Administration of the broadly neutralizing, CD4-binding site targeting antibody VRC07-523LS in dual- and triple-antibody combinations with 10-1074, PGT121, and/or PGDM1400: impact on pharmacokinetics compared to VRC07-523LS administration alone

Title

Presenter

Stephen Walsh

Authors

S. Walsh * (1), C. Gay (2), M. Sobieszczyk (3), S. Mannheimer (3), O. Hyrien (4), C. Yu (4), K. Seaton (5), T. Skalland (4), J. Dumond (2), P. Andrew (6), C. Karg (4), C. Paez (4), T. Gamble (6), Z. He (4), B. Hanscom (4), B. Dye (6), E. Piwowar-Manning (7), J. Hural (4), L. Polakowski (8), M. Yacovone (8), W. Chege (8), D. Montefiori (5), L. Gama (8), J. Mascola (8), G. Tomaras (5), Y. Huang (4), S. Karuna (4), HVTN127/HPTN087 and HVTN130/HPTN089 Study Teams

Institutions

(1) Brigham & Women''s Hospital, Infectious Diseases, Boston, United States, (2) University of North Carolina, Chapel Hill, United States, (3) Columbia University, New York, United States, (4) Fred Hutchinson Cancer Research Center, Seattle, United States, (5) Duke University, Durham, United States, (6) FHI 360, Durham, United States, (7) Johns Hopkins University, Baltimore, United States, (8) National Institute of Allergy and Infectious Diseases, Bethesda, United States

BACKGROUND: Broadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. In the only bnAb HIV prevention efficacy studies to date (the AMP studies), intravenous (IV) administration of a CD4-binding site targeting bnAb (VRC01) prevented infection only against highly susceptible viruses. BnAb combinations, particularly using bnAbs engineered for increased potency, breadth, and half-life, may be more efficacious. Clinical data assessing potential interactions between co-administered antibodies is limited. We present the first interim clinical data comparing VRC07-523LS pharmacokinetics (PK) when administered alone (HVTN 127/HPTN 087) versus co-administered with other bnAbs that bind non-overlapping HIV Env epitopes, including V2-binding PGDM1400 and V3-binding 10-1074 and PGT121 (HVTN 130/HPTN 089).
METHODS: Healthy, HIV-uninfected adults received VRC07-523LS administered IV at four'month intervals alone at five timepoints (n=29; 2.5, 5, or 20 mg/kg), sequentially in dual combination with 10-1074, PGT121, or PGDM1400 at one timepoint (n=18; 20 mg/kg), or in triple combination with PGDM1400 and PGT121 at two timepoints (n=9; 20 mg/kg). VRC07-523LS serum concentration kinetics were measured by anti-idiotype Binding Antibody Multiplex Assay. A two-compartment population PK model was fitted to estimate PK parameters.
RESULTS: Participant demographics and baseline characteristics were similar between the two studies. Predicted VRC07'523LS levels from the fitted model were in excellent agreement with observed levels (see Figure). Small changes in clearance, intercompartmental clearance, and peripheral volume PK parameters of VRC07-523LS were observed with co-administration of 10-1074, PGT121, and/or PGDM1400. VRC07-523LS alone has an estimated median half-life of ~54.8 days versus ~52.3 days when co-administered with 10-1074, PGT121, and/or PGDM1400 (p=0.55).

CONCLUSIONS: VRC07-523LS appears to be cleared more rapidly with a larger peripheral volume when co-administered with 10'1074, PGT121, and/or PGDM1400 versus administration alone. With an insignificant impact on elimination half-life, these data suggest that the duration of PK coverage for single anti-HIV bnAbs, like VRC07-523LS, is preserved in bnAb combinations.

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