Abstract
Monoclonal antibodies (mAbs) are valuable as research reagents, in diagnosis and in therapy. Their high specificity, the ease in production, favorable biophysical properties and the opportunity to engineer different properties make mAbs a versatile class of biologics. mAbs targeting peptide–major histocompatibility molecule (pMHC) complexes are often referred to as “TCR-like” mAbs, as pMHC complexes are generally recognized by T-cell receptors (TCRs). Presentation of self- and non-self-derived peptide fragments on MHC molecules and subsequent activation of T cells dictate immune responses in health and disease. This includes responses to infectious agents or cancer but also aberrant responses against harmless self-peptides in autoimmune diseases. The ability of TCR-like mAbs to target specific peptides presented on MHC allows for their use to study peptide presentation or for diagnosis and therapy. This extends the scope of conventional mAbs, which are generally limited to cell-surface or soluble antigens. Herein, we review the strategies used to generate TCR-like mAbs and provide a structural comparison with the analogous TCR in pMHC binding. We further discuss their applications as research tools and therapeutic reagents in preclinical models as well as challenges and limitations associated with their use.
Highlights
Antibodies and T-cell receptors (TCRs) are highly diverse antigen-specific receptors expressed by B cells and T cells, respectively
We focus on the generation of such TCR-like Monoclonal antibodies (mAbs), how they bind peptide–major histocompatibility molecule (pMHC) compared to TCRs and their use as research tools and in therapy
We have recently developed a TCR-like mAb specific for one of the immunodominant epitopes of wheat gluten presented on human leukocyte antigen (HLA)-DQ2.5, a pMHC complex characteristic of the autoimmune condition celiac disease (CeD) [91]
Summary
Antibodies and T-cell receptors (TCRs) are highly diverse antigen-specific receptors expressed by B cells and T cells, respectively. Antibodies are usually directed against cell-surface or soluble target antigens. The use of soluble TCRs as research reagents and as therapeutics is hampered by low target affinity and challenges related to expression [5]. Engineered high-affinity, soluble TCRs, on the other hand, have shown great promise in preclinical models both regarding specificity and potency, but are still in early clinical development as a novel class of therapeutics [20,21,22,23]. The challenges associated with soluble TCR expression and low target affinity have motivated development of antibodies with TCR-like specificity. Whereas monoclonal antibodies (mAb) used in therapy usually bind cell surface or soluble antigens, TCR-like mAbs provide a complementary strategy by targeting intracellular or extracellular antigens presented on MHC. We focus on the generation of such TCR-like mAbs, how they bind pMHC compared to TCRs and their use as research tools and in therapy
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