More than two million people in the U.S. alone are infected with human immunodeficiency virus (HIV) by current estimates. The majority of infected individuals will develop significant clinical manifestations of acquired immunodeficiency syndrome (AIDS) over seven to ten years from seroconversion. The impact of this epidemic on society will be devastating unless means can be developed to halt the spread of the virus and arrest the disease in already exposed individuals. No effective therapy for AIDS and other HIV-causative infections exists, although some promising results in preliminary clinical trials have been reported with 3'- azido-3-deoxythymidine (AZT). Both AZT and 2,3-dideoxycytidine (ddCyd) have shown high antiviral activity against HIV in in vitro assays. We propose to enhance the efficacy of these two antiviral drugs and reduce their systemic toxicity by targeting them to HIV-infected cells using monoclonal antibodies (MAbs) directed toward viral envelope glycoproteins expressed on the surface of these cells. Specifically, we propose (a) to prepare and characterize immunoconjugates of AZT and ddCyd with murine MAbs that are reactive with HIV envelope antigenic detrminants, and (b) to evaluate the MAb-antiviral drug conjugates in vitro for specific binding to HIV-infected cells and internalization, inhibition of HIV replication in T4 and monocyte/macrophage cells, antiviral activity against a panel of HIV isolates, and cellular toxicity. Immunodrug conjugates that have promising in vitro activity against HIV and low cellular toxicity will be evaluated in vivo for pharmacokinetic distribution and toxicity. Screening controls will consist of MAbs, free drugs, and combinations of MAbs and unbound drugs.
