In previous commentaries (http://evmedreview.com/?p=1863; http://evmedreview.com/?p=837; http://evmedreview.com/?p=385), I have discussed the critical role of extensive B-cell and immunoglobulin gene evolution in generating broadly neutralizing antibodies for HIV-1. Of course, the unprecedented magnitude of antibody evolution necessary to achieve potent neutralization of a high percentage of HIV strains reflects the unprecedented evolutionary plasticity of HIV that originates in both high mutation and recombination rates for the HIV genome (Korber et al., 2001). A new study by Caskey et al. (Nature, 2015) from the Nussenzweig Laboratory reports results for a first-in-human dose escalation phase I clinical trial of a human monoclonal antibody (mAb) specific for the HIV envelope (env) protein.
This mAb, 3BNC117, is specific for the CD4 binding site of the HIV envelope protein. It neutralizes 195 out of 237 HIV-1 strains tested from 6 clades. The average half-maximal inhibitory concentration of 0.08 ug/ml is a feasible concentration for a passively administered serum antibody.
Purified 3BNC117 was administered once to 17 HIV-1 infected patients and 12 healthy controls at one of 4 doses: 1, 3, 10, and 30 mg/kg. Serum antibody concentrations were followed by both an ELISA using an anti-idiotypic antibody specific for the variable domains of 3BNC117 and an assay that measures neutralization activity. The antibody serum half-life was approximately 17 days in uninfected recipients and 9 days in HIV-1-infected recipients. More rapid clearance in the infected individuals was presumed by the authors to reflect clearance of antibody-antigen complexes, but they acknowledge the possibility of other unspecified mechanisms.
Assessment of serum viral titers revealed only minimal effects by 3BNC117 infused at 1 or 3 mg/kg. However, the mAb at doses of 10 or 30 mg/kg was variably effective at reducing viral copies in the peripheral blood by from 0.8 to 2.5 log10. The authors noted that the magnitude of the decrease in viral load was related to the starting viral load and the initial sensitivity of the viral population to neutralization by 3BNC117. Substantial decrements in viral load were sustained throughout the observation period of 56 days only for individuals receiving 30 mg/kg of mAb.
Paired samples of virus from treated individuals taken seven days before the mAb infusion started and 28 days after the infusion were compared for neutralization sensitivity. Even virus from some HIV-infected patients given 1 mg/kg of mAb showed decreases in sensitivity to neutralization suggestive of the selection of genetic escape variants by 3BNC117. Decreases in sensitivity of comparable magnitude were seen for viruses from some but not other recipients of 3 or 10 mg/kg of mAb. At 30 mg/kg of 3BNC117, only two of the five treated patients showed decreases in neutralization sensitivities of greater than five-fold. The authors conclude that in only some HIV-infected individuals treated with 3BNC117 does virus evolve a high degree of resistance to neutralization.
Finally, the authors cloned and sequenced the envelope genes from paired plasma samples, taken before and 28 days after infusion, for ten patients from prior to and 28 days after administration of 3BNC117. The results reveal evidence for selection of escape variants in some but not other patients. Evidence of selected amino acid substitutions correlated with greater decreases in neutralization sensitivity. Some amino acids that were found at given positions only after treatment, suggestive of selection by the mAb, were at envelope positions known to be contacted by antibody while others were at sites not known to participate directly in contacting the antibody. Most of these sites were near contact sites and could influence the interaction between envelope protein and 3BNC117.
Overall, the results suggest that passive transfer of a potent broadly HIV-neutralizing mAb can be safe, mediate reductions in viremia, and exert selective pressure on virus. The evidence for selection in some but not other receipients of antibody infusion suggests, as the authors discuss, the use of combinations of potent broadly neutralizing mAbs or combinations of one or more mAbs with one or more anti-retroviral drugs. Use of multiple therapeutic agents would be anticipated to constrain the evolutionary paths available to the virus.
Cocktails of mAbs or of mAbs and anti-retroviral drugs would also likely increase the number of patients who experience substantial therapeutic effects. Much additional research will be required to optimize such regimens.