The development of safe and effective passive immunotherapies for the treatment and prevention of HIV-1 infection is a major goal. The leading candidate immunotherapeutics include the broadly neutralizing human monoclonal antibodies (HuMAbs) IgG1b12, to the CD4-binding site on gp120, 2F5 to a conserved epitope on gp41, and 2g12 to a discontinuous region on gp120. In addition, CD4-IgG2 exhibits potent and broad neutralization of HIV-1, including primary isolates. It is a third generation CD4- based molecule containing two chains of a CD4-human IgG2 heavy chain fusion protein and two chains of a CD4-human kappa light chain fusion protein. While IgG1b12, 2F5, 2G12 and CD4-IgG2 exhibit significant neutralization activity as single agents, the development of an effective passive immunotherapy may require the use of mixtures of two or more of these agents. In order to evaluate their performance in the clinical setting, we have formed a consortium of the three groups which developed these agents (IgG1b12 - Dr. Dennis Burton; 2F5 and 2G12 - Dr. Hermann Katinger; and, CD4-IgG2 - Drs. Graham Allaway and Paul Maddon) to coordinate and expedite clinical trials of single agents and combinations of agents. The goal of this proposal is to manufacture, prepare Investigational New Drug applications and gain regulatory approval for clinical investigation from the U.S. Food and Drug Administration, and perform clinical trials of the agents to evaluate tolerability, antiviral activity, and pharmacology in HIV-1 infected adults and children. As part of our clinical development program, we have already arranged for certain pilot Phase I clinical trials to be performed with single agents in 1997-98 under the sponsorship of the National Institute of Allergy and Infectious Diseases. Based on their performance in clinical trials as well as in in vitro, ex vivo, and animal studies performed as separate projects at the Aaron Diamond AIDS Research Center and the Scripps Research Institute, we will select an optimum combination of 2, 3, or 4 of the agents for evaluation in Phase I/II clinical trials in HIV-1 infected adults and children. If successful, then subsequent to this proposal, the optimum combination would be taken to large-scale, pivotal clinical trials in order to gain marketing approval for the product.
