Use of TCR-mimic bispecific antibodies against pMHC-II for monitoring antigen processing and redirecting cytolytic effector cells

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Abstract HIV-1 infects CD4+ T cells and macrophages and is currently incurable due to a latent reservoir. Targeting infected cells using TCR-mimic antibodies to peptide-MHC (pMHC) would provide a specific, high-affinity platform for immune system activation and monitoring antigen processing. However, antibodies to pMHC are notoriously difficult to isolate. Using a phage display platform, we panned for phage expressing variable fragments against immunodominant HIV pMHC complexes. These Fab fragments were cloned into a bispecific antibody (bsAb) backbone, such that one Fab fragment is specific for an HIV pMHC and the other fragment binds to CD3. These antibodies utilize the sensitivity of T cell signaling as readouts for antigen processing and potentially as therapeutic formats. Using this approach, we have shown that bsAbs specific for the most conserved MHC-II HIV capsid epitope (Gag293) can recognize the processed epitope on human monocyte-derived dendritic cells (moDCs) fed with the whole Gag protein antigen. Recognition is exquisitely epitope-specific. Additionally, human monocyte-derived macrophages infected with HIV were able to present Gag293 using the endogenous MHC-II pathway, as read out by a Gag-specific bsAb. To our knowledge, this is the first description of endogenous class II presentation of HIV in a major cell type that supports viral replication. By developing bsAbs to detect HIV peptide presentation, we can begin to address the kinetics, pathways, and cell types contributing to the priming events in early HIV infection, which will inform improved vaccine therapies. Additionally, given the potential for therapeutic application, these bsAbs may be used to redirect cytolytic effector cells towards infected targets.