Mascola: BNAbs for Passive Immunization
The overall aim of this proposal is to develop an improved HIV neutralizing antibody that prevents HIV infection in adult and pediatric populations at risk for HIV-1 infection. Advances in the identification of broadly neutralizing antibodies to HIV have raised new opportunities to prevent infection through the administration of antibodies that neutralize diverse strains of the virus. Among these antibodies, an exceptionally broadly neutralizing antibody, VRC01, has been isolated by the Vaccine Research Center, National Institute of Allergy and Infection Diseases, NIH (VRC, NIAID, NIH). VRC01 neutralizes more than 90% of genetically diverse HIV strains by binding to the conserved CD4 binding site of the HIV-1 gp120 envelope. While this antibody is currently advancing into phase I clinical studies in human subjects, with the goal of evaluating its safety and tolerability in the target populations , a solution to the global HIV epidemic relies on improvements in antibody design that increase potency and circulating half-life, while maintaining the high breadth of neutralization. This increase in efficacy would reduce the amount of product and the frequency of dosing required to prevent HIV infection. Additionally, improvements in manufacturing to improve product yield are likely attainable. The cumulative effect of these improvements in potency, half-life and manufacturing efficiency could have a substantial impact on the cost and feasibility of an antibody product to prevent HIV infections.
The Consortium, led by Dr. Gary Nabel at the VRC, NIAID aims to develop second-generation antibody products to test the concept of passive immunization in adults. This antibody will be optimized using several different approaches, including improved FcγIII binding to improve ADCC activity, and modifications to enhance binding to FcRn in order to prolong serum half-life and augment mucosal transport. These modifications are intended to reduce the requirement for product while retaining the ability of the antibody to confer protection against infection by diverse strains. The research performed by Dr. Nabel, his VRC colleagues, and his extramural collaborators at the University of Minnesota and Brigham and Women’s Hospital will potentially prepare for Phase I clinical trial testing of the passive immunization concept of HIV prevention in adult and pediatric populations.
Significant progress has been achieved by this Consortium to optimize VRC01-like antibodies for potency, breadth and in vivo stability. VRC investigators identified VRC07, a clonal relative of VRC01 that is several times more potent. Rational structure-based and bioinformatics design was used to optimize VRC07 neutralization potential, minimize immunogenicity, and increase in vivo half-life. Over 200 VRC07 variants were designed, expressed, and tested, yielding some with more than 10-fold improvements in potency, along with improvements in breadth of viruses neutralized, and longer in-vivo half life. The optimized 2nd generation antibody will be combined with a second antibody to an independent site on the virus, in order to expand breadth of coverage and reduce likelihood of virus escape. The current lead candidate is a complementary antibody derived from the recently described 10E8 mAb that targets the membrane proximal region (MPER) of HIV-1 gp41. Together, these VRC07 and 10E8 derived mAbs neutralize nearly all HIV-1 isolates with high potency.
In work carried out parallel to this Consortium activity, the initial VRC01 antibody is scheduled to enter a phase I clinical trial in early 2013. With the additional Consortium progress described above, the foundation has been laid to initiate manufacturing next generation antibody products in humans.
- Generation of FcγIII binding mutants of VRC01 with increased ADCC activity, compared to wild type VRC01 IgG1
- Generation of FcRn mutants of VRC01 with prolonged half-life compared to wild type VRC01 IgG1
- Generation of combination FcγIII and FcRn mutants of VRC01 with increased ADCC activity and prolonged half-life compared to wild type VRC01 IgG1
- Evolution of improved affinity CD4 binding site (CD4bs) activity
- Conduct transgenic mouse and NHP studies to determine biodistribution and pharmacokinetics, comparison of ADCC, NK, and neutralization activity in vivo and comparative efficacy in NHP SHIV challenges