Highly protective antimalarial antibodies via precision library generation and yeast display screening

This study applied innovative antibody screening technologies to discover antimalarial antibody variants with enhanced protective potency. Study authors applied precision DNA library generation, high-throughput screening, and analysis of next generation sequencing data to identify mutations that improved malaria protection following in vivo infectious challenge. The monoclonal antibody CIS43 targets the Plasmodium falciparum circumsporozoite protein (PfCSP) and prevents malaria infection in humans for up to 9 mo following a single intravenous administration. To enhance the potency and clinical utility of CIS43, we used iterative site-saturation mutagenesis and DNA shuffling to screen precise gene-variant yeast display libraries for improved PfCSP antigen recognition. We identified several mutations that improved recognition, predominately in framework regions, and combined these to produce a panel of antibody variants. The most improved antibody, CIS43_Var10, had three mutations and showed approximately sixfold enhanced protective potency in vivo compared to CIS43. Co-crystal and cryo-electron microscopy structures of CIS43_Var10 with the peptide epitope or with PfCSP, respectively, revealed functional roles for each of these mutations. The unbiased site-directed mutagenesis and screening pipeline described here represent a powerful approach to enhance protective potency and to enable broader clinical use of antimalarial antibodies.

Automated summary

This study used innovative antibody screening technologies to discover antimalarial antibody variants with enhanced protective potency. By applying precise mutations and screening methods, the researchers were able to identify an antibody that showed sixfold enhancement in protection compared to the original antibody. This study provides a practical approach to improving the efficacy and expanding the clinical use of antimalarial antibodies.