T-cell-receptor-like antibodies – generation, function and applications

Abstract

Tumour and virus-infected cells are recognised by CD8+ cytotoxic T cells that, in response, are activated to eliminate these cells. In order to be activated, the clonotypic T-cell receptor (TCR) needs to encounter a specific peptide antigen presented by the membrane surface major histocompatibility complex (MHC) molecule. Cells that have undergone malignant transformation or viral infection present peptides derived from tumour-associated antigens or viral proteins on their MHC class I molecules. Therefore, disease-specific MHC-peptide complexes are desirable targets for immunotherapeutic approaches. One such approach transforms the unique fine specificity but low intrinsic affinity of TCRs to MHC-peptide complexes into high-affinity soluble antibody molecules endowed with a TCR-like specificity towards tumour or viral epitopes. These antibodies, termed TCR-like antibodies, are being developed as a new class of immunotherapeutics that can target tumour and virus-infected cells and mediate their specific killing. In addition to their therapeutic capabilities, TCR-like antibodies are being developed as diagnostic reagents for cancer and infectious diseases, and serve as valuable research tools for studying MHC class I antigen presentation.

Functional Comparison of Engineered T Cells Carrying a Native TCR versus TCR-like Antibody–Based Chimeric Antigen Receptors Indicates Affinity/Avidity Thresholds

“…Specific peptide-MHCs (pMHCs) can also be targeted by generating recombinant Abs mimicking TCR specificity, which are termed "TCR-like Abs" (26). We and others have isolated Abs that recognize HLA-A2 complexes bearing peptides derived from tumor and viral Ags by means of phage display and hybridoma strategies (27)(28)(29)(30).…”

Specific Targeting of a Naturally Presented Osteosarcoma Antigen, Papillomavirus Binding Factor Peptide, Using an Artificial Monoclonal Antibody

“…Generation of antibodies recognizing HLA⅐peptide complexes derived from tumor-associated antigens has been reported mainly in the field of melanoma (28). Development of such antibodies against HLA⅐peptide complexes is significant because assessment of the expression status of HLA⅐vaccine peptide complexes is important to select candidate patients and predict the efficacy of peptide-based immunotherapy.…”

T cell immunotherapy in hepatitis B Virus related hepatocellular carcinoma

“…This simplistic criteria only takes into consideration the HLA component of the complex recognized by the TCRs [29] For the therapy to be effective, one has to be able to account for the presence or absence of the T cell epitope on the HCC cells. Ideally, this can be achieved using TCR-like antibodies specific for every HLA/HBV-epitope complex [43,44] but the diversity of complexes makes this approach unfeasible [45] . Peptide elution and mass spectrometry strategies [46] might seem possible, but such techniques is highly specialized and complex, and at the moment restricted primarily to academic research and not clinical application.…”