Ho: Engineered Bispecific bNabs for Prevention
The overall aim of this grant is to accelerate the development of a broadly neutralizing antibody (bNab) product for passive immunization against HIV. Passive administration of an HIV-neutralizing monoclonal antibody on an infrequent basis has the potential, like long-acting anti-retrovirals (ARVs), to fill a critical gap between now and the launch of an effective, active vaccine against HIV.
The key obstacle for development of bNabs for HIV prevention has been the discovery of an antibody that possesses suitable breadth, potency, and pharmacokinetics (PK). Through work funded in part by the foundation, Dr. David D. Ho of the Aaron Diamond AIDS Research Center (ADARC) is developing a lead HIV-neutralizing monoclonal antibody (mAb) named ibalizumab, a humanized mouse monoclonal antibody that binds to the CD4 receptor that HIV needs for entry into target cells, for passive immunization against HIV. Though this mAb is currently moving through a Phase 1 and 2a safety and PK clinical study, next generation molecules that could achieve greater potency and breadth would provide a more practical, low cost product generally more feasible for most of the countries hit hardest by HIV/AIDS.
This grant to Dr. Ho seeks to capture promising new results based on bispecific antibodies. Bispecific antibodies targeting both an epitope on HIV and the CD4 receptor on HIV's target cells can have a 100-fold increase in potency and increased breadth of coverage, over either antibody alone or the combination, in laboratory studies. If fully developed, such next generation engineered bNabs would meet the requirements for the low cost products for populations in developing countries.
1. Develop a lead bispecific antibody-like molecule with much enhanced anti-HIV breadth and potency that could be administered on a bimonthly basis
2. Assess the “developability” of the best candidate bispecific antibodies and advance one lead molecule into clinical development
3. Express a bispecific antibody in vivo by gene transfer using mini-circle DNA delivered into muscle via electroporation
The Ho research consortium has generated a library of over 100 bispecific and next-generation antibodies that block HIV infection. Among these, a handful of constructs with superior potency and breadth against HIV as compared to traditional monoclonal antibodies have been identified. In collaboration with Dr. Michael Seaman at the Beth Israel Deaconess Medical Center, part of the Montefiore Antibody Vaccine Immune Monitoring Consortium (Ab VIMC), top candidates were tested for their neutralization activity against a large panel of HIV isolates. Several constructs demonstrated near 100% breadth (as measured by >80% neutralization) against the panel. One construct, PG9-iMab, a bispecific antibody with the scFv of PG9 fused to the N-terminus of ibalizumab heavy chain, demonstrated a breadth of 100%, as well as a significant increase in potency (> 200-fold by IC90) against the panel of HIV isolates. A second construct known as LM52, developed by structure-guided introduction of glycan variants into ibalizumab over a defined set of residues near the CD4-gp120 interaction site, also demonstrated a breadth of 100% with 5-fold greater potency than ibalizumab. The Ho consortium continues to systematically create an array of bispecific antibody constructs that target different combinations of HIV epitopes in order to further characterize the mechanistic basis of enhanced potency of certain bispecific and next-generation antibody constructs. In collaboration with Sino Biological, Inc., the Ho consortium is also characterizing the developability of top candidates by optimizing upstream and downstream development processes through the investigation of protein expression yields, aggregation profiles, and stability at high concentrations using a matrix of production, purification and formulation conditions. In parallel to these activities, the Ho consortium is also developing an antibody gene-transfer method to deliver DNA encoding for potent bispecific antibodies by electroporation. Our ultimate goal is to create a novel bispecific antibody-like molecule that has dramatically improved anti-HIV breadth and potency as well as a pharmacokinetic profile suitable for bimonthly administration to humans.