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PRO 542 (CD4-IgG2) is a recombinant antibody-like fusion protein wherein the Fv portions of both the heavy and light chains of human IgG2 have been replaced with the D1D2 domains of human CD4. Unlike monovalent and divalent CD4-based proteins, tetravalent PRO 542 potently neutralizes diverse primary human immunodeficiency virus (HIV) type 1 isolates. In this phase 1 study, the first evaluation of this compound in humans, HIV-infected adults were treated with a single intravenous infusion of PRO 542 at doses of 0.2–10 mg/kg. PRO 542 was well tolerated, and no dose-limiting toxicities were identified. Area under the concentration-time curve, and peak serum concentrations increased linearly with dose, and a terminal serum half-life of 3–4 days was observed. No patient developed antibodies to PRO 542. Preliminary evidence of antiviral activity was observed as reductions in both plasma HIV RNA and plasma viremia. Sustained antiviral effects may be achieved with repeat dosing with PRO 542.

Antibody-dependent cell-mediated cytotoxity (ADCC) can eliminate HIV-1 infected cells, and may help reduce the reservoir of latent virus in infected patients. Sera of HIV-1 positive individuals include a number of antibodies that recognize epitopes usually occluded on HIV-1 envelope glycoprotein (Env) trimers. We have recently described eCD4-Ig, a potent and exceptionally broad inhibitor of HIV-1 entry that can be used to protect rhesus macaques from multiple high-dose challenges with simian-human immunodeficiency virus AD8 (SHIV-AD8). Here we show that eCD4-Ig bearing an IgG1 Fc domain (eCD4-IgG1) can mediate efficient ADCC activity against HIV-1 isolates with differing tropisms, and that it does so at least 10-fold more efficiently than CD4-Ig, even when more CD4-Ig molecules bound cell surface-expressed Env. An ADCC-inactive IgG2 form of eCD4-Ig (eCD4-IgG2) exposes V3-loop and CD4-induced epitopes on cell-expressed trimers, and renders HIV-1-infected cells susceptible to ADCC mediated by antibodies of these classes. Moreover, eCD4-IgG2, but not IgG2 forms of the broadly neutralizing antibodies VRC01 and 10-1074, enhances the ADCC activities of serum antibodies from patients by 100-fold, and significantly enhanced killing of two latently infected T-cell lines reactivated by vorinostat or TNFα. Thus eCD4-Ig is qualitatively different from CD4-Ig or neutralizing antibodies in its ability to mediate ADCC, and it may be uniquely useful in treating HIV-1 infection or reducing the reservoir of latently infected cells.

Antibodies capable of neutralizing a wide array of HIV isolates are rarely elicited by the adaptive immune response during HIV infection, and it is not known how to elicit such protective antibodies by vaccination. Philip Johnson and his colleagues have circumvented this hurdle through gene transfer technology. They show that it is possible to protect monkeys from SIV infection by administering intramuscular injections of adeno-associated virus vectors that express broadly neutralizing antibodies that can access the circulation ( 841–842 pages 951–954 ). The key to an effective HIV vaccine is development of an immunogen that elicits persisting antibodies with broad neutralizing activity against field strains of the virus. Unfortunately, very little progress has been made in finding or designing such immunogens. Using the simian immunodeficiency virus (SIV) model, we have taken a markedly different approach: delivery to muscle of an adeno-associated virus gene transfer vector expressing antibodies or antibody-like immunoadhesins having predetermined SIV specificity. With this approach, SIV-specific molecules are endogenously synthesized in myofibers and passively distributed to the circulatory system. Using such an approach in monkeys, we have now generated long-lasting neutralizing activity in serum and have observed complete protection against intravenous challenge with virulent SIV. In essence, this strategy bypasses the adaptive immune system and holds considerable promise as a unique approach to an effective HIV vaccine.

Human immunodeficiency virus type 1 (HIV-1) entry proceeds via a cascade of events that afford promising targets for therapy. PRO 542 neutralizes HIV-1 by blocking its attachment to CD4 cells, and T-20 blocks gp41-mediated fusion. Both drugs have shown promise in phase 1/2 clinical trials. Here, the drugs were tested individually and in combination in preclinical models of HIV-1 infection, and inhibition data were analyzed for cooperativity by using the combination index method. Synergistic inhibition of virus-cell and cell-cell fusion was observed for phenotypically diverse viruses for a broad range of drug concentrations, often resulting in ⩾10-fold dose reductions in vitro. Additional mechanism-of-action studies probed the molecular basis of the synergies. The markedly enhanced activity observed for the PRO 542:T-20 combination indicates that the multistep nature of HIV-1 entry leaves the virus particularly vulnerable to combinations of entry inhibitors. These findings provide a strong rationale for evaluating combinations of these promising agents for therapy in vivo

The use of recombinant CD4-IgG2 in pediatric human immunodeficiency virus type 1 (HIV-1) infection was evaluated by single and multidose intravenous infusions in 18 children in a phase 1/2 study. The study drug was well tolerated, and dose proportionality was observed in terms of area under time-concentration curve and peak serum concentration. Acute decreases of >0.7 log(10) copies/mL in serum HIV-1 RNA concentration were seen in 4 of the 6 children treated with 4 weekly 10 mg/kg doses. At 14 days after treatment, 3 children had sustained reductions in serum HIV-1 RNA; the other children had rebounded to baseline levels or above. By 28 days after therapy, the peak HIV-1 cellular infectious units was reduced in all 6 children, including the 2 who had experienced an earlier transient increase in values. Thus, recombinant CD4-IgG2 treatment of HIV-1-infected children appears to be well tolerated and capable of reducing HIV-1 burden.