Enhanced Fc-mediated complement activity with broadly neutralizing antibody 10E8v4 does not improve viral outcomes following SHIV challenge in rhesus macaques

Abstract

Abstract Fc modified broadly neutralizing antibodies (bNAbs) are being developed for both prophylactic and therapeutic treatment of HIV with some success in extending half-life, but in vivo benefits of enhanced FcγR interaction remain unclear. Here we sought to improve bNAb efficacy by increasing Fc-mediated complement activity. A panel of Fc variants was screened for complement enhancement of 10 bNAbs. Modified 10E8v4, which weakly neutralizes SHIVSF162p3 (IC80 30 mg/ml) and does not mediate ADCC, was selected for macaque studies. Compared to wildtype, the EFTAE modification resulted in greater affinity for multiple FcγRs, >2-fold enhanced complement deposition, viral lysis, and antibody-mediated complement dependent cytotoxicity, but reduced serum half-life. Subcutaneous infusion with a sub-protective 5 mg/kg dose of 10E8v4 followed by a single high dose intrarectal challenge with SHIVSF162p3 showed unmodified 10E8v4 treated animals displayed lower plasma viremia compared to the complement/FcgR dual knockout (LALA) and controls. Unexpectedly, the EFTAE group displayed higher plasma viremia than controls, and viral DNA was significantly enhanced in tissues at necropsy (9 wpi, p <0.0001). Viremia in EFTAE treated animals inversely correlated with plasma neutralization titer at time of challenge; however, elevated viremia was not seen in animals treated with 10 and 20 mg/kg Ab, suggesting that complement mediated enhanced infection was mitigated by greater neutralizing activity. These are the first in vivo results substantiating in vitro reports of complement dependent enhanced infection mediated by non-neutralizing HIV Abs and indicate that future studies modulating complement induction by therapeutic bNAbs are warranted.