Nussenzweig: Discovery & Characterization of bNAbs
An effective vaccine against HIV remains elusive and AIDS continues to be a major source of morbidity and mortality worldwide. The failure of many HIV vaccine products has elevated the importance of pursuing an alternative form of prevention, namely the concept of using anti-HIV monoclonal antibodies as a passive form of prevention. Recent studies in macaques have shown that antibodies can prevent HIV infection. Moreover, a significant fraction of HIV infected individuals develop serum antibodies that neutralize a broad spectrum of viruses even at low concentration. Until two years ago, only a very small number of such antibodies had been characterized and the most potent of these, b12, was not a naturally occurring product.
The consortium assembled and led by Dr. Michel Nussensweig seeks to push the passive prevention avenue forward by discovering and characterizing additional neutralizing antibodies. They plan on accomplishing this by building upon techniques developed by Dr. Nussensweig for the cloning of anti-HIV human antibodies from single cells. Dr. Chris Love at MIT has developed methods for high throughput antibody cloning that can be adapted to anti-HIV antibodies produced by plasma cells which may address the scalability issues.
An additional step for the development of broadly neutralizing antibodies for passive prevention will be the optimization of
in vivo effector functions such as antibody dependent cytotoxicity or antibody dependent anti-viral activity. Dr. Jeffrey Ravetch at Rockefeller University discovered and characterized the Fc receptors responsible for antibody effector function and developed methods to optimize antibody effector function
Drs. Nussenzweig, Love and Ravetch propose to use their complementary skill sets to collaborate on discovering a pipeline of new bNAbs against HIV. The bNAbs will provide potential reagents that might be translated into passive immunization products and may inform HIV vaccine design and clinical trials.
1. Isolate broadly neutralizing antibodies from the memory cells and plasma cells from a large group of patients with high titers of serum neutralizing activity,
2. Engineer a scalable, highly cost-effective platform to rapidly identify natural human MAbs capable of neutralizing HIV-1,
3. Determine the optimal Fc effector function in novel in vitro and in vivo systems and combine broadly neutralizing antibodies with optimal Fc function and validate their efficacy in relevant in vivo systems and
4. Select clones for manufacturing antibodies for preclinical and clinical trials.