Broadly neutralizing antibodies (bNAbs) 10-1074 and 3BNC117 are in clinical development for HIV prevention and treatment. In macaque models, passively administered 10-1074 or 3BNC117 protects against repeated rectal or vaginal SHIV challenges; however, their efficacy against other HIV acquisition routes relevant to men (penile) or persons who inject drugs (intravenous, IV) has not been discerned. Here, we evaluated the protective efficacy of a single subcutaneous (SC) injection of 10-1074 alone, or in combination with 3BNC117, against repeated penile or IV SHIV challenges, respectively.
Macaques (6 rhesus, 5 cynomolgus) were injected SC once with 10-1074, or a combination of 10-1074+3BNC117, respectively (10mg each bNAb/kg). Beginning one week later, macaques were challenged repeatedly once weekly with SHIVsf162P3 (rhesus) or SHIVAD8-EO (cyno) via penile (200 TCID[sub]50[/sub] into the prepuce pouch, 16 TCID[sub]50[/sub] into the distal urethra) or IV (130 TCID[sub]50[/sub]) routes, respectively, until SHIV infection was confirmed via plasma viral load assay. Control macaques, which received no antibody, were challenged identically (10 penile, 2 IV). Longitudinal plasma samples were assayed via Tzmbl neutralization assay, using virions pseudotyped with 10-1074-sensitive (X2088_c9) or 3BNC117-sensitive (Q769.d22) HIV Envs to determine bNAb concentrations.
Macaques administered 10-1074 and challenged via the penis were protected against a median of 15.5 weekly challenges, as compared to controls (median=2.5; P=0.0007, Log-rank test) and exhibited a median 10-1074 plasma level of 0.50μg /ml (range=0.10-0.70μg/ml) at SHIV breakthrough. Macaques administered both bNAbs and challenged IV were protected against a median of 5 weekly challenges, as compared to controls (median=1; P=0.0143, Log-rank test) and exhibited a median 10-1074 plasma level of 1.1µg/ml (range=0.6-1.6µg/ml), but undetectable 3BNC117, at SHIV breakthrough.
A single subcutaneous administration of 10-1074 durably protected macaques against repeated penile SHIV challenges providing the first evidence of efficacy by a bNAb against penile infection. Significant protection also was observed against repeated IV SHIV challenges following administration of 10-074+3BNC117, which was mainly due to 10-1074 that exhibited longer persistence. Our data support the continued development of 10-1074 as a long-acting PrEP candidate for men or persons who inject drugs who may not be able to adhere to daily PrEP.