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A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens
- Source :
- Journal of Clinical Investigation. 127:3557-3557
- Publication Year :
- 2017
- Publisher :
- American Society for Clinical Investigation, 2017.
-
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.
- Subjects :
- 0301 basic medicine
Male
Receptors, Antigen, T-Cell
Human leukocyte antigen
Epitope
Mice
03 medical and health sciences
0302 clinical medicine
Antigen
Antigens, Neoplasm
Cell Line, Tumor
Cytotoxic T cell
Animals
Humans
Receptor
HLA-A1 Antigen
030304 developmental biology
PRAME
0303 health sciences
biology
Chemistry
T-cell receptor
Neoplasms, Experimental
General Medicine
Xenograft Model Antitumor Assays
3. Good health
030104 developmental biology
Immunoglobulin G
030220 oncology & carcinogenesis
Cancer research
biology.protein
Female
Antibody
Corrigendum
Research Article
Subjects
Details
- ISSN :
- 15588238 and 00219738
- Volume :
- 127
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....49ffaa064cecf4bd6b68f78ca0acc474