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Antimicrob. Agents Chemother. doi:10.1128/AAC.00942-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Safety, Pharmacokinetics, and Antiretroviral Activity of Multiple Doses of Ibalizumab (formerly TNX-355), an Anti-CD4 Monoclonal Antibody, in HIV-1 Infected Adults

Drexel University College of Medicine, Philadelphia, Pennsylvania, Brigham & Women's Hospital and Harvard University School of Medicine, Boston, Massachusetts, Bach & Godofsky, Bradenton, Florida; IDC Research Initiative, Altamonte Springs, Florida; Tanox, Inc., Houston, Texas; TaiMed Biologics, Inc., Bellaire, Texas; University of Texas Medical School-Houston, Houston, Texas

^* To whom correspondence should be addressed. Email: jeffrey.jacobson{at}drexelmed.edu.

	Abstract

Ibalizumab (formerly TNX-355) is a humanized monoclonal antibody that binds CD4, the primary receptor for HIV-1, and inhibits the viral entry process. A phase lb multi-dose study of the safety, pharmacokinetics, and antiviral activity of ibalizumab was conducted in 22 HIV-1 infected patients. Nineteen patients were randomized to receive either 10 mg/kg weekly (Arm A) or a 10 mg/kg loading dose followed by 6 mg/kg every 2 weeks (Arm B) intravenously for nine weeks. Three patients were assigned to receive 25 mg/kg every 2 weeks for five doses (Arm C). During the study, patients remained off other antiretrovirals or continued a stable failing regimen. Treatment with ibalizumab resulted in substantial reductions inHIV-1 RNA levels (0.5-1.7 log₁₀) in 20 of 22 subjects. In most patients, HIV-1 RNA fell to nadir levels after one to two weeks of treatment, and then returned toward baseline despite continued treatment. Baseline viral isolates were susceptible to ibalizumab in vitro, regardless of coreceptor tropism. Emerging resistance to ibalizumab was manifested by reduced maximal percent inhibition in a single cycle HIV infectivity assay. Resistant isolates remained CD4-dependent and were susceptible to enfuvirtide in vitro. Complete coating of CD4⁺ T-cell receptors correlated with ibalizumab serum concentrations. There was no evidence of CD4⁺ T-cell depletion in ibalizumab-treated patients. Ibalizumab was not immunogenic, and no serious drug-related adverse effects occurred. In conclusion, ibalizumab administered either weekly or bi-weekly was safe, well tolerated, and demonstrated antiviral activity. Further studies with ibalizumab in combination with standard antiretroviral treatments are warranted.