An antibody drug engineered for prevention of malaria in global populations

Abstract Over 80% of malaria-attributable deaths are in children under five. However, the only malaria vaccine recommended by the World Health Organization (WHO) for paediatric use, Mosquirix™, has limited efficacy. Complementary strategies, like monoclonal antibodies (mAbs), will be required to eradicate malaria. To discover new anti-malaria mAbs, we evaluated >28,000 antibody sequences from circulating B cells obtained from 45 Mosquirix™ vaccinees and selected 369 for testing. Many antibodies bound the circumsporozoite protein (CSP), a main surface protein on malaria and the malaria antigen in Mosquirix™, and several were exceptionally protective in mouse models of malaria. Through this work, we identified surprising correlations that suggest certain CSP sequences in Mosquirix™ may induce immunodominant antibody responses that dilute protective immunity. Further, we selected the antibodies most protective in preclinical mouse models and engineered them for improved manufacturability and developability to meet WHO guidelines. An optimised clinical candidate, MAM01, suitable for paediatric populations living in low-to-middle-income countries, was selected for clinical development.