T-Cell Receptor-Like Antibodies: Targeting the Intracellular Proteome Therapeutic Potential and Clinical Applications

Abstract

Major histocompatibility complex (MHC) class I molecules are key in the immune response against malignant cells by shaping the T-cell repertoire and presenting peptides from endogenous antigens to CD8+ cytotoxic T cells. Because of their unique specificity, MHC-peptide complexes are a desirable target for novel immunotherapeutic approaches. These complexes can be targeted by recombinant T-cell receptors (TCRs). However, most TCRs produced thus far have affinities which are too low for target detection under normal assay conditions, and limited stability (due to their generation in a single-chain version). Developing high-affinity soluble antibody molecules endowed with a TCR-like specificity toward tumor epitopes, termed TCR-like antibodies, addresses the low affinity of TCRs. These TCR-like antibodies are being developed as a new immunotherapeutic class for targeting tumor cells and mediating their specific killing. In addition, these antibodies are valuable research reagents enabling the study of human class I peptide-MHC ligand-presentation and TCR–peptide–MHC interactions

A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens

“…They also bypass the patient-specific limitations of CTL-based therapies. Only a few TCRm have been studied in preclinical models as agents for cancer therapy (15,29,36,(52)(53)(54)(55). Therefore, the present study on Pr20 adds additional proof-of-concept that TCRm can be potent and selective therapeutic agents.…”

Therapeutic Antibodies against Intracellular Tumor Antigens

“…Antibodies targeting disease-associated peptide–MHC-I complexes, the so-called TCRm antibodies or TCR-like antibodies, are similar to the TCR in that they bind both the peptide and the MHC-I molecule and, therefore, their binding is both peptide-specific and MHC-restricted ( 52 , 53 ). TCRm antibodies have expanded the range of targetable antigens to include intracellular proteins without the delivery complications associated with intracellular antibodies.…”

“…TCRm antibodies have been produced either by immunization or by phage display, with both strategies presenting their respective pros and cons. One of the main limitations in the production of TCRm antibodies by both strategies was the correct refolding of recombinant peptide–MHC complexes and their purification ( 53 ). Recombinant peptide–MHC complexes are made by using bacterial expression to generate inclusion bodies containing the extracellular domains of the heavy chain of human leukocyte antigen (HLA) and β2-microglobulin.…”

“…Most TCRm antibodies published thus far have used phage display libraries for antibody production. Investigators argue that the main advantage of phage display is that it is efficient while being a relatively fast method ( 53 ). On the other hand, hybridoma technology is a relatively slower strategy, and it requires the immunogenic peptide and the MHC complex to bind with high affinity and form a very stable complex in order for the complex to persist throughout the immunization and in vivo IgG maturation.…”

Targeting Epstein-Barr virus–transformed B lymphoblastoid cells using antibodies with T-cell receptor–like specificities

“…As antibodies, TCR-like mAbs also exhibit better stabilities and higher affinities than TCRs. 9 Over the years, increasing interest in TCR-like mAbs has led to a rapid expansion of the repertoire of TCRlike mAbs targeting both viral [10][11][12][13] and tumor-associated antigens. [14][15][16][17][18][19] These studies have demonstrated the feasibility of TCR-like mAbs to target cells expressing neoantigen, independent of the immunoregulatory microenvironment that might inhibit T-cell function.…”