Ho Ibalizumab Development Consortium
OVERVIEW:
This projects involves administering a monoclonal antibody (mAb) capable of blocking HIV infection. Ibalizumab is a humanized mAb that binds to the CD4 molecule, the primary receptor for HIV infection, thereby interfering with the penetration of the virus into the cell. It is the first entry-blocking humanized mAb to be tested in clinical trials as treatment for HIV/AIDS. Administration of ibalizumab to SIV-infected rhesus macaques resulted in a greater than 1-log decrease in viral load without adversely affecting CD4 T-cell count or CD4-dependent immune functions. The U.S. FDA granted ibalizumab fast-track status in October 2003. In Phase Ib and Phase IIa clinical trials, multiple doses of ibalizumab given intravenously decreased viral load by ~1 log in HIV-infected volunteers, and no evidence of adverse effects on CD4 T-cells was noted. The Phase IIb clinical trial in 120 HIV-infected subjects is now well underway. These results demonstrate that ibalizumab is safe and active against HIV in humans, although it has yet to be administered to seronegative healthy volunteers. The objective of this proposal is to assess the potential use of ibalizumab in HIV prevention.
RESEARCH OBJECTIVES:
Under Dr. Ho's direction, the researchers will undertake the preclinical and clinical development necessary in the coming two years to aggressively advance this effort and to establish the proof of concept of using ibalizumab for HIV prevention. Specifically, the researchers will:
- Thoroughly evaluate and analyze the HIV-blocking activity of ibalizumab in vitro as well as look for potential interference with MHC class-II function
- Examine the effectiveness of ibalizumab in protecting rhesus monkeys from SIV challenge given by the intravenous or intra-rectal route
- Ascertain the safety and tolerability of ibalizumab in healthy human volunteers in a Phase I clinical trial
- Explore the feasibility of applying an antibody gene-transfer approach to express a rhesus variant of ibalizumab in vivo (monkeys) using a recombinant adeno-associated virus vector (rAAV)