Annual and Interim Progress Report Summaries
Principal Investigator: David Ho
Project: Ibalizumab Development Consortium
Submitted July 31, 2012
Ibalizumab is a humanized mAb with high affinity (~100pM) for human and rhesus CD4. It blocks HIV entry after binding to a region in domain-2 of CD4 that is opposite from the site in domain-1 crucial for MHC class-II binding. Ibalizumab is currently under development as a therapeutic agent and has been tested in phase 1a, 1b, 2a, and 2b studies in infected patients in need of salvage therapy. Through the CAVD, our group is developing ibalizumab as a HIV prevention agent for passive immunization.
In collaboration with Dr. Michael Seaman at the Beth Israel Deaconess Medical Center, part of the Montefiore Antibody Vaccine Immune Monitoring Consortium (Ab VIMC), we previously reported the exquisite potency and breadth of ibalizumab against a diverse panel of 116 Env-pseudotyped viruses selected to represent envelope diversity by geography, clade, tropism, and stage of infection, including thirty transmitted/founder viruses. During this reporting period, we commenced a Phase 1 clinical trial to evaluate the safety and pharmacokinetics of ibalizumab in healthy, at-risk for HIV infection volunteers in collaboration with TaiMed Biologics. All subjects completed dosing and are now in follow-up with no injection site reactogenicities or SAEs observed to date.
In collaboration with the Tulane National Primate Research Center (TNPRC), we are constructing novel rhesus variants of ibalizumab and evaluating their pharmacokinetic and immunogenic properties in vivo in preparation for an in vivo challenge study. In parallel, we are developing novel gene-transfer constructs expressing ibalizumab in collaboration with Dr. Phil Johnson’s group at the Children’s Hospital of Philadelphia using recombinant adeno-associated virus vector (rAAV). We have generated several rhesus ibalizumab constructs and identified top candidates that express high levels of functional antibody in mice. Once an optimal rhesus ibalizumab variant is identified, we will proceed with rhesus ibalizumab-AAV manufacture and evaluation in non-human primates.