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
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 2

Pr20M mediates Ab-dependent cellular cytotoxicity in vitro on PRAME+HLA-A2+ leukemias and lymphoma.

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Pr20M mediates Ab-dependent cellular cytotoxicity in vitro on PRAME+HLA-...
(A) ADCC assay was performed on hematopoietic cancers. 51Cr-labeled target leukemia or lymphoma cells were incubated with healthy donor PBMCs at an effector/target ratio of 50:1. Pr20M or an afucosylated isotype control Ab was added at the indicated concentration. Supernatant was collected after 6 hours, and scintillation counting was used to determine percentage of specific lysis. Data represent at least 3 experiments for each cell line except SKLY16 and MAC2A (done twice). (B) Healthy donor PBMCs were incubated overnight with 1 μg/ml of Pr20M or afucosylated isotype control. Flow cytometry was used to determine populations of B cells (CD19+CD3–), T cells (CD3+CD19–), monocytes (CD14+CD19–), and myeloid cells (CD33+CD19–). One representative analysis (n = 3) is shown, including a positive control to demonstrate that PBMCs in all assays were capable of depleting a PRAME+HLA-A2+ lymphoma (CD19– and transduced with GFP). Data from HLA-A2+ healthy donor PBMCs (n = 3) performed independently are summarized and plotted. Data analyzed by paired Wilcoxon signed-rank test.