Rapamycin Enhanced Efficiency of Anti-HIV Antibodies

DESCRIPTION (provided by applicant): This document contains proprietary information that Profectus BioSciences requests not be released to persons outside the Government, except for purposes of review and evaluation. Abstract Polyclonal and monoclonal antibody preparations were among the first agents identified that block HIV entry into target cells. Passive transfer experiments in macaque models have affirmed their clinical potential. Unfortunately, clinical trials have demonstrated that they suffer from one of the same challenges as small molecule antivirals - that of the rapid outgrowth of resistant virus. Recently, cell cycle agents such as rapamycin that downregulate the CCR5 receptor, were found to synergize with the entry inhibitor T20, know also as Fuzeon or Enfuvirtide. Preliminary experiments further demonstrate that the addition of rapamycin in vitro prevents the outgrowth of T20 resistant viruses and enhances the susceptibility to T20 of otherwise resistant viruses. We have found that rapamycin also synergizes with scFv M9, a potent neutralizing monoclonal antibody fragment. The objective of this project is to evaluate whether rapamycin can improve the therapeutic potential of monoclonal antibodies (mAbs) that inhibit HIV entry. We propose to pursue this objective by fulfilling the following 3 aims. Aim 1: Identify anti-HIV Env, anti-CD4 and anti-CCR5 antibodies that synergize with rapamycin to inhibit viral growth in human PBMCs; Aim 2: Demonstrate that the addition of rapamycin inhibits the outgrowth of antibody-mediated neutralization resistant viruses in vitro; Aim 3: Demonstrate that the addition of rapamycin can recover antibody-mediated neutralization of the corresponding resistant viruses. Based on the success of this phase I SBIR, a phase II SBIR will evaluate the potential of rapamycin/antiviral mAb coformulations in a primate model as the first step towards developing this approach to treat HIV infection. This document contains proprietary information that Profectus BioSciences requests not be released to persons outside the Government, except for purposes of review and evaluation. Project Narrative Rapamycin (Wyeth, Madison, NJ) is an immunosuppressant drug used in kidney transplantation that downregulates the expression of CCR5, a key receptor for HIV. In vitro, rapamycin enhances the efficacy of antibodies that block HIV entry. We are developing Rapamycin as an anti-HIV drug in conjunction with these antiviral antibodies. The objective of this Phase I SBIR proposal is to identify potential combinations of rapamycin and antiviral antibodies that may have clinical potential.