TCR-like antibodies targeting autoantigen-mhc complexes: a mini-review

Abstract

T cell receptors (TCRs) recognize peptide antigens bound to major histocompatibility complex (MHC) molecules (p/MHC) that are expressed on cell surfaces; while B cell-derived antibodies (Abs) recognize soluble or cell surface native antigens of various types (proteins, carbohydrates, etc.). Immune surveillance by T and B cells thus inspects almost all formats of antigens to mount adaptive immune responses against cancer cells, infectious organisms and other foreign insults, while maintaining tolerance to self-tissues. With contributions from environmental triggers, the development of autoimmune disease is thought to be due to the expression of MHC risk alleles by antigen-presenting cells (APCs) presenting self-antigen (autoantigen), breaking through self-tolerance and activating autoreactive T cells, which orchestrate downstream pathologic events. Investigating and treating autoimmune diseases have been challenging, both because of the intrinsic complexity of these diseases and the need for tools targeting T cell epitopes (autoantigen-MHC). Naturally occurring TCRs with relatively low (micromolar) affinities to p/MHC are suboptimal for autoantigen-MHC targeting, whereas the use of engineered TCRs and their derivatives (e.g., TCR multimers and TCR-engineered T cells) are limited by unpredictable cross-reactivity. As Abs generally have nanomolar affinity, recent advances in engineering TCR-like (TCRL) Abs promise advantages over their TCR counterparts for autoantigen-MHC targeting. Here, we compare the p/MHC binding by TCRs and TCRL Abs, review the strategies for generation of TCRL Abs, highlight their application for identification of autoantigen-presenting APCs, and discuss future directions and limitations of TCRL Abs as immunotherapy for autoimmune diseases.

Keywords: TCR-like antibodies; antigen-specific therapy; autoantigen presentation; autoimmune diseases; immunotherapy.

Figure 1

Therapeutic potential of TCRL mAbs in autoimmune diseases. TCRL mAbs specific for autoantigen/HLA complexes can elicit therapeutic effects via depleting (pink) or non-depleting (cyan) mechanisms. (A) TCRL mAbs either block autoantigen presentation or induce apoptosis of target cells. (B) TCRL mAbs induce Fc-mediated cytotoxicity through various effector mechanisms. (C, F) Bispecific antibodies targeting autoantigen/HLA complexes and either a surface marker of target cells or a pathogenic-related cytokine; (D) TCRL mAb–toxin conjugates induce auto-APC depletion by payload effector molecules, including cytokines, toxins or radioactive substances. (E) TCLR mAb-cytokine conjugates guide the delivery of immunomodulatory cytokines (e.g., IL-10, TGF-β) to auto-APCs for tolerance induction. (G) TCRL scFv fragments are reformatted into CARs for auto-APC targeting and depletion. (H) CD4+CD25+ TCRL CAR T_reg cells suppress T_eff function and induce tolerance. (This figure was created with BioRender.com).