Treatment and Prevention of HIV-1 Infection by Highly Potent Neutralizing Monoclonal Antibodies
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Treatment and Prevention of HIV-1 Infection by Highly Potent Neutralizing Monoclonal Antibodies

Team Representative:
Marina Caskey, MD
Associate Professor of Clinical Investigation, The Rockefeller University
Phone: 212-327-7396

Media Contact:
Franklin Hoke
Phone: 212-327-8998

Summary of findings in layman's terms:

Over the last several years, a new generation of HIV neutralizing antibodies has been discovered. These antibodies occur naturally in individuals who are HIV positive. The scientists used genetic sequences from the antibodies from these participants to make the synthetic antibody that has been tested in this study. This antibody is highly potent and able to effectively prevent infection of cells by a large number of different HIV strains from all over the world. Therefore, it might play an important role in the quest for treatment of HIV infection. The knowledge gained about the antibodies may also help in the development of an HIV vaccine.

This paper describes a first in human clinical trial that investigates this approach. The broadly neutralizing antibody 10-1074 targets a specific structure on the surface of the HIV virus. In the study, the investigators, led by Dr. Marina Caskey, show that this antibody was well tolerated and the antibody lowered the levels of HIV virus in the circulation of the research participants. The research team was also able to specifically investigate the development of resistant HIV variants. The scientists performed a comprehensive analysis of the genetic sequences of the resistant HIV viruses to investigate the dynamics and mechanisms HIV uses to escape from the antibody. Fortunately, even the resistant viruses appear to be sensitive to other antibodies that could potentially be given in combination. 

Specific biological innovation of study: 

A team of researchers at The Rockefeller University are developing an antibody-based drug that may provide a better strategy for long-term control of HIV infection as well as serve as a model for HIV-1 prevention and vaccine development. This paper describes results from a clinical trial that demonstrates that a single dose of a broadly neutralizing anti-HIV-1 monoclonal antibody is well tolerated and reduces viral load in a cohort of 33 research participants. Thirteen individuals with viremia received the highest dose of 30 mg/kg of 10-1074. Eleven of these participants were 10-1074-sensitive and showed a rapid decline in viremia by a mean of 1.52 log10 copies/ml. Virologic analysis revealed the emergence of multiple independent 10-1074-resistant viruses in the first weeks after infusion. Emerging escape variants were generally resistant to the related V3-specific antibody PGT121, but remained sensitive to antibodies targeting nonoverlapping epitopes, such as the anti-CD4-binding-site antibodies 3BNC117 and VRC01. Thus, combining 10-1074 with one of these antibodies may be especially effective. The results demonstrate the safety and activity of 10-1074 in humans and support the idea that antibodies targeting the V3 glycan supersite might be useful for the treatment and prevention of HIV-1 infection. 

Potential impact on human care and/or how the findings contributed to an improved understanding:

Dr. Caskey and her team describe the first in human, phase 1 clinical trial of a first in class fully human highly neutralizing anti-HIV monoclonal antibody. In addition to demonstrating that this new class of anti-HIV drugs is safe and well tolerated, this new molecule also has a significant anti-viral effect in HIV positive research participants. Following the discovery described in this paper, this class of drug and this test article, 10-1074 is being developed clinically for both prevention and for therapy as part of a cocktail of monoclonal antibodies and/or drugs. 

Until there is an effective HIV-1 vaccine, pre-exposure prophylaxis (PrEP) with anti-retroviral drugs is the standard of care for individuals at high risk. Currently the highly effective anti-retroviral drugs that are used for treatment of HIV-1 are used as PrEP. A fully human, well tolerated monoclonal antibody, if formulated for long duration may be a very attractive alternative to daily PrEP oral treatment for some individuals. Dr. Caskey and her team are planning clinical efficacy trials of this approach. The antibodies for the 2b trials are being manufactured with funding from the Bill and Melinda Gates Foundation. This approach will also elucidate mechanisms of anti-body mediated protection from infection by HIV- that are highly likely to inform vaccine design. 

Journal citation:

Antibody 10-1074 suppresses viremia in HIV-1- infected individuals

Nat Med. 2017 Feb;23(2):185-191. doi:10.1038/nm.4268. Epub 2017 Jan 16