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

Authors: Chang, A. Y.; Dao, T.; Gejman, R. S.; Jarvis, C. A.; Scott, A.; Dubrovsky, L.; Mathias, M. D.; Korontsvit, T.; Zakhaleva, V.; Curcio, M.; Hendrickson, R. C.; Liu, C.; Scheinberg, D. A.
Article Title: A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens
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.
Journal Title: Journal of Clinical Investigation
Volume: 127
Issue: 7
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation  
Date Published: 2017-06-30
Start Page: 2705
End Page: 2718
Language: English
DOI: 10.1172/jci92335
PROVIDER: scopus
PMCID: PMC5490756
PUBMED: 28628042
Notes: Article -- Export Date: 2 August 2017 -- Source: Scopus
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MSK Authors
  1. Tao Dao
    57 Dao
  2. Michael J Curcio
    26 Curcio
  3. Andrew Crosbie Scott
    11 Scott
  4. Melissa Divya Mathias
    14 Mathias
  5. Ron Shlomo Gejman
    8 Gejman
  6. Aaron   Chang
    10 Chang
  7. Casey   Jarvis
    3 Jarvis