HIV-1 Therapy with CCR5 mAB PRO 140-Overview

Olson, William

Abstract

There is an urgent need for new HIV-1 therapies targeting different steps of the viral replicative cycle to combat the growing prevalence of multidrug-resistant viruses and to reduce treatment toxicities. We demonstrated that 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, and therefore represents an attractive target for new HIV-1 therapies. PRO 140 is a unique humanized CCR5 monoclonal antibody (mAb) that offers a novel therapeutic profile. Unlike small-molecule CCR5 antagonists under development, PRO 140 broadly and potently inhibits CCR5-mediated HIV-1 entry without blocking or otherwise dysregulating the natural activities of CCR5. In addition, PRO 140 has demonstrated favorable tolerability and pharmacokinetic profiles in an ongoing Phase la clinical trial in healthy volunteers. PRO 140 is clearly differentiated from small molecules in terms of its lack of CCR5 antagonism, non-overlapping patterns of viral resistance, antiviral synergy, excellent tolerability profile, and potential for infrequent (e.g., monthly) dosing. PRO 140 may therefore define a unique CCR5 inhibitor subclass. The highly innovative nature of this therapeutic approach is further underscored by the fact that no CCR5 inhibitor and no mAb to any target have been approved for HIV-1 therapy. The overall goal of this IPCP is to optimally translate PRO 140 from a novel treatment concept into a promising new investigational agent via an integrated series of preclinical and clinical studies. The IPCP comprises three interrelated Projects supported by two administrative and technical Cores to develop, evaluate, and optimize PRO 140. The IPCP encompasses in vitro and ex vivo studies of the viral, host and combinatorial influences on PRO 140 activity and resistance in vitro and in vivo (Project 1), first-in-HIV clinical trials (Project 2), and integrated analyses of viral tropism and susceptibility using cutting-edge technology (Project 3). The Cores provide overall project management as well as scientific, medical, regulatory, manufacturing, quality, bioanalytical, and biometrics support. The IPCP includes distinguished investigators in the fields of viral entry (Drs. Olson, Maddon, Moore, and Petropoulos) and HIV-1 therapy (Drs. Jacobson, Gulick, and Hammer). Success in this IPCP would establish clinical proof-of-concept for PRO 140 as a novel, long acting, and non-toxic treatment strategy for HIV-1 infection and would identify the critical viral and host determinants of effective CCR5- targeted therapy.