Background:
Young women in sub-Saharan Africa continue to bear a high burden of HIV infection. Combination anti-HIV monoclonal antibodies are a potential HIV prevention technology that may overcome adherence challenges of daily oral pre-exposure prophylaxis. CAPRISA 012B, a first-in-human dose-escalation phase 1 trial evaluated the safety, pharmacokinetics and neutralization activity of the monoclonal antibody CAP256V2LS alone and in combination with VRC07-523LS in young HIV-negative women in Durban, South Africa.
Methods:
From 13 July 2020 to 13 January 2021, 42 healthy women, aged 18-45 years, were enrolled. Groups 1 and 2 were open-label and CAP256V2LS was administered at 5mg/kg and 10mg/kg intravenously; and 5mg/kg, 10mg/kg and 20mg/kg subcutaneously. In Group 3 participants were randomized to receive a combination of CAP256V2LS and VRC07-523LS at 10mg/kg and 20mg/kg subcutaneously co-mixed with a recombinant human hyaluronidase. Neutralizing activity was measured using env-pseudotyped viral particles in the TZM-bl assay. A quantitative electrochemiluminescence sandwich immunoassay was performed to determine antibody concentrations.
Results:
There were no serious adverse events or dose-limiting toxicities. Most commonly reported symptoms following intravenous administration were headaches [7/8 (88%)] and nausea [4/8 (50%)]. Commonly reported symptoms following subcutaneous administration were headaches [31/34 (91%)], chills [25/34 (74%)] and malaise/fatigue [19/34 (56%)]. Adverse events included transient lymphocytopenia [8/42 (19%)], proteinuria [9/42 (21%)], elevated aspartate aminotransferase [10/42 (24%)] and alanine aminotransferase [5/42 (12%)]. At 6 months, the median serum concentration of CAP256V2LS and VRC07-523LS in participants who received 20mg/kg, was 6μg/mL and 26μg/mL respectively. Overall, the estimated half-life was 43 days for CAP256V2LS and 66 days for VRC07-523LS. Neutralization data showed that both antibodies retained their functional activity post-administration.
Conclusions:
CAP256V2LS and VRC07-523LS administered subcutaneously alone and in combination with recombinant hyaluronidase was safe and well tolerated, with detectable antibody concentrations up to 6 months post administration. CAP256V2LS is one of the most potent antibodies described to date and in combination with VRC07-523LS is predicted to provide significant coverage of global HIV strains. These data support further assessment in larger clinical studies.
Figure 1: Median concentrations of CAP256V2LS and VRC07-523LS through 168 days post study product administration observed in the CAPRISA 012B trial. 