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 3

Pr20M is therapeutically active against ALL and AML in vivo, and target epitope downregulation is not a mechanism of Pr20M resistance.

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Pr20M is therapeutically active against ALL and AML in vivo, and target ...
BV173 (ALL), SET2 (AML), and AML14 (AML) were transduced to express luciferase and GFP. NSG mice were engrafted though tail-vein injection, and on day 6 or 7, mice were randomized into groups and treated with 50 μg of Pr20M twice a week, left untreated (control for BV173 and SET2), or treated with an afucosylated isotype control Ab (AML14). Tumor burden was determined by BLI for BV173 (n = 5 mice) (A), SET2 (n = 5 mice) (B), and AML14 (n = 4 mice) (C) once a week throughout the experiment, and the BLI data are summarized below the images. The scales for days 7 and 14 for AML14 are lowered to indicate engraftment and early tumor growth. Total flux (photos/s) was normalized to each mouse’s total flux on day 6 or 7 immediately before initiation of Pr20M therapy and summarized with mean ± SEM. (D) Mice from the AML14 experiment were sacrificed on day 29, and bone marrow was harvested to determine tumor burden by flow cytometry for GFP+HLA-A2+ AML14 cells. Representative plots (n = 4 mice per group) are shown, and data are summarized. (E) MFI of AML14 for HLA-A2 and Pr20 was determined by flow cytometry. Because Pr20M-treated mice presumably had Pr20M already bound on tumor cells, staining was performed by an additional Pr20 stain on all samples followed by a secondary PE-conjugated anti-human Ab (n = 4 mice per group). Experiments were performed once per model. Differences were evaluated using the unpaired t tests on indicated times and samples. AML14 BLI data are representative of 3 similar experiments, while SET2 and BV173 BLI data are from 1 experiment. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.