Developing monoclonal antibodies that broadly neutralize HIV-1 (bnMAbs) through passive transfer is a key goal in the prevention and treatment of HIV-1 infection. N6LS is a bnMAb isolated from a patient who was HIV infected for 21 years and was not on antiretroviral treatment. It was produced as an IgG1 with an LS mutation to the Fc region to increase half-life through increased binding affinity to the neonatal Fc receptor. N6LS targets the CD4-binding site (CD4bs) of the HIV-1 envelope glycoprotein and is a member of the VRC01 class of CD4bs antibodies. It is broader and more potent than VRC01, neutralizing up to 98% of viral strains. N6LS achieves this via two recognition characteristics. First, it is minimally insensitive to mutations in the variable gp120 V5 loop that typically diminish contacts and interrupt binding in other CD4bs antibodies. Second, it binds at a unique angle that avoids steric clashes with the highly glycosylated V5 region, which is a major mechanism of resistance for other bnMAbs in this class.
We conducted a first-in-human dose-escalation open-label phase 1 clinical trial of N6LS in healthy HIV-1 negative adults aged 18-50 to determine its safety, tolerability, and pharmacokinetic (PK) profile. Three groups received a single IV dose of 5, 20, or 40 mg/kg, and one group received a single SC dose of 5 mg/kg. Two groups received three doses of either 5 mg/kg SC or 20 mg/kg IV at 12-week intervals.
We enrolled 23 volunteers between June 18, 2018 and February 12, 2019, including 9 (39%) males and 14 (61%) females. 22 participants received all N6LS administrations for a total of 42 product administrations. N6LS was safe and well tolerated with no SAEs or dose-limiting toxicities. No infusion reactions occurred. All reported reactogenicity was mild to moderate in severity. Initial PK up to 4 weeks following initial N6LS administration from 21 subjects showed that maximum (CMAX) and 4 week post-infusion serum concentrations increased proportionally with antibody dose (Table 1). Estimated half-life exceeded 30 days in all 15 subjects with at least 12 weeks of PK results. This preliminary analysis has shown that N6LS demonstrates linear PK with a promising half-life for infrequent administration.
N6LS was safe and well tolerated by IV and SC administration and displayed encouraging PK parameters. Given its high neutralization breadth and potency, N6LS is a promising candidate for inclusion in HIV-1 prevention and therapeutic strategies.