Pharmacokinetics and pharmacodynamics of a long-acting monoclonal antibody against malaria in African adults

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Abstract

Background. CIS43LS is a long-acting mAb that targets the Plasmodium falciparum circumsporozoite protein. A phase 2 trial showed that a single dose of CIS43LS conferred >85% sterile protection against infection in Malian adults over 6 months. Understanding the pharmacokinetics and pharmacodynamics (PK/PD) of CIS43LS is critical for the further development of CIS43LS and other anti-malaria mAbs. Methods. Using 3,777 serum samples collected from 348 trial participants over the 6-month study period, we performed a PK/PD analysis of CIS43LS that included assessments for anti-drug antibodies and target-mediated drug disposition. A two-compartment, non-linear mixed effects population PK model that evaluated demographic, anthropometric, hematologic, baseline parasitemia, and endogenous IgG and IgG1 as potential covariates was used to estimate PK parameters and serum concentrations required to achieve 80% efficacy. Results. The median CIS43LS t1/2 was 63.2 days (95%CI 59.4–67.2 days). Serum concentrations ≥64 μg/mL (95%CI 49–93 μg/mL) corresponded to ≥80% efficacy against infection over 6 months. A simulated dose of 30 mg/kg maintained serum concentrations >64 µg/mL in >97.5% of individuals for 4 months, the timeframe for the World Health Organization preferred product characteristics for anti-malaria mAbs. There was no evidence of anti-drug antibodies. Among infected individuals who received CIS43LS, no marked evidence of target-mediated drug disposition was observed. Conclusion. This study indicates that protective CIS43LS levels can be maintained over the course of a single malaria season and provides guidance for PK/PD analyses of anti-malaria mAbs in malaria-endemic populations. Trial registration. NCT04329104. Funding. National Institutes of Health and Gates Foundation.

Authors

Tuan M. Tran, Zonghui Hu, Kassoum Kayentao, Aissata Ongoiba, Sam Jones, Nada Abla, Sara A. Healy, Hamidou Cisse, Bickey H. Chang, Jeff Skinner, Leonid Serebryannyy, Sandeep R. Narpala, Robin Schlesinger, Kwang Huei Low, Rachel Kazmierski, Bob C. Lin, Joana Dias, Safiatou Doumbo, Didier Doumtabe, Anne C. Preston, Shanping Li, Mary E. Peterson, Amit Oberai, Adam D. Shandling, Joseph J. Campo, Sean C Murphy, Shinyi Telscher, Emily E. Coates, Edmund V. Capparelli, Amagana Dolo, Boubacar Traore, Robert A. Seder, Peter D. Crompton