cytokines produced, particularly in the joints, neutralizing TNF with antibodies has a beneficial effect. These results led M. Feldmann and R. Maini's London team to treat patients with severe forms of RA. The results were convincing and led to a series of studies establishing that the injection of anti-TNF antibodies, combined with the classic RA drug methotrexate, has become the reference treatment for RA. By extension, the same type of antibody is used effectively and with "acceptable" toxicity to treat juvenile forms of arthritis, psoriasis, inflammatory bowel disease (Crohn's disease and ulcerative colitis) and other forms of inflammatory rheumatism. By the same token, monoclonal antibody neutralization of other pro-inflammatory cytokines, such as IL1 or IL6, is effective in other inflammatory diseases.

Recent years have seen the emergence of monoclonal antibodies to treat certain forms of cancer. Several strategies are used: destroying tumor cells, blocking their proliferation or vascularization, and promoting the host immune response against cancer. The first strategy has been successfully applied to the treatment of B lymphomas, by targeting a molecule present on the surface of B lymphocytes called CD20. The most spectacular successes in recent years have been achieved by targeting molecules that physiologically inhibit (control the amplitude of) immune responses. In this way, a natural brake on the immune responses of T lymphocytes directed against neo antigens (derived from somatic mutations in cancer cells) has been lifted. Two molecular systems have been targeted: CTLA4 and PD1/PDL1. At the cost of significant - but largely controllable - toxicity, the injection of such antibodies has led to remissions or improvements in hitherto incurable cancers such as metastatic melanoma, refractory forms of Hodgkin lymphoma, non-small-cell lung cancer, kidney or bladder cancer. These antibodies are now part of the therapeutic arsenal for these cancers. Their combined use and the development of new antibodies will undoubtedly further amplify this veritable therapeutic revolution in cancer treatment.

The story of the therapeutic use of monoclonal antibodies does not end there. The genetic engineering of bispecific monoclonal antibodies - artificially combining the recognition of two distinct antigens through the double valence of the antibodies - is generating a promising new type of mode of action (bringing together, for example, immune system cells and tumour cells). What's more, small chemical molecules, synthetic mimics of antibodies, have recently been obtained. These molecules, which are 20 times smaller than antibodies, have little or no immunogenicity, diffuse better than antibodies in tissues and.... their production cost is much lower! Finally, with a view to the therapeutic use of antibodies in the treatment of severe viral infections (AIDS, influenza), it is envisaged to recompose, by combining monoclonal antibodies, a population of polyclonal antibodies targeting several antigens but each with high neutralizing properties. Research along these lines in the treatment of HIV infection, using models of immunodeficient mice "humanized" by the presence of HIV-infected lymphocytes of human origin, appears highly promising.

In this way, a revolutionary technology invented 40 years ago is making a major contribution to the treatment of severe chronic diseases (rheumatology, inflammation, cancer, etc.). Further technological developments should further expand their use... and perhaps their replacement by chemical molecules with equivalent functions!