Background:
Immunization with a broadly neutralizing monoclonal antibody (bnMAb) is a potential strategy for the prevention and treatment of HIV-1 infection. N6 is a human bnMAb that was derived from a patient who was HIV infected for 21 years without antiretroviral treatment. An LS mutation was introduced to extend serum half-life. N6LS is a member of the VRC01 class of antibodies that targets the CD4-binding site of the HIV-1 envelope glycoprotein. Its neutralizing abilities are broader and more potent than VRC01, neutralizing up to 98% of viral strains on a 181 pseudovirus panel.
Methods:
In this first-in-human phase 1 clinical trial (NCT03538626), we assessed the safety and pharmacokinetics (PK) of N6LS administered to healthy adults either by intravenous (IV) or subcutaneous (SC) routes. Additional participants received SC administrations with recombinant human hyaluronidase PH20 (rHuPH20, 2000 U/mL), for rapid high dose/volume drug delivery. Previously N6LS was demonstrated to be safe and well tolerated when administered by IV or SC routes (5, 20 or 40 mg/kg IV or 5 mg/kg SC) to 22 participants with a serum half-life of over 40 days. Ten additional participants were enrolled and received 5 or 20 mg/kg N6LS SC co-administered with rHuPH20.
Results:
Infusion site erythema was reported in all 10 newly enrolled participants and five participants met grade 3 severity criteria based off erythema dimensions. Participants tolerated the post-infusion period well, without concomitant systemic reactions or complications. The erythema was self-limiting with most cases resolving within days. Systemic reactogenicity was mild. No serious adverse events, dose-limiting toxicities or infusion reactions occurred. PK following N6LS 5 mg/kg SC was similar with and without rHuPH20. N6LS demonstrated broad and potent neutralization following administration, and there was no evidence of development of anti-drug antibodies to N6LS.
Conclusions:
In summary, N6LS was safe and well tolerated when administered with or without rHuPH20. Given its broad and potent neutralization of circulating HIV-1 clades, N6LS remains a promising candidate for HIV-1 prevention and therapy. As demonstrated in this trial, the ability to safely administer higher doses/volumes of N6LS subcutaneously opens new potential avenues for prophylactic and therapeutic self-administration of bnMAbs.
Serum Concentrations of N6LS