Antiviral Activity of Single-Dose PRO 140, a CCR5 Monoclonal Antibody, in HIV-Infected Adults

• Published in: The Journal of infectious diseases 2008-11, Vol.198 (9), p.1345-1352
• Main Authors: Jacobson, Jeffrey M., Saag, Michael S., Thompson, Melanie A., Fischl, Margaret A., Liporace, Ralph, Reichman, Richard C., Redfield, Robert R., Fichtenbaum, Carl J., Zingman, Barry S., Patel, Mahesh C., Murga, Jose D., Pemrick, Suzanne M., D'Ambrosio, Paul, Michael, Marti, Kroger, Hans, Ly, Hieu, Rotshteyn, Yakov, Buice, Robert, Morris, Stephen A., Stavola, Joseph J., Maddon, Paul J., Kremer, Alton B., Olson, William C.
• Format: Article
• Language: English
• Subjects: AIDS; Anti-HIV Agents - blood; Anti-HIV Agents - pharmacology; Antibodies, Monoclonal - blood; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; Antivirals; Applied microbiology; Area Under Curve; Biological and medical sciences; Dosage; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance, Viral; Female; Fundamental and applied biological sciences. Psychology; HIV 1; HIV Antibodies - blood; HIV Antibodies - pharmacology; HIV Infections - drug therapy; HIV-1 - drug effects; HIV/AIDS; Human immunodeficiency virus 1; Human viral diseases; Humans; Infectious diseases; Lymphocyte Count; Lymphocytes; Lymphocytes - immunology; Male; Medical sciences; Microbiology; Monoclonal antibodies; Placebos; Receptors, CCR5; RNA; RNA, Viral - blood; Time Factors; Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies (general aspects); Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Viral load; Viruses
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/592169

Background. The current goal of human immunodeficiency virus type 1 (HIV-1) therapy is to maximally suppress viral replication. Securing this goal requires new drugs and treatment classes. The chemokine receptor CCR5 provides an entry portal for HIV-1, and PRO 140 is a humanized monoclonal antibody that binds to CCR5 and potently inhibits CCR5-tropic (R5) HIV-1 in vitro. Methods. A randomized, double-blind, placebo-controlled, dose-escalating study was conducted in 39 individuals with HIV-1 RNA levels ⩾5000 copies/mL, CD4+ cell counts ⩾250 cells/µL, no antiretroviral therapy for 3 months, and only R5 HIV-1 detectable. Cohorts were randomized 3:10 to receive placebo or doses of PRO 140 of 0.5, 2, or 5 mg/kg. Subjects were monitored for 58 days for safety, antiviral effects, and serum concentrations of PRO 140. Results. PRO 140 was generally well tolerated and demonstrated potent, rapid, prolonged, and dose-dependent antiviral activity. Mean reductions in HIV-1RNAlevel of 0.58 log10, 1.20 log10 (P = .0002) and 1.83 log10 (P < .0001) were observed for the 0.5-, 2-, and 5-mg/kg dose groups, respectively. Reductions in mean viral load of ⩾10-fold were observed within 4 days and persisted for 2–3 weeks after treatment. Conclusions. This trial established clear proof of concept for PRO 140 as a potent antiretroviral agent with extended activity after a single dose. Trial registration. ISRCTN Register: ISRCTN45537485.