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

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

Research output: Contribution to journalArticleResearchpeer-review

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2705-2718
Number of pages14
JournalJournal of Clinical Investigation
Volume127
Issue number7
DOIs
Publication statusPublished - 30 Jun 2017
Externally publishedYes

Cite this

Chang, A. Y., Dao, T., Gejman, R. S., Jarvis, C. A., Scott, A., Dubrovsky, L., ... Scheinberg, D. A. (2017). A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens. Journal of Clinical Investigation, 127(7), 2705-2718. https://doi.org/10.1172/JCI92335
Chang, Aaron Y. ; Dao, Tao ; Gejman, Ron S. ; Jarvis, Casey A. ; Scott, Andrew ; Dubrovsky, Leonid ; Mathias, Melissa D. ; Korontsvit, Tatyana ; Zakhaleva, Victoriya ; Curcio, Michael ; Hendrickson, Ronald C. ; Liu, Cheng ; Scheinberg, David A. / A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 7. pp. 2705-2718.
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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.",
author = "Chang, {Aaron Y.} and Tao Dao and Gejman, {Ron S.} and Jarvis, {Casey A.} and Andrew Scott and Leonid Dubrovsky and Mathias, {Melissa D.} and Tatyana Korontsvit and Victoriya Zakhaleva and Michael Curcio and Hendrickson, {Ronald C.} and Cheng Liu and Scheinberg, {David A.}",
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Chang, AY, Dao, T, Gejman, RS, Jarvis, CA, Scott, A, Dubrovsky, L, Mathias, MD, Korontsvit, T, Zakhaleva, V, Curcio, M, Hendrickson, RC, Liu, C & Scheinberg, DA 2017, 'A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens', Journal of Clinical Investigation, vol. 127, no. 7, pp. 2705-2718. https://doi.org/10.1172/JCI92335

A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens. / Chang, Aaron Y.; Dao, Tao; Gejman, Ron S.; Jarvis, Casey A.; Scott, Andrew; Dubrovsky, Leonid; Mathias, Melissa D.; Korontsvit, Tatyana; Zakhaleva, Victoriya; Curcio, Michael; Hendrickson, Ronald C.; Liu, Cheng; Scheinberg, David A.

In: Journal of Clinical Investigation, Vol. 127, No. 7, 30.06.2017, p. 2705-2718.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens

AU - Chang, Aaron Y.

AU - Dao, Tao

AU - Gejman, Ron S.

AU - Jarvis, Casey A.

AU - Scott, Andrew

AU - Dubrovsky, Leonid

AU - Mathias, Melissa D.

AU - Korontsvit, Tatyana

AU - Zakhaleva, Victoriya

AU - Curcio, Michael

AU - Hendrickson, Ronald C.

AU - Liu, Cheng

AU - Scheinberg, David A.

PY - 2017/6/30

Y1 - 2017/6/30

N2 - 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.

AB - 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.

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