T-cell receptor mimic (TCRm) antibody therapeutics against intracellular proteins

Xu, Yixiang; Salazar, Georgina To’a; Zhang, Ningyan; An, Zhiqiang

doi:10.1093/abt/tbz001

Cited by 12 publications

(20 citation statements)

References 99 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Many groups have attempted to augment TCR and antibody designs by swapping binding sites between these two receptors [e.g., (37, 52)]. TCR-mimic antibodies were developed in the hope of transferring the ability of TCRs to target intracellular proteins, to antibodies for the use in cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of the CDR Loops of Antigen Receptors

2019

View full text Add to dashboard Cite

The adaptive immune system uses two main types of antigen receptors: T-cell receptors (TCRs) and antibodies. While both proteins share a globally similar β-sandwich architecture, TCRs are specialized to recognize peptide antigens in the binding groove of the major histocompatibility complex, while antibodies can bind an almost infinite range of molecules. For both proteins, the main determinants of target recognition are the complementarity-determining region (CDR) loops. Five of the six CDRs adopt a limited number of backbone conformations, known as the “canonical classes”; the remaining CDR (β3in TCRs and H3 in antibodies) is more structurally diverse. In this paper, we first update the definition of canonical forms in TCRs, build an auto-updating sequence-based prediction tool (available at http://opig.stats.ox.ac.uk/resources) and demonstrate its application on large scale sequencing studies. Given the global similarity of TCRs and antibodies, we then examine the structural similarity of their CDRs. We find that TCR and antibody CDRs tend to have different length distributions, and where they have similar lengths, they mostly occupy distinct structural spaces. In the rare cases where we found structural similarity, the underlying sequence patterns for the TCR and antibody version are different. Finally, where multiple structures have been solved for the same CDR sequence, the structural variability in TCR loops is higher than that in antibodies, suggesting TCR CDRs are more flexible. These structural differences between TCR and antibody CDRs may be important to their different biological functions.

show abstract

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of the CDR Loops of Antigen Receptors

2019

View full text Add to dashboard Cite

show abstract

“…Many groups have attempted to augment TCR and antibody designs by swapping binding sites between these two receptors ( e.g. 56, 57). TCR-mimic antibodies were developed in the hope of transferring the ability of TCRs to target intracellular proteins, to antibodies for the use in cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

“…TCR and antibody structures were numbered in the IMGT scheme (31) using ANARCI (15): CDR1 (27–38), CDR2 (56–65), and CDR3 (105–117). To compare the CDR loops of TCRs and antibodies, we assumed equivalence between β /heavy chains and α /light chains (30), as TCR β and antibody heavy chains rely on VDJ recombination, while TCR α and antibody light chains are formed by VJ recombination.…”

Section: Methodsmentioning

confidence: 99%

Comparative analysis of the CDR loops of antigen receptors

Wong

Leem

Deane

2019

Preprint

View full text Add to dashboard Cite

5The adaptive immune system uses two main types of antigen receptors: T-cell receptors (TCRs) 6 and antibodies. While both proteins share a globally similar β-sandwich architecture, TCRs are 7 specialised to recognise peptide antigens in the binding groove of the major histocompatibility 8 complex, while antibodies can bind an almost infinite range of molecules. For both proteins, 9 the main determinants of target recognition are the complementarity-determining region (CDR) 10 loops. Five of the six CDRs adopt a limited number of backbone conformations, known as the 11 'canonical classes'; the remaining CDR (β3 in TCRs and H3 in antibodies) is more structurally 12 diverse. In this paper, we first update the definition of canonical forms in TCRs, build an auto-13 updating sequence-based prediction tool (available at http://opig.stats.ox.ac.uk/resources) and 14 demonstrate its application on large scale sequencing studies. Given the global similarity of TCRs 15 and antibodies, we then examine the structural similarity of their CDRs. We find that TCR and 16 antibody CDRs tend to have different length distributions, and where they have similar lengths, 17 they mostly occupy distinct structural spaces. In the rare cases where we found structural simi-18 larity, the underlying sequence patterns for the TCR and antibody version are different. Finally, 19 where multiple structures have been solved for the same CDR sequence, the structural variability 20 in TCR loops is higher than that in antibodies, suggesting TCR CDRs are more flexible. These 21 structural differences between TCR and antibody CDRs may be important to their different bio-22 logical functions. 23 1 Introduction 24The adaptive immune system defends the host organism against a wide range of foreign molecules, 25 or antigens, using two types of receptors: T-cell receptors (TCRs) and antibodies (23). TCRs typi-26 cally recognise peptide antigens presented via the major histocompatibility complex (MHC; 44), 27 while antibodies can bind almost any antigen, including proteins, peptides, and haptens (46). 28Despite their different roles in the immune response, these proteins share a β-sandwich fold (Fig-29 ure 1; 16, 51).30 In humans, most TCRs are αβTCRs, consisting of one TCRα chain and one TCRβ chain, while 31 most antibodies are comprised of two heavy(H)-light(L) chain dimers (Figure 1). All four types 32 of chains (α, β, H and L) are formed from the somatic rearrangement of the respective V, D, and 33 J genes of the TCR or antibody loci. The random combination of these genes, alongside further 34 diversification mechanisms (e.g. random nucleotide addition), are estimated to yield trillions of 35 unique TCRs and antibodies (5, 20). TCRα and antibody light chains are made from the V and J 36 genes, while TCRβ and antibody heavy chains are assembled from the V, D, and J genes, making 37 the L-chain equivalent to α-chain and H-chain equivalent to β-chain (5, 45). In both types of 38 antigen receptors, sequence and structural diversity is concentrated i...

show abstract

“…One is that a therapeutic BiTE/TriTE can target intracellular proteins in tumor cells, such as oncoprotein WT1 [ 95 ]. T cell receptor mimics (TCRm) or T cell receptor (TCR)-like antibodies recognize “aggretopes” on the peptide/MHC-I bimolecular complex, and this recognition is similar to that mediated by T cell expressed TCR [ 96 , 97 ]. These antibodies could be further developed as BiTEs [ 95 , 98 ].…”

Section: Despite Many Strengths There Remain Significant Hurdles mentioning

confidence: 99%

Bi- and Tri-Specific T Cell Engager-Armed Oncolytic Viruses: Next-Generation Cancer Immunotherapy

et al. 2020

View full text Add to dashboard Cite

Oncolytic viruses (OVs) are potent anti-cancer biologics with a bright future, having substantial evidence of efficacy in patients with cancer. Bi- and tri-specific antibodies targeting tumor antigens and capable of activating T cell receptor signaling have also shown great promise in cancer immunotherapy. In a cutting-edge strategy, investigators have incorporated the two independent anti-cancer modalities, transforming them into bi- or tri-specific T cell engager (BiTE or TriTE)-armed OVs for targeted immunotherapy. Since 2014, multiple research teams have studied this combinatorial strategy, and it showed substantial efficacy in various tumor models. Here, we first provide a brief overview of the current status of oncolytic virotherapy and the use of multi-specific antibodies for cancer immunotherapy. We then summarize progress on BiTE and TriTE antibodies as a novel class of cancer therapeutics in preclinical and clinical studies, followed by a discussion of BiTE- or TriTE-armed OVs for cancer therapy in translational models. In addition, T cell receptor mimics (TCRm) have been developed into BiTEs and are expected to greatly expand the application of BiTEs and BiTE-armed OVs for the effective targeting of intracellular tumor antigens. Future applications of such innovative combination strategies are emerging as precision cancer immunotherapies.

show abstract

T-cell receptor mimic (TCRm) antibody therapeutics against intracellular proteins

Cited by 12 publications

References 99 publications

Comparative Analysis of the CDR Loops of Antigen Receptors

Comparative Analysis of the CDR Loops of Antigen Receptors

Comparative analysis of the CDR loops of antigen receptors

Bi- and Tri-Specific T Cell Engager-Armed Oncolytic Viruses: Next-Generation Cancer Immunotherapy

Contact Info

Product

Resources

About