Ho: Ibalizumab for HIV Prevention
This project 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. Ibalizumab has also been given to 247 HIV-positive individuals in four clinical trials. In Phase 1a, 1b, 2a and 2b trials, ibalizumab given intravenously decreased viral load by ~1 log in HIV-infected volunteers and no drug-related serious adverse events were observed. These results demonstrate that ibalizumab is safe and active against HIV in infected patients. The objective of this Gates-funded program is to assess the potential use of ibalizumab as a HIV prevention agent for passive immunization.
Under Dr. Ho's direction, the researchers will undertake the preclinical and clinical development necessary to advance this effort and to establish the proof of concept of using ibalizumab for HIV prevention. Specifically, the researchers will:
1. Thoroughly evaluate and analyze the HIV-blocking activity of ibalizumab in vitro as well as look for potential interference with MHC class-II function
2. Examine the effectiveness of ibalizumab in protecting rhesus monkeys from SIV challenge given by the intravenous or intra-rectal route
3. Ascertain the safety and tolerability of ibalizumab in healthy human volunteers in Phase 1 and 2 clinical trials
4. 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)
The Ho research consortium characterized the ibalizumab epitope by extensive mutagenesis studies and identified key residues at the interface of domains 1 and 2 of the CD4 molecule important for the ibalizumab-CD4 interaction. To assess the potency and breadth of ibalizumab, they tested its ability to neutralize infection by a diverse panel of HIV-1 isolates in collaboration with Dr. Michael Seaman at the Beth Israel Deaconess Medical Center, part of the Montefiore Antibody Vaccine Immune Monitoring Consortium (Ab VIMC). Of the one hundred-sixteen Env-pseudotyped viruses tested, ibalizumab demonstrated potent neutralization against almost all viruses at nanomolar concentrations and exhibited extremely broad neutralization irrespective of envelope diversity by geography, clade, tropism, and stage of infection, including transmitted/founder viruses.
In collaboration with TaiMed Biologics, the researchers are testing the feasibility of using a newly developed subcutaneous (SC) formulation of ibalizumab, which has the potential to improve the feasibility of large scale drug administration over the currently available intravenous (IV) formulation. They are completing a Phase 1 dose escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of subcutaneously administered ibalizumab in HIV-negative volunteers. To date, no injection site reactogenicities or serious adverse events have been observed. A target dose range for further clinical evaluation is currently under determination.
In collaboration with the Tulane National Primate Research Center (TNPRC), researchers 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, novel gene-transfer constructs expressing ibalizumab have been developed in collaboration with Dr. Phil Johnson's group at the Children's Hospital of Philadelphia using recombinant adeno-associated virus vector (rAAV). Several ibalizumab-AAV constructs have been generated and top candidates that express high levels of functional antibody in mice were identified. Once an optimal rhesus ibalizumab variant is selected, the researchers will proceed with rhesus ibalizumab-AAV manufacture and evaluation in non-human primates.