Characterization of a novel therapeutic antibody targeting peptide/HLA-E

Abstract

Abstract T-cell receptor mimic antibodies (TCRm) have become an attractive therapeutic modality group as they allow for the targeting of intracellular proteins presented by HLA, which may allow for a large potential of new targets. However, the polymorphic nature of classical HLA class I and findings of HLA downregulation in cancer cells might limit the use of these agents for cancer treatment. An alternative approach would be to target peptides presented by HLA-E, a highly monomorphic molecule often found upregulated in cancer cells. Thus, we aimed to generate a TCRm against HLA-E presenting the leader sequence peptide from HLA-G since both HLAs are often expressed in multiple cancer types. An antibody was identified from a naïve human phage library and further affinity matured using yeast display. The final clone, ABX-001, had an affinity constant (K D) of 7.9nM. Specificity studies using both peptide-loaded cells and tumor cell lines showed that ABX-001 only bound when both HLA-E and HLA-G were present. Extensive profiling was done on immune cells to also confirm that they did not bind ABX-001. Finally, ABX-001 was assessed for its ability to direct killing of target-positive tumor cell lines. We observed that cytotoxicity in CD8 +T cells was enhanced with the addition of an ABX-001-CD3 T cell engager. We also observed that ABX-001 can act as a checkpoint inhibitor by blocking the interaction of HLA-E with NKG2A in cytotoxicity experiments using NK cells. These data indicate that we can effectively target peptide/HLA-E and highlights its potential therapeutic applications in cancer treatment.