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Monoclonal Antibodies Show Promise As Effective HIV Therapy

Preclinical study provides strong basis for clinical trials in humans

BOSTON – A research team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) has demonstrated that a group of recently discovered antibodies may be a highly effective therapy for the treatment of HIV. Published on-line today in the journal Nature, the findings encourage the development of these monoclonal antibodies as a novel therapy in humans.

“Our data demonstrate, for the first time, profound therapeutic efficacy of broad and potent HIV-specific monoclonal antibodies in rhesus monkeys chronically infected with a highly pathogenic simian-human immunodeficiency virus,” said the study’s lead author Dan H. Barouch, MD, PhD, Director of the Center for Virology and Vaccine Research at BIDMC, Director of the Vaccine Program at the Ragon Institute of MGH, MIT, and Harvard, and Professor of Medicine at Harvard Medical School. Simian-human immunodeficiency virus is a monkey version of HIV.

Antibodies work through a mechanism that is distinct from that of traditional antiretroviral therapies, which are the standard treatment for HIV.

“Antibodies directly target free virus as well as virally infected cells, whereas existing antiretroviral drugs only inhibit the replicating virus,” explains Barouch. “Antibodies may, therefore, offer a unique therapeutic strategy that could potentially be combined with antiretroviral drugs.”

Although highly effective in the majority of patients, current antiretroviral therapies are limited by toxicities and resistance, and are unable to cure HIV infection.

Barouch and his colleagues administered a cocktail of HIV-specific monoclonal antibodies or single monoclonal antibodies into rhesus monkeys chronically infected with simian-human immunodeficiency virus.

“The antibody treatments resulted in a rapid and precipitous decline of virus in both blood and tissues of the infected monkeys,” notes Barouch. Following a single antibody infusion, viral loads dropped sharply to undetectable levels in three to seven days, and cell-associated virus levels were also reduced in the blood, lymph nodes and the gut. Moreover, antibody infusions significantly boosted the monkeys’ own immune responses against the virus, which appeared to have long-term benefit.

“In most cases, the virus rebounded when antibody titers declined after a median of 56 days, but, remarkably, the subset of animals with the lowest starting levels of virus maintained undetectable viral loads for the duration of the study, in the absence of further antibody infusions,” adds Barouch.

“These data strongly encourage the development of monoclonal antibodies as a novel therapy for HIV in humans,” he notes. “Monoclonal antibodies in conjunction with antiretroviral drugs can be explored for treatment intensification, pre- and post-exposure prophylaxis, and virus eradication strategies for HIV in humans.”

Senior collaborating investigators of this study are Dennis Burton, PhD, of the Scripps Research Institute and Michel Nussenzweig, MD, PhD, of The Rockefeller University. Other coauthors include BIDMC investigators James B. Whitney, Jinyan Liu, Kathryn E. Stephenson, Hui-Wen Chang, Joseph P. Nkolola, Michael S. Seaman, Kaitlin M. Smith, Erica N. Borducchi, Crystal Cabral, Jeffrey Y. Smith, Stephen Blackmore, Srisowmya Sanisetty and James R. Perry, as well as investigators from the New England Primate Research Center, Alpha Genesis, Inc., and Bioqual, Inc.

Support for this work was provided by grants from the National Institutes of Health (AI055332; AI060364; AI078526; AI084794; AI095985; AI096040; AI10063; AI100148, AI100663); the Bill and Melinda Gates Foundation; the Ragon Institute of MGH, MIT, and Harvard; the Lundbeck Foundation; and the Stavros Niarchos Foundation.

Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and currently ranks third in National Institutes of Health funding among independent hospitals nationwide.

 
BIDMC has a network of community partners that includes Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, Signature Health Care, Commonwealth Hematology-Oncology, Beth Israel Deaconess HealthCare, Community Care Alliance, and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Senior Life and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.org.