Direct discovery and validation of a peptide/MHC epitope expressed in primary human breast cancer cells using a TCRm monoclonal antibody with profound antitumor properties.
The identification and validation of new cancer-specific T cell epitopes continues to be a major area of research interest. Nevertheless, challenges remain to develop strategies that can easily discover and validate epitopes expressed in primary cancer cells. Regarded as targets for T cells, peptides presented in the context of the major histocompatibility complex (MHC) are recognized by monoclonal antibodies (mAbs). These mAbs are of special importance as they lend themselves to the detection of epitopes expressed in primary tumor cells. Here, we use an approach that has been successfully utilized in two different infectious disease applications (WNV and influenza). A direct peptide-epitope discovery strategy involving mass spectrometric analysis led to the identification of peptide YLLPAIVHI in the context of MHC A*02 allele (YLL/A2) from human breast carcinoma cell lines. We then generated and characterized an anti-YLL/A2 mAb designated as RL6A TCRm. Subsequently, the TCRm mAb was used to directly validate YLL/A2 epitope expression in human breast cancer tissue, but not in normal control breast tissue. Moreover, mice implanted with human breast cancer cells grew tumors, yet when treated with RL6A TCRm showed a marked reduction in tumor size. These data demonstrate for the first time a coordinated direct discovery and validation strategy that identified a peptide/MHC complex on primary tumor cells for antibody targeting and provide a novel approach to cancer immunotherapy.
Department of Pharmaceutical Sciences, School of Pharmacy, Center for Immunotherapeutic Research, Texas Tech University Health Sciences Center, 1718 Pine Street, Abilene, TX 79601, USA.
Bhavna
B
Verma
Oriana E
OE
Hawkins
Francisca A
FA
Neethling
Shannon L
SL
Caseltine
Sherly R
SR
Largo
William H
WH
Hildebrand
Jon A
JA
Weidanz
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology; D015153:Blotting, Western; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000276:immunology / Q000628:therapy*; D019496:Cancer Vaccines / Q000627:therapeutic use; D053487:DEAD-box RNA Helicases / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D018716:Molecular Mimicry; D010446:Peptide Fragments / Q000276:immunology / Q000627:therapeutic use*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D020349:Surface Plasmon Resonance; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D053487:DEAD-box RNA Helicases