Humanized PRO 140 for CCR5-Targeted Therapy of HIV

DESCRIPTION (provided by applicant): A major goal of HIV-1 research is the development of a new generation of antiretroviral agents that target novel stages of the viral replicative cycle. New agents are needed both to combat the growing incidence of HIV-1 strains that are broadly resistant to existing medications and to reduce the considerable toxicities associated with current therapies. HIV- 1 entry comprises a cascade of sequential events that provide attractive targets for new therapies. The chemokine receptor CCR5 serves as a critical portal of HIV-1 entry by acting as a fusion coreceptor in conjunction with CD4, the primary receptor for HIV-1. CCR5 plays a central role in virus transmission and pathogenesis, but is dispensable for human health. Accordingly, CCR5-targeted therapies represent a promising new treatment modality. PRO 140 (PA14) is a unique monoclonal antibody (mAb) to CCR5. The Phase I project demonstrated that PRO 140 broadly, potently, and durably suppresses HIV-1 replication both in vitro and in vivo. Moreover, unlike other candidate CCR5 inhibitors, PRO 140 does not block CCR5's natural activity, suggesting that this agent may be exceptionally well tolerated. Because of this compelling therapeutic profile, the murine PRO 140 antibody was successfully humanized to enable repeat dosing in man. The overall goals of the Phase II project are to explore the therapeutic potential of humanized PRO 140 in the best available preclinical models of HIV-1 infection, and concurrently to advance the molecule into human clinical testing. The preclinical studies will examine the ability of humanized PRO 140 to broadly inhibit genetically diverse and multidrug-resistant HIV-1 isolates in vitro and to control established HIV-1 infection in vivo. Additional studies will explore the antibody's interaction with the immune system. The project also encompasses essential product development activities that culminate in the first-in-man clinical trial of this innovative new agent. Success in the preclinical studies will be achieved by demonstrating that humanized PRO 140 both reproduces the compelling therapeutic profile of the parent mouse mAb and possesses superior pharmacology. Successful clinical outcomes are defined as favorable tolerability, pharmacology, and antiviral profiles in man. Favorable clinical outcomes would warrant expanded human trials designed to establish safe and effective dosing regimens, and ultimately to support FDA licensure of this new mode of therapy. Accordingly, this project will provide important milestones in development of a new class of viral entry inhibitors that target HIV-1 fusion coreceptors.