PK/PD Modeling of Anti-Circumsporozoite Protein (CSP) Antibodies to Predict Dosing Requirements for Malaria Prevention


In the context of infectious disease, such as malaria, monoclonal antibodies (mAbs) have the potential to provide protection to both adults and the pediatric population. Under development are half-life extended antibodies that bind to circumsporozoite protein (CSP) on the surface of the infectious sporozoites carried by mosquitoes. There are several antibodies currently in development that demonstrate protection against malaria infection as well as long circulating half-lives, which may provide season-long protection with only a single dose.

Here we develop a PK/PD model of CSP entry and distribution, anti-CSP mAb PK, and mAb-CSP binding. The model was used to study mouse efficacy models, calibrated to cyno PK and translated to human to determine the extent to which the mAb prevents escape of CSP to the liver. Modeling and analysis is performed here for MAM01, a mAb currently in development at GatesMRI, and the performance is compared to CIS43LS.

Model Development



Figure 1

Figure 1: Schematic of sporozoite infection

Figure 2: Full model diagram. Sporozoite enters bloodstream (central compartment) from bite compartment and escapes to liver. mAb binding to CSP occurs in bite and central compartments. Peripheral compartment included to capture mAb PK


Mouse modeling and analysis predicts > 99.99% reduction in escape-to-liver which corresponds to 95% protection from infection. This is in agreement with the reduction predicted for 3 mg/kg CIS43LS in CHMI and 40 mg/kg dose in Ph II studies. Efficacy was predicted at lower doses of MAM01 than CIS43LS due to its higher binding affinity.

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