Preferentially expressed
antigen in
melanoma (PRAME) is a
cancer-testis antigen that is expressed in many
cancers and
leukemias. In healthy tissue, PRAME expression is limited to the testes and ovaries, making it a highly attractive
cancer target. PRAME is an intracellular
protein that cannot currently be drugged. After proteasomal processing, the PRAME300-309
peptide ALYVDSLFFL (ALY) is presented in the context of
human leukocyte antigen HLA-A*02:01 molecules for recognition by the
T cell receptor (TCR) of cytotoxic T cells. Here, we have described Pr20, a TCR mimic (TCRm) human
IgG1 antibody that recognizes the cell-surface ALY
peptide/HLA-A2 complex. Pr20 is an immunological tool and potential therapeutic agent. Pr20 bound to PRAME+HLA-A2+
cancers. An afucosylated Fc form (Pr20M) directed antibody-dependent cellular cytotoxicity against PRAME+HLA-A2+
leukemia cells and was therapeutically effective against mouse xenograft models of human
leukemia. In some
tumors, Pr20 binding markedly increased upon IFN-γ treatment, mediated by induction of the immunoproteasome catalytic subunit β5i. The immunoproteasome reduced internal destructive cleavages within the ALY
epitope compared with the constitutive
proteasome. The data provide rationale for developing TCRm
antibodies as therapeutic agents for
cancer, offer mechanistic insight on proteasomal regulation of
tumor-associated
peptide/HLA
antigen complexes, and yield possible therapeutic solutions to target
antigens with ultra-low surface presentation.