TCR Mimic Monoclonal Antibody Targets a Specific Peptide/HLA Class I Complex and Significantly Impedes Tumor Growth In Vivo Using Breast Cancer Models
- 11 January 2010
- journal article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 184 (4), 2156-2165
- https://doi.org/10.4049/jimmunol.0902414
Abstract
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)-β. 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 hCGβ 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 hCGβ 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.Keywords
This publication has 53 references indexed in Scilit:
- Her2-positive breast cancer: Herceptin and beyondEuropean Journal Of Cancer, 2008
- Identification of new accessible tumor antigens in human colon cancer by ex vivo protein biotinylation and comparative mass spectrometry analysisInternational Journal of Cancer, 2008
- Antitumor Activity of Immunotoxins with T-Cell Receptor–like Specificity against Human Melanoma XenograftsCancer Research, 2008
- Identification of new cytotoxic T-lymphocyte epitopes from cancer testis antigen HCA587Biochemical and Biophysical Research Communications, 2008
- Identification of novel tumor antigens with patient-derived immune-selected antibodiesCancer Immunology, Immunotherapy, 2008
- Targeting TARP, a novel breast and prostate tumor‐associated antigen, with T cell receptor‐like human recombinant antibodiesEuropean Journal of Immunology, 2008
- Antibody tumor penetration: Transport opposed by systemic and antigen-mediated clearanceAdvanced Drug Delivery Reviews, 2008
- Factors determining antibody distribution in tumorsTrends in Pharmacological Sciences, 2008
- Identification of a Novel Cancer-Testis Antigen CRT2 Frequently Expressed in Various Cancers Using Representational Differential AnalysisClinical Cancer Research, 2007
- Cancer Regression in Patients After Transfer of Genetically Engineered LymphocytesScience, 2006