Developing a new bispecific antibody mimicking rapid antigen-specific memory CD8+ T cell-mediated protection

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Abstract While the main function of memory CD8+ T cells is to recognize and kill intracellular pathogens and tumors, they can also produce multiple effector cytokines and chemokines that contribute to protective immune responses. The precise mechanism for development of memory CD8+ T cell protection in vaccinated hosts is not well understood. We have been investigating this question over the past 15 years with the underlying goal to develop novel therapeutic strategies that harness the power of memory CD8+ T cells to the benefit of the host. Our past and most recent mechanistic studies have established that, upon recall infection of vaccinated hosts, memory CD8+ T cells can rapidly sense both inflammatory signals and cognate antigen to produce interferon gamma (IFNγ) and sets of early coordinated chemokines. We reported that both signals are required to promote potent activation of inflammatory Ly6C+ monocytes microbicidal effector function and achieve optimal protection of vaccinated hosts. Building on these results, we propose in this exploratory proposal to design, develop and test a novel bispecific IFNγ-chemokine Fc-fusion “ligand-trap” biologics that target and activates Ly6C+ monocytes microbicidal functions for protection against infectious diseases, mimicking the mechanism by which memory CD8+ T cells mediate effective protection of vaccinated host during recall infection. We believe that such reagent has the potential to be used as a rapid and broad therapeutic against multiple acute infections.