Development of Neutralizing Antibodies to Machupo Virus

PROJECT SUMMARY/ABSTRACT In this Phase I STTR grant proposal, we will develop neutralizing antibodies against Machupo virus, a New World arenavirus (NWA), by using an innovative, stabilized-trimer immunogen. Antibodies are thus far only known to target the receptor-binding site. This novel immunogen will support discovery and characterization of neutralizing antibodies against other critical sites in the pre-fusion conformation of the surface glycoprotein. This proposal builds on the proof-of-concept for the related Lassa virus of the Arevirumab antibody cocktail, which combines mAbs against both receptor-binding and fusion-blocking quaternary (trimer-bridging) epitopes to achieve late- stage, low-dose in vivo protection. Our approach involves utilizing advanced immunization techniques, an innovative stabilized antigen, and high- throughput biotechnological screening to identify and characterize antibodies of complementary activities. Provision of mAbs against complementary epitopes is also desired for development of cocktails that will prevent mutagenic escape. The successful development of these antibodies in Phase I will set the foundation for Phase II, where we plan to humanize and enhance the antibodies through sophisticated engineering, optimizing their specificity and binding affinity to Machupo virus GPC. Additionally, Phase II will encompass preclinical development, including efficacy and safety studies, to advance these antibodies towards clinical trials. This project not only promises to advance our scientific understanding of Arenavirus pathogenesis but also aims to develop a new class of therapeutics with potential commercial applications. Our goal is to bridge the gap from laboratory research to clinical solutions, in line with NIH's mission to support innovative health research with practical implications.