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Antibody 10-1074 suppresses viremia in HIV-1-infected individuals
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Nature Medicine
ABSTRACT: Monoclonal antibody 10-1074 targets the V3 glycan supersite on the HIV-1 envelope (Env) protein. It is among the most potent anti-HIV-1 neutralizing antibodies isolated so far. Here we report on its safety and activity in 33 individuals who received a single intravenous infusion of the antibody. 10-1074 was well tolerated and had a half-life of 24.0 d in participants without HIV-1 infection and 12.8 d in individuals with HIV-1 infection. Thirteen individuals with viremia received the highest dose of 30 mg/kg 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. 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.
Antibodies have a unique role in the therapeutic armamentarium against human cancers and inflammatory diseases because they engage the host immune system to attack tumor cells or modify inflammatory responses by binding to Fc receptors on host leukocytes. Similarly, in individuals with HIV-1 infection, passively transferred antibodies accelerate the clearance of infected cells and induce host immunity against HIV-1 (refs. 30,32,33,37). These unique features of immunotherapy suggest that antibodies should be further explored as adjuncts to conventional ART for the prevention or treatment of HIV-1 infection. Anti-CD4-binding-site antibodies 3BNC117 and VRC01 have been generally safe and effective at decreasing plasma HIV-1 RNA levels34, 35 and preventing rebound viremia during analytical treatment interruption in humans38, 52. The two antibodies differ in their relative potency and half-lives; 3BNC117 has a somewhat longer half-life and greater potency than VRC01 (refs. 34,35,38). As expected, these properties are reflected by the relative ability of the two antibodies to prevent infection in macaques and to prolong viral suppression in humans undergoing analytical treatment interruption38, 52. The finding that 10-1074 has favorable safety and pharmacokinetics profiles and is effective at decreasing viremia extends these observations to an additional nonoverlapping target of vulnerability on the HIV-1 spike.
10-1074 is more potent and has a comparable half-life to, but has a narrower spectrum of activity than, either of the two CD4-binding-site antibodies. Its effect on viremia is similar to 3BNC117, but a higher frequency of fully resistant escape variants was detected for 10-1074 than for 3BNC117 (refs. 34,37,38). We speculate that this difference in occurrence of escape might be due to the relative cost of altering the CD4 binding site, which makes viable escape from antibodies that target this site more difficult, as has been shown in vitro53. As a consequence, the number of distinct escape variants that can give rise to high-level viremia might be reduced. This idea is consistent with the relative paucity of naturally arising viruses that are resistant to 3BNC117 in comparison to 10-1074 or all other glycan patch bNAbs54. However, we did observe that 10-1074 escape mutations are selected against in several individuals when antibody levels drop. This finding suggests that these mutations are also associated with a fitness cost in vivo. In humanized mice and in humans, a single antibody, such as a single small-molecule drug, is insufficient to prevent the emergence of resistant viral variants because the infection produces a swarm of related mutant viruses26, 34, 35, 55. Similarly to what has been described for small-molecule drugs, resistance to antibodies seems to arise from pre-existing minority variants and/or de novo mutations produced during rapid HIV-1 turnover. Our findings underscore some of the similarities in antiviral activity between small-molecule drugs and antibodies and emphasize that combinations of antibodies that target nonoverlapping epitopes will be required for effective therapy and possibly prevention.
10-1074 targets an epitope that is distinct from other second-generation bNabs that have been tested in humans34, 35. It has favorable clinical characteristics and potent anti-viral activity, and therefore, 10-1074 is a promising candidate for antibody-mediated combination immunotherapy and the prevention of HIV-1 infection.

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