TOXICITY AND SAFETY STUDY OF DB4C7 ANTIBODY IN BABOONS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Previously, we have made a mouse monoclonal antibody, B4, specific against HIV receptor on CD4-positive T-lymphocytes. Injection ofB4 antibody into chimpanzees before challenge with a HIV-1 isolate prevented infection; in a second study, injection of B4 antibody in previously infected chimpanzees immediately dropped the HIV-1 leve1s in plasma to near baseline when compared to viremic animals without antibody treatment. HIV-1 is the retrovirus that causes AIDS (Acquired Immunodeficiency Syndrome) in humans. Since multiple administrations of the mouse B4 antibody is contraindicated for treatment of patients with AIDS, we have humanized thus antibody (dB4C7) to make it less antigenic/allergeric, and therefore safe as a immunotherapeutic agent for treatment of HIV infection in humans. Now, we need to show before dB4C7 antibody is used in human clinical trials, that the antibody (l) does not cause adverse reactions upon infusion into baboons and (2) does not adversely affect the normal function of CD4+ subset of T-Iymphocytes due to its anticipated binding to the HlV receptor binding site. These are safety criteria for the FDA-defined lND-enabling toxicology study of an immunotherapeutic antibody. The proposed study has two specific objectives as described in Part N. Study Plan A will assess the pharmacokinetics and safety over a 30 day period. Study Plan B will consist of a repeat dose GLP-complaint toxicology study involving 8 doses of antibody administered at weekly intervals. Overall this study will assess safety, tolerability and immunotoxicity of the dB4C7 antibody in baboons. We anticipate that dB4C7 antibody will be safe and well tolerated and it will provide an immunotherapy option for individuals with HN infection either alone or in combination with drugs (targeting the virus) or other HIV entry inhibitor drugs (targeting for virus receptor) or for patients infected with multiple' drug resistant HIV.