A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens
Aaron Y. Chang, … , Cheng Liu, David A. Scheinberg
Aaron Y. Chang, … , Cheng Liu, David A. Scheinberg
Published June 30, 2017; First published June 19, 2017
Citation Information: J Clin Invest. 2017;127(7):2705-2718. https://doi.org/10.1172/JCI92335.
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Categories: Research Article Immunology Therapeutics

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.

Authors

Aaron Y. Chang, Tao Dao, Ron S. Gejman, Casey A. Jarvis, Andrew Scott, Leonid Dubrovsky, Melissa D. Mathias, Tatyana Korontsvit, Victoriya Zakhaleva, Michael Curcio, Ronald C. Hendrickson, Cheng Liu, David A. Scheinberg

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Figure 6

The immunoproteasome catalyzes increased nondestructive cleavages on an ALY-precursor peptide.

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The immunoproteasome catalyzes increased nondestructive cleavages on an ...
A 20-mer ALY-elongated precursor peptide was incubated with purified constitutive proteasome or immunoproteasome for the indicated times. (A) All detectable fragments and their respective ion intensities were assigned to be nondestructive or destructive depending on whether the N- or C-terminal cleavages required to generate that fragment would have resulted in destruction of the ALY 10-mer. Ratios of ion intensity sums for nondestructive/destructive products are plotted. (B) Major cleavage sites along the precursor peptide after 1 hour were mapped by summing the ion intensities of each fragment resulting from a cleavage after the specific residue. Heat map with arbitrary units corresponding to ion intensities is shown, with 3 replicates illustrated in 3 bars for each proteasome preparation. Only fragments identified as at least 2 residues or more could be mapped, and thus cleavages before Q296 or after L313 were not accounted for. (C) Major differences in cleavage specificity between constitutive and immunoproteasome are schematized and mapped by red arrows. The green arrows denote the canonical proteasomal cleavage to generate the C-terminal end of the ALY 10-mer. Data are from 3 technical replicates per experimental condition with mean ± SEM plotted. Groups compared using multiple t tests. ***P < 0.001; ****P < 0.0001.