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Human monoclonal antibodies against viruses and cancer

par Webmaster - 2 novembre 2007

Orateur :

Dimiter S. Dimitrov, Protein Interaction Group, Center for Cancer Research, National Cancer Institute at Frederick, MD, USA

Salle :

C023 (RDC LR6 côté CECAM)

Sujet :

Sixty million people have been infected with HIV of whom twenty million have died. Emerging and biodefense-related viruses with SARS coronavirus as a recent example exert enormous psychological, health and economic impact ; in the past hundreds of millions have died from small pox. Cancer kills even more. The major goal of my group is to develop human monoclonal antibodies (hmAbs) and antibody-guided nanoparticles for prevention, diagnosis and treatment of viral diseases and cancer. We identify such antibodies, study their mechanisms of interactions with antigens and nanoparticles, and apply the knowledge gained to medicine. HmAbs are effective weapons of low or lacking toxicity and immunogenicuty because they have evolved to fight diseases in human bodies. The antibodies can be used not only for therapy but also for prophylaxis and diagnosis. The structures forming their epitopes may have potential as vaccine immunogens and targets for inhibitors. To further increase their efficacy they can be engineered to smaller fragments as Fabs and scFvs. We use our antibodies and antibody-guided nanoparticles to attack a fundamental problem - the ability of viruses and cancer cells to undergo genetic and epigenetic alterations creating heterogeneity, which decreases the efficacy of treatment and may result in the development of resistance to any drug including antibody-based therapeutics. Possible solutions of this fundamental problem include identification of conserved targets, improvement of neutralizing activity, and hitting multiple targets that would affect large subpopulations of heterogeneous pools and decrease the probability of development of escape mutants. An ultimate solution of this problem, especially for chronic diseases as HIV and cancer, is the development of highly potent antibody-based therapeutics against multiple conserved targets.

To identify such antibodies we have used perhaps the most powerful technology available today based on phage display. By using phage display and various viral and cancer-related proteins as antigens for screening of antibody libraries we have identified a number of potent hmAbs against HIV, Hendra and Nipah viruses, SARS-CoV, components of the IGF systems, and other proteins. Some of these antibodies have been extensively characterized - their crystal structures in free and antigen-bound state were solved and they exhibited high activity in vitro and in animal models. I will describe these antibodies and our current efforts to use them for the development of therapeutics and vaccines which hopefully could save lives.

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