Examining Variable Domain Orientations in Antigen Receptors Gives Insight into TCR-Like Antibody Design

Abstract

The variable domains of antibodies and T-Cell receptors (TCRs) share similar structures. Both molecules act as sensors for the immune system but recognise their respective antigens in different ways. Antibodies bind to a diverse set of antigenic shapes whilst TCRs only recognise linear peptides presented by a major histocompatibility complex (MHC). The antigen specificity and affinity of both receptors is determined primarily by the sequence and structure of their complementarity determining regions (CDRs). In antibodies the binding site is also known to be affected by the relative orientation of the variable domains, VH and VL. Here, the corresponding property for TCRs, the Vβ-Vα orientation, is investigated and compared with that of antibodies. We find that TCR and antibody orientations are distinct. General antibody orientations are found to be incompatible with binding to the MHC in a canonical TCR-like mode. Finally, factors that cause the orientation of TCRs and antibodies to be different are investigated. Packing of the long Vα CDR3 in the domain-domain interface is found to be influential. In antibodies, a similar packing affect can be achieved using a bulky residue at IMGT position 50 on the VH domain. Along with IMGT VH 50, other positions are identified that may help to promote a TCR-like orientation in antibodies. These positions should provide useful considerations in the engineering of therapeutic TCR-like antibodies.

CDR3 binding chemistry controls TCR V-domain rotational probability and germline CDR2 scanning of polymorphic MHC

“…Moreover, TCR affinity for pMHC is generally micromolar binding-weak reactions by antibody standards [42][43][44]. Related factors including the orientation of CDR2, 3°-structure of -chain constant domains and inter-chain disulfides, differences in CDR3 packing and the extra HV4, all likely contribute to pMHC-elicited monoclonal antibody Fab binding not like TCR [4,45,46]. Simply put, if positive/negative selection is based on TCR-affinity, it would be more logical that the selected repertoire reflects an optimum TCR-affinity; and thus, a qualitatively different mechanism might drive MHC restriction.…”

How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire

“…We thus compared TCR and antibody germ-line CDR loops. Previous antibody/TCR sequence comparisons indicate a VH = Vβ/VL = Vα equivalence (49). The antibody equivalents to CDR2β and CDR1α are accordingly CDR2-H and CDR1-L.…”

Comparative analysis of the CDR loops of antigen receptors

“…Although TCRs and antibodies are derived from similar genetic mechanisms and share a similar architecture, only a handful of studies have compared them ( e.g. 3, 6, 8, 16, 31, 42). Furthermore, analyses have largely focussed on sequence-based features.…”

“…Given the similarity in the genetic mechanisms, fold and the limited conformational variability in the canonical CDRs, it might be reasonable to expect structural similarity between TCRs and antibodies. Comparing TCRs and antibodies should identify potential characteristics that may inspire antibody-like TCR design, TCR-mimic antibodies and soluble TCRs (14, 16, 52, 57). Such analyses can also highlight structural signatures that may relate to their different biological functions, such as MHC restriction in TCRs (5) and the virtually unconstrained antigen binding in antibodies (46).…”