PlanB2CureHIV (the 'PlanB' consortium)

About This Grant

PROJECT SUMMARY Antibodies capable of neutralizing the global diversity of HIV strains are difficult to elicit in humans. This is because such antibodies require unusual features deriving from rare precursor B cells that must undergo extensive affinity maturation. To date, only a small number of potent broadly neutralizing antibodies (bnAbs) have been isolated after screening thousands of patients responding to unsuppressed infection. Passive immunization with recombinant monoclonal HIV bnAbs however, can maintain suppression of viremia in patients after anti-retroviral treatment (ART) interruption for as long as serum titers remain above threshold effective serum concentrations. This suggests that establishing durable bnAb titers above these thresholds could result in an HIV functional cure, defined as life-long suppression of viremia. Since HIV bnAbs cannot be elicited through vaccination, gene therapies are being considered as an approach to deliver such long- lasting bnAb titers in vivo. Of these, genome-edited B cells are a novel and promising approach that may hold several key advantages. Primary B cell antigen receptors (BCRs) can be reprogrammed to express novel specificities by inserting antibody transgene cassettes into the IgH-locus downstream of endogenous heavy chain (HC) immunoglobulin (Ig) variable region exons. These modified cells can be expanded and differentiated in vivo by vaccination into memory and long-lived plasma cells that can durably secrete the new antibody specificity in wild type immunocompetent mice by independent research groups. The overall purpose of the PlanB consortium is to accelerate the pre-clinical development of safe and effective IgH- reprogrammed B cell-based therapies that would provide life-long bnAb titers capable of maintaining suppression of the viral reservoir, allowing patients to discontinue ART therapy. Our aim is to develop and compare two distinct options from which one could be selected for clinical development upon completion of the program. The first is an ex vivo reprogrammed B cell product that can be autologously transferred and vaccinated in patients. The second is an in vivo B cell targeting and IgH-reprogramming system that will be used in conjunction with vaccination. In both cases, durable HIV broadly neutralizing antibody memory responses must be elicited from the engineered cells.