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J Clin Invest. 2017 Jun 30;127(7):2705-2718. doi: 10.1172/JCI92335. Epub 2017 Jun 19.

A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens.

Author information

1
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.
2
Biochemistry Cell and Molecular Biology Program.
3
Pharmacology Program, and.
4
Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine, Cornell University, New York, New York, USA.
5
Eureka Therapeutics, Emeryville, California, USA.

Abstract

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.

PMID:
28628042
PMCID:
PMC5490756
DOI:
10.1172/JCI92335
[Indexed for MEDLINE]
Free PMC Article

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