AEGiS-15IAC: In vivo control of HIV-1 replication with PRO 140, a humanized monoclonal antibody to CCR5.

15th International AIDS Conference

Bangkok, Thailand - July 11-16, 2004

In vivo control of HIV-1 replication with PRO 140, a humanized monoclonal antibody to CCR5.

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. WeOrA1230)

Franti M, Ramos L, Maloveste S, Geerdes D, Nagashima KA, Ketas TJ, Delgado K, Maddon PJ, Olson WC, Poignard P
Progenics Pharmaceuticals, Inc., Tarrytown NY, United States

BACKGROUND: The CC-chemokine receptor CCR5 serves as requisite fusion coreceptor for primary HIV-1 isolates. The potential merits of CCR5-targeted therapy have been demonstrated in a host of in vitro studies, molecular epidemiological studies and early-stage human clinical trials. PRO 140 is a novel anti-CCR5 monoclonal antibody that has been humanized and developed for HIV-1 therapy. In this study, PRO 140 was examined for its ability to treat an established infection in a well-recognized small-animal model of HIV-1 infection.

METHODS: CB-17 severe combined immunodeficiency (SCID) mice were reconstituted with peripheral blood mononuclear cells from a CCR5 wild-type donor and infected with the primary R5 isolate JR-CSF. When viral steady state was reached, the animals were treated in groups of 5 for 8 days with 1mg intraperitoneal doses PRO 140 and monitored for viral burden using quantitative RT-PCR. Post-treatment viruses were isolated and examined for susceptibility to PRO 140.

RESULTS: PRO 140 reduced the median viral loads in the animals from 2.1x10[4] copies/mL to undetectable levels (<400 copies/mL) at 6 and 12 days post-treatment. This 1.7log₁₀ reduction in viral load was statistically significant (P< 0.01, 2-sided), and we observed no evidence of the emergence of drug-resistant variants. In contrast, viral loads increased by 0.2 log₁₀ in untreated control animals over the same period. In separate studies, the pharmacokinetics of PRO 140 in SCID mice compared favorably with that of a human isotype-control antibody.

CONCLUSIONS: Humanized PRO 140 effectively controlled an established HIV-1 infection in vivo. The findings provide strong support and guidance for advancing this novel agent into human clinical testing, and the first such study is planned for 2004.

Keywords: AEGIS, Receptors, CCR5, Anti-HIV Agents, HIV-1, Virus Replication, Viral Load, HIV Infections, Antibodies, Monoclonal, Receptors, Chemokine, Mice, SCID, Epidemiologic Studies, PRO 140, Mice, Animal, Humans, In Vitro, virology, immunology

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