TCR mimic monoclonal antibody targets a specific peptide/HLA class I complex and significantly impedes tumor growth in vivo using breast cancer models.
Our laboratory has developed a process for generating mAbs with selectivity to unique peptides in the context of MHC molecules. Recently, we reported that RL4B, an mAb that we have called a TCR mimic (TCRm) because it recognizes peptide in the context of MHC, has cytotoxic activity in vitro and prevented growth of tumor cells in a prophylactic setting. When presented in the context of HLA-A2, RL4B TCRm recognizes the peptide GVLPALPQV derived from human chorionic gonadotropin (hCG)-beta. In this study, we show that RL4B TCRm has strong binding affinity for the GVLPALPQV peptide/HLA-A2 epitope and fine binding specificity for cells that express endogenous hCGbeta Ag and HLA-A2. In addition, suppression of tumor growth with RL4B TCRm was observed in orthotopic models for breast cancer. Using two aggressive human tumor cell lines, MDA-MB-231 and MCF-7, we provide evidence that RL4B TCRm significantly retards tumor growth, supporting a possible role for TCRm agents in therapeutic settings. Moreover, tumors in mice responded to RL4B TCRm therapy in a dose-dependent manner, eliminating tumors at the highest dose. RL4B TCRm strongly detects the hCGbeta peptide/HLA-A2 epitope in human primary breast tumor tissue, but does not react or reacts weakly with normal breast tissue from the same patient. These results further illustrate the selective nature of TCRm Abs and the clinical relevance of the GVLPALPQV peptide/HLA-A2 epitope expression in tumor cells, because they provide the first evidence that Abs that mimic the TCR can be used to markedly reduce and suppress tumor growth.
Verma
Bhavna
B
Center for Immunotherapeutic Research, School of Pharmacy, Texas Tech University Health Sciences Center, TX, USA.
Neethling
Francisca A
FA
Caseltine
Shannon
S
Fabrizio
Ginger
G
Largo
Sherly
S
Duty
J Andrew
JA
Tabaczewski
Piotr
P
Weidanz
Jon A
JA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism* / Q000502:physiology / Q000627:therapeutic use; D000915:Antibody Affinity; D000918:Antibody Specificity; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000276:immunology / Q000378:metabolism; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000276:immunology* / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics; D018390:Gene Targeting; D006131:Growth Inhibitors / Q000502:physiology* / Q000627:therapeutic use; D015234:HLA-A Antigens / Q000276:immunology / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018716:Molecular Mimicry / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018997:Chorionic Gonadotropin, beta Subunit, Human; D018984:Epitopes, T-Lymphocyte; D006131:Growth Inhibitors; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010446:Peptide Fragments