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HIV:抗体治疗的希望
时间:2015-05-18 12:14来源:地坛也云感染论坛阅读:3360 次

Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117

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HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned1, 2, 3. However, recently developed single-cell-based antibody cloning methods have uncovered a new generation of far more potent broadly neutralizing antibodies to HIV-1 (refs 4, 5). These antibodies can prevent infection and suppress viraemia in humanized mice and nonhuman primates, but their potential for human HIV-1 immunotherapy has not been evaluated6, 7, 8, 9, 10.

Here we report the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody11, in uninfected and HIV-1-infected individuals. 3BNC117 infusion was well tolerated and demonstrated favourable pharmacokinetics. A single 30 mg kg−1 infusion of 3BNC117 reduced the viral load in HIV-1-infected individuals by 0.8–2.5 log10 and viraemia remained significantly reduced for 28 days. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days. We conclude that, as a single agent, 3BNC117 is safe and effective in reducing HIV-1 viraemia, and that immunotherapy should be explored as a new modality for HIV-1 prevention, therapy and cure.

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"What's special about these antibodies is that they have activity against over 80 percent of HIV strains and they are extremely potent," Marina Caskey, assistant professor of clinical investigation at Rockefeller University in New York City and co-first author of the study, said in a press release.

Results of immunotherapy using first-generation monoclonal antibodies were disappointing in preclinical and early clinical trials against HIV. The more potent bNAbs bind several types of antigens on the viral envelope and have been discovered in 10% to 30% of patients who have been infected with HIV-1 for a few years. Although usually ineffective in the patients in whom they originate, because the virus has had time to evolve, these antibodies can be isolated, amplified, and administered to patients in early stages of HIV infection, a method that has shown promise in humanized mice and macaques.

In an open-label, dose-escalation phase 1 study, Dr Caskey and colleagues tested passive antibody-mediated immunotherapy in humans using 3BNC117, a bNAb that targets the CD4 binding site and is active against 195 of 237 HIV strains.

Twelve uninfected and 17 HIV-1-infected individuals matched for age, race, and sex received a single intravenous dose of 1, 3, 10, or 30 mg/kg 3BNC117. The investigators monitored serum concentrations, plasma HIV-1 viral load, CD41 and CD81 T-cell counts, and safety for 56 days.

The eight infected individuals who received the highest dose had up to 300-fold decreases in viral load, many within a week. "[T]he drop in viraemia was highly significant from days 4 through 28," the researchers write. In four of these patients, viral load remained below starting levels by the end of the 8-week study period, and resistance to 3BNC117 did not arise.

The investigators conclude that although 3BNC117 will likely become part of combination therapy, repeat treatments may only be needed every few months, in contrast to daily antiretroviral therapy. The antibody may also enhance the immune response, destroy intracellular viruses, and prevent infection, the researchers suggest, as well as opening up new possibilities for the development of an HIV-1 vaccine.

The researchers have disclosed no relevant financial relationships.