CD1a-reactive t cell receptors and uses thereof

Abstract

The invention relates to CD1a-reactive T-cell receptors (TCRs), and their use in treating or preventing an inflammatory skin or mucosal disorder or disease or one or more associated systemic disease or disorder, one or more inflammatory drug reaction which manifests systemically, a CD1a-expressing malignancy or a malignancy wherein CD1a is altered in expression or function.

Description

[0001] T CELL RECEPTORS AND USES THEREOF

[0002] TECHNICAL FIELD

[0003] The present invention relates to T cell receptors (TCRs) which are CD la-reactive. The invention also relates to the use of TCR receptors in treating and / or preventing diseases or disorders associated with altered CD la expression or function.

[0004] BACKGROUND

[0005] CD la is an MHC class I-like molecule expressed at constitutively high levels by Langerhans cells and is inducible on other myeloid cell subsets, as well as on populations of lymphocytes. It presents lipid antigens to CD la-reactive T cells but despite it being the first named CD (Cluster of Differentiation) antigen, we still know relatively little about CD la fundamental biology and its contribution to disease. This is due to technical and scientific challenges of identifying and growing CD la-reactive T cells.

[0006] It is becoming clear that CD la-reactive T cells are a major part of the repertoire of skin and blood T cells and can contribute to skin and systemic inflammation (PMID: 25584012, 26865566, 27670592, 36477177, 37267382, 27548435, 36550321). Such discoveries are stimulating an interest in targeting CD la therapeutically. Furthermore, some malignancies express CD la including Langerhans cell histiocytosis, Langerhans cell sarcoma and subsets of T cell lymphoma / leukaemias. Therefore, understanding the biological role of CD la and its recognition by T cells has broad relevance for biology and therapeutic and vaccination interventions across inflammation, infection and malignancy.

[0007] Most CD la-reactive T cells express the alpha-beta T cell receptor (TCR), while some can express a gamma-delta TCR (PMID 21037579, 25642819, 35790773). Although CD la is relatively monomorphic, existing data suggest diverse alpha beta T cell receptor usage (PMID 21037579, 24362891) perhaps with some enriched variable chain usage, although shared variable regions have not been consistently found across studies (PMID 37951348, 37267382). In contrast to the well-documented invariant NKT cells which respond to lipids presented by CD Id and express a conserved “invariant” TCR, despite decades of work, similar invariant TCR have not been found for CD la-reactive T cells. The field has therefore concluded that CD la-reactive T cells express relatively diverse TCR. This conclusion has likely limited our understanding of CD la-reactive T cell biology, for example in finding such invariant TCR within different tissues and / or disease settings. Such a possibility may open discoveries of the relevance of the CD la pathway in diseases, and new treatments and vaccination. Furthermore, existence of the invariant TCR would inform the biology of CD la recognition and potential use of such highly selected TCR diagnostically, prognostically or in therapeutic approaches.

[0008] There is therefore a need for the development of new or improved CD la-reactive T- cells and TCRs.

[0009] SUMMARY OF INVENTION

[0010] In a first aspect, there is provided a CD la-reactive T-cell receptor (TCR). The TCR may comprise a TCR alpha chain including a TCR alpha chain variable domain and a TCR beta chain including a TCR beta chain variable domain; or a TCR gamma chain including a TCR gamma chain variable domain and a TCR delta chain including a TCR delta chain variable domain.

[0011] The TCR may be an invariant or shared TCR. Also provided are TCRs with sequences related to an invariant or shared TCR of the invention.

[0012] The TCR may comprise an alpha chain variable domain and a beta chain variable domain comprising: a CDR3-alpha of amino acid sequence CAASAXGNQFYF, wherein X is F or W.

[0013] Within the CDR3 -alpha, a central motif of 4 or 5 amino acids was often conserved across the TCRs isolated, and most commonly comprised the amino acid sequence AFGN.

[0014] It was noted that the central motif may be AXGN, wherein X is F or W. Closely related central motifs included VFGN, AFNN, LWANN, showing that the amino acids either side of X, can tolerate those with similar side chains. Although there is a common motif, it is anticipated that variation within this central motif may occur in other examples by hydrophobic, hydrophilic, non-polar, aliphatic or aromatic side chains.

[0015] Such a TCR may also comprise a CDRl-alpha of amino acid sequence NSMFDY, and / or a CDR2-alpha of amino acid sequence ISSIKDK. The CDR2-alpha may comprise acidic / basic pair motifs. Such a TCR may also comprise a CDR3-beta wherein the first four amino acids are CASS.

[0016] The TCR may comprise a gamma chain variable domain and a delta chain variable domain comprising: a CDR3-gamma of amino acid sequence CALWX1X2QELGKKIKVF, where X1is E or D, and where X2is P or H, and optionally a TRGV9 gamma chain. The delta chain may comprise a TRDV2 variable region. Such a TCR is surprising as it has not previously been possible to show that T cells bearing the TRDV2 variable region show CD la reactivity. Indeed, TRDV2-expressing T cells have been the focus of intense debate in the literature about the nature and pathways of their antigen presentation, and so the invention helps solve that longstanding question.

[0017] The TCR may comprise a gamma chain variable domain and a delta chain variable domain comprising: a CDR3 -gamma of amino acid sequence CATWDRPXIX2YI<I<LF. where X1is G or L, and where X2is Y or R, and optionally a non-TRDV2 variable region, and a gamma variable region of TRGV5 or TRGV3, or related variants, for example SEQ ID NO: 65. Such a TCR may have a TRDV1 or TRDV3 variable region. It is noted that there are common features across the gamma CDR3 region that are shared across the CDla-reactive gamma-delta TCR suggesting strong selective pressure for the conserved motifs.

[0018] The TCRs of the invention bind CD la housing mixed “endogenous” (endo) lipids which include different families such as phospholipids, lysophospholipids, steroids, fatty acids, ceramides, sphingomyelins and others which, as recently described, form major species of the CD la lipidome (PMID 37539748). The binding of CD la multimeric complexes containing mixed lipids to the TCR shows the reactivity to many endogenous and exogenous lipids and is consistent with the TCR having high affinity and functional avidity as demonstrated herein.

[0019] The invention provides solutions to many of the pre-existing technical and scientific challenges to accurately capture large numbers of CD la-reactive T cells for functional and transcriptomic studies including TCR sequence analysis.

[0020] More specifically, the inventors find that, surprisingly and in contrast to existing literature, many CDla-reactive T cells do indeed share an identical invariant alpha TCR chain, including the CDR3 region (CAASAFGNQFYF). Of those which don’t have the invariant alpha TCR chain, many share related alpha chain CDR3 motifs, particularly focussed around a central 4-5 amino acids, typically AFGN, AWGN, VFGN, AFNN, LWANN. It was further noted that the CDR1 -alpha and CDR2-alpha regions also contained recognisable patterns, for example adjacent acidic-basic pairs in the CDR2- alpha. Further, the inventors surprisingly find that the CD la-reactive T cells can share motifs in the gamma CDR3 regions including CALWX1X2QELGKKIKVF for TRDV2- expressing cells and CATWDRPXIX2YI<KLF for non-TRDV2-expressing cells. Further, the gamma delta TCRs identified by the inventors also share common motifs in their CDR1 -gamma and CDR2 -gamma sequences, as well as their CDR1 -delta and CDR2-delta sequences.

[0021] The inventors also surprisingly noted that other CDR3 alpha sequences were occasionally also observed which showed partial shared features with the common central alpha motif and the central gamma motif, for example “CALDSNY QLIW” (TCR 18), where aspartate (D) can be a feature of the gamma CDR3 motif and the underlined amino acids LDSN are more in keeping with the central alpha CDR3 motif. Such an alpha / gamma CDR3 motif combination is the first observation of its kind and suggests strong selective pressure on the CD la-reactive motif.

[0022] The TCR may comprise an alpha chain variable domain and a beta chain variable domain, or a gamma chain variable domain and a delta chain variable domain, comprising: a) a CDR3-alpha of amino acid sequence CAASAFGNQFYF (SEQ ID NO: 7), and / or a CDR3-beta of amino acid sequence CASSYRGNIQETQYF (SEQ ID NO: 31); or b) a CDR3-alpha of amino acid sequence CAASAFGNQFYF (SEQ ID NO: 7), and / or a CDR3-beta of amino acid sequence CASSLDRGAEAFF (SEQ ID NO: 32); or c) a CDR3-alpha of amino acid sequence CAASAFGNQFYF (SEQ ID NO: 7), and / or a CDR3-beta of amino acid sequence CASSEGSSNQPQHF (SEQ ID NO: 33); or d) a CDR3-alpha of amino acid sequence CAASAFGNQFYF (SEQ ID NO: 7), and / or a CDR3-beta of amino acid sequence CASSPLWGGETQYF (SEQ ID NO: 34); or e) a CDR3-alpha of amino acid sequence CAASAFGNQFYF (SEQ ID NO: 7), and / or a CDR3-beta of amino acid sequence CASSSPTEAYGYTF (SEQ ID NO: 35); or f) a CDR3-alpha of amino acid sequence CAASAWGNQFYF (SEQ ID NO: 8), and / or a CDR3-beta of amino acid sequence CASSFLSSSVEQFF (SEQ ID NO: 36); or g) a CDR3-alpha of amino acid sequence CAASAWGNQFYF (SEQ ID NO: 8), and / or a CDR3-beta of amino acid sequence CASSPVDRAYEQYF (SEQ ID NO: 37); or h) a CDR3-alpha of amino acid sequence CAASAFNNDMRF (SEQ ID NO: 9), and / or a CDR3-beta of amino acid sequence CAISEGGSYYGYTF (SEQ ID NO: 38); or i) a CDR3-alpha of amino acid sequence CAASAFNNDMRF (SEQ ID NO: 9), and / or a CDR3-beta of amino acid sequence CASSPRDDYGYTF (SEQ ID NO: 39); or j) a CDR3-alpha of amino acid sequence CAASAFGNVLHC (SEQ ID NO: 10), and / or a CDR3-beta of amino acid sequence CASSRPGPGYGYTF (SEQ ID NO: 40); or k) a CDR3-alpha of amino acid sequence CAVDVFGNEKLTF (SEQ ID NO:

[0023] 11), and / or a CDR3-beta of amino acid sequence CASSLSDGRWGQGAAYNEQFF (SEQ ID NO: 41); or l) a CDR3-alpha of amino acid sequence CIVRTLWANNLFF (SEQ ID NO:

[0024] 12), and / or a CDR3-beta of amino acid sequence CASSPSYNEQFF (SEQ ID NO: 42); or m) a CDR3-alpha of amino acid sequence CIVRYYNDYKLSF (SEQ ID NO: 43), and / or a CDR3-beta of amino acid sequence CASSPLGGNEKLFF (SEQ ID NO: 46); or n) a CDR3-gamma of amino acid sequence CALWEPQELGKKIKVF (SEQ ID NO: 51), and / or a CDR3-delta of amino acid sequence CACDAMELGDKVTDKLIF (SEQ ID NO: 61); or o) a CDR3 -gamma of amino acid sequence CALWDHQELGKKIKVF (SEQ ID NO: 52), and / or a CDR3-delta of amino acid sequence CACDTVPESGDSPPEYTDKLIF (SEQ ID NO: 62); or p) a CDR3 -gamma of amino acid sequence CATWDRPGYYKKLF (SEQ ID NO: 53), and / or a CDR3-delta of amino acid sequence CALGALWHPQTQPWYTDKLIF (SEQ ID NO: 63); or q) a CDR3 -gamma of amino acid sequence CATWDRPLRYKKLF (SEQ ID NO: 54), and / or a CDR3-delta of amino acid sequence CAYNWPPFLQHWGIPDPMTKPDKLIF (SEQ ID NO: 64); or r) a CDR3-alpha of amino acid sequence CALDSNYQLIW (SEQ ID NO: 107), and / or a CDR3-beta of amino acid sequence CASSLEEGVRGALNTEAFF (SEQ ID NO: 110).

[0025] The TCR may comprise an alpha chain variable domain and a beta chain variable domain, or a gamma chain variable domain and a delta chain variable domain, comprising: a) a CDRl-alpha of amino acid sequence NSMFDY (SEQ ID NO: 1), a CDR2- alpha of amino acid sequence ISSIKDK (SEQ ID NO: 4), and a CDR3-alpha of amino acid sequence CAASAFGNQFYF (SEQ ID NO: 7), and / or a CDRl-beta of amino acid sequence SGHNT (SEQ ID NO: 13), a CDR2-beta of amino acid sequence YYREEE (SEQ ID NO: 22), and a CDR3-beta of amino acid sequence CASSYRGNIQETQYF (SEQ ID NO: 31); or b) a CDRl-alpha of amino acid sequence NSMFDY (SEQ ID NO: 1), a CDR2- alpha of amino acid sequence ISSIKDK (SEQ ID NO: 4), and a CDR3-alpha of amino acid sequence CAASAFGNQFYF (SEQ ID NO: 7), and / or a CDRl-beta of amino acid sequence SGHDT (SEQ ID NO: 14), a CDR2-beta of amino acid sequence YYEEEE (SEQ ID NO: 23), and a CDR3-beta of amino acid sequence CASSLDRGAEAFF (SEQ ID NO: 32); or c) a CDRl-alpha of amino acid sequence NSMFDY (SEQ ID NO: 1), a CDR2- alpha of amino acid sequence ISSIKDK (SEQ ID NO: 4), and a CDR3-alpha of amino acid sequence CAASAFGNQFYF (SEQ ID NO: 7), and / or a CDRl-beta of amino acid sequence SGDLS (SEQ ID NO: 15), a CDR2-beta of amino acid sequence YYNGEE (SEQ ID NO: 24), and a CDR3-beta of amino acid sequence CASSEGSSNQPQHF (SEQ ID NO: 33); or d) a CDRl-alpha of amino acid sequence NSMFDY (SEQ ID NO: 1), a CDR2- alpha of amino acid sequence ISSIKDK (SEQ ID NO: 4), and a CDR3-alpha of amino acid sequence CAASAFGNQFYF (SEQ ID NO: 7), and / or a CDRl-beta of amino acid sequence SGHAT (SEQ ID NO: 16), a CDR2-beta of amino acid sequence FQNNGV (SEQ ID NO: 25), and a CDR3-beta of amino acid sequence CASSPLWGGETQYF (SEQ ID NO: 34); or e) a CDRl-alpha of amino acid sequence NSMFDY (SEQ ID NO: 1), a CDR2- alpha of amino acid sequence ISSIKDK (SEQ ID NO: 4), and a CDR3-alpha of amino acid sequence CAASAFGNQFYF (SEQ ID NO: 7), and / or a CDRl-beta of amino acid sequence SGHRS (SEQ ID NO: 17), a CDR2-beta of amino acid sequence YFSETQ (SEQ ID NO: 26), and a CDR3-beta of amino acid sequence CASSSPTEAYGYTF (SEQ ID NO: 35); or f) a CDRl-alpha of amino acid sequence NSMFDY (SEQ ID NO: 1), a CDR2- alpha of amino acid sequence ISSIKDK (SEQ ID NO: 4), and a CDR3-alpha of amino acid sequence CAASAWGNQFYF (SEQ ID NO: 8), and / or a CDRl-beta of amino acid sequence SGHDT (SEQ ID NO: 14), a CDR2-beta of amino acid sequence YYEEEE (SEQ ID NO: 23), and a CDR3-beta of amino acid sequence CASSFLSSSVEQFF (SEQ ID NO: 36); or g) a CDRl-alpha of amino acid sequence NSMFDY (SEQ ID NO: 1), a CDR2- alpha of amino acid sequence ISSIKDK (SEQ ID NO: 4), and a CDR3-alpha of amino acid sequence CAASAWGNQFYF (SEQ ID NO: 8), and / or a CDRl-beta of amino acid sequence SEHNR (SEQ ID NO: 18), a CDR2-beta of amino acid sequence FQNEAQ (SEQ ID NO: 27), and a CDR3-beta of amino acid sequence CASSPVDRAYEQYF (SEQ ID NO: 37); or h) a CDRl-alpha of amino acid sequence NSMFDY (SEQ ID NO: 1), a CDR2- alpha of amino acid sequence ISSIKDK (SEQ ID NO: 4), and a CDR3-alpha of amino acid sequence CAASAFNNDMRF (SEQ ID NO: 9), and / or a CDRl-beta of amino acid sequence ENHRY (SEQ ID NO: 19), a CDR2-beta of amino acid sequence SYGVKD (SEQ ID NO: 28), and a CDR3-beta of amino acid sequence CAISEGGSYYGYTF (SEQ ID NO: 38); or i) a CDRl-alpha of amino acid sequence NSMFDY (SEQ ID NO: 1), a CDR2- alpha of amino acid sequence ISSIKDK (SEQ ID NO: 4), and a CDR3-alpha of amino acid sequence CAASAFNNDMRF (SEQ ID NO: 9), and / or a CDRl-beta of amino acid sequence LGHDT (SEQ ID NO: 20), a CDR2-beta of amino acid sequence YNNKEL (SEQ ID NO: 29), and a CDR3-beta of amino acid sequence CASSPRDDYGYTF (SEQ ID NO: 39); or j) a CDRl-alpha of amino acid sequence NSMFDY (SEQ ID NO: 1), a CDR2- alpha of amino acid sequence ISSIKDK (SEQ ID NO: 4), and a CDR3-alpha of amino acid sequence CAASAFGNVLHC (SEQ ID NO: 10), and / or a CDRl-beta of amino acid sequence SEHNR (SEQ ID NO: 18), a CDR2-beta of amino acid sequence FQNEAQ (SEQ ID NO: 27), and a CDR3-beta of amino acid sequence CASSRPGPGYGYTF (SEQ ID NO: 40); or k) a CDRl-alpha of amino acid sequence TTSDR (SEQ ID NO: 2), a CDR2- alpha of amino acid sequence LLSNGAV (SEQ ID NO: 5), and a CDR3-alpha of amino acid sequence CAVDVFGNEKLTF (SEQ ID NO: 11), and / or a CDRl-beta of amino acid sequence MDHEN (SEQ ID NO: 21), a CDR2-beta of amino acid sequence SYDVKM (SEQ ID NO: 30), and a CDR3-beta of amino acid sequence CASSLSDGRWGQGAAYNEQFF (SEQ ID NO: 41); or l) a CDRl-alpha of amino acid sequence TISGNEY (SEQ ID NO: 3), a CDR2- alpha of amino acid sequence GLKNN (SEQ ID NO: 6), and a CDR3-alpha of amino acid sequence CIVRTLWANNLFF (SEQ ID NO: 12), and / or a CDRl-beta of amino acid sequence LGHDT (SEQ ID NO: 20), a CDR2-beta of amino acid sequence YNNKEL (SEQ ID NO: 29), and a CDR3-beta of amino acid sequence CASSPSYNEQFF (SEQ ID NO: 42); or m) a CDRl-alpha of amino acid sequence TISGNEY (SEQ ID NO: 3), a CDR2- alpha of amino acid sequence GLKNN (SEQ ID NO: 6), and a CDR3-alpha of amino acid sequence CIVRYYNDYKLSF (SEQ ID NO: 43), and / or a CDRl-beta of amino acid sequence SSHAT (SEQ ID NO: 44), a CDR2-beta of amino acid sequence FNYEAQ (SEQ ID NO: 45), and a CDR3-beta of amino acid sequence CASSPLGGNEKLFF (SEQ ID NO: 46); or n) a CDRl-gamma of amino acid sequence GITISATS (SEQ ID NO: 47), a CDR2-gamma of amino acid sequence ISYDGTV (SEQ ID NO: 49), and a CDR3- gamma of amino acid sequence CALWEPQELGKKIKVF (SEQ ID NO: 51), and / or a CDRl-delta of amino acid sequence GEAIGNYY (SEQ ID NO: 55), a CDR2- delta of amino acid sequence EKD (SEQ ID NO: 58), and a CDR3-delta of amino acid sequence CACDAMELGDKVTDKLIF (SEQ ID NO: 61); or o) a CDRl-gamma of amino acid sequence GITISATS (SEQ ID NO: 47), a CDR2-gamma of amino acid sequence ISYDGTV (SEQ ID NO: 49), and a CDR3- gamma of amino acid sequence CALWDHQELGKKIKVF (SEQ ID NO: 52), and / or a CDRl-delta of amino acid sequence GEAIGNYY (SEQ ID NO: 55), a CDR2- delta of amino acid sequence EKD (SEQ ID NO: 58), and a CDR3-delta of amino acid sequence CACDTVPESGDSPPEYTDKLIF (SEQ ID NO: 62); or p) a CDRl-gamma of amino acid sequence VINAFY (SEQ ID NO: 48), a CDR2- gamma of amino acid sequence YDVSNSKD (SEQ ID NO: 50), and a CDR3-gamma of amino acid sequence CATWDRPGYYKKLF (SEQ ID NO: 53), and / or a CDRl-delta of amino acid sequence TSWWSYY (SEQ ID NO: 56), a CDR2- delta of amino acid sequence QGS (SEQ ID NO: 59), and a CDR3-delta of amino acid sequence CALGALWHPQTQPWYTDKLIF (SEQ ID NO: 63); or q) a CDRl-gamma of amino acid sequence VINAFY (SEQ ID NO: 48), a CDR2- gamma of amino acid sequence YDVSNSKD (SEQ ID NO: 50), and a CDR3-gamma of amino acid sequence CATWDRPLRYKKLF (SEQ ID NO: 54), and / or a CDRl-delta of amino acid sequence TVYSNPD (SEQ ID NO: 57), a CDR2- delta of amino acid sequence GDNSR (SEQ ID NO: 60), and a CDR3-delta of amino acid sequence CAYNWPPFLQHWGIPDPMTKPDKLIF (SEQ ID NO: 64); or r) a CDRl-alpha of amino acid sequence ATGYPS (SEQ ID NO: 105), a CDR2- alpha of amino acid sequence ATKADDK (SEQ ID NO: 106), and a CDR3-alpha of amino acid sequence CALDSNYQLIW (SEQ ID NO: 107), and / or a CDRl-beta of amino acid sequence SGHNT (SEQ ID NO: 108), a CDR2-beta of amino acid sequence YENEEA (SEQ ID NO: 109), and a CDR3-beta of amino acid sequence CASSLEEGVRGALNTEAFF (SEQ ID NO: 110).

[0026] The TCR may comprise: a) an alpha chain variable domain comprising a variable segment encoded by the TRAV29DV5 gene, a Joining segment encoded by the TRAJ49 gene, a CDRl- alpha of SEQ ID NO: 1, a CDR2-alpha of SEQ ID NO: 4 and a CDR3-alpha of SEQ ID NO: 7; and / or a beta chain variable region comprising a variable segment encoded by the TRBV5-4 gene, a Joining segment encoded by the TRBJ2-5 gene, a CDRl-beta of SEQ ID NO: 13, a CDR2-beta of SEQ ID NO: 22 and a CDR3-beta of SEQ ID NO: 31; or b) an alpha chain variable domain comprising a variable segment encoded by the TRAV29DV5 gene, a Joining segment encoded by the TRAJ49 gene, a CDRl- alpha of SEQ ID NO: 1, a CDR2-alpha of SEQ ID NO: 4 and a CDR3-alpha of SEQ ID NO: 7; and / or a beta chain variable region comprising a variable segment encoded by the TRBV5-6 gene, a Joining segment encoded by the TRBJ1-1 gene, a CDRl-beta of SEQ ID NO: 14, a CDR2-beta of SEQ ID NO: 23 and a CDR3-beta of SEQ ID NO: 32; or c) an alpha chain variable domain comprising a variable segment encoded by the TRAV29DV5 gene, a Joining segment encoded by the TRAJ49 gene, a CDR1- alpha of SEQ ID NO: 1, a CDR2-alpha of SEQ ID NO: 4 and a CDR3-alpha of SEQ ID NO: 7; and / or a beta chain variable region comprising a variable segment encoded by the TRBV9 gene, a Joining segment encoded by the TRBJ1- 5 gene, a CDRl-beta of SEQ ID NO: 15, a CDR2-beta of SEQ ID NO: 24 and a CDR3-beta of SEQ ID NO: 33; or d) an alpha chain variable domain comprising a variable segment encoded by the TRAV29DV5 gene, a Joining segment encoded by the TRAJ49 gene, a CDR1- alpha of SEQ ID NO: 1, a CDR2-alpha of SEQ ID NO: 4 and a CDR3-alpha of SEQ ID NO: 7; and / or a beta chain variable region comprising a variable segment encoded by the TRBV11-2 gene, a Joining segment encoded by the TRBJ2-5 gene, a CDRl-beta of SEQ ID NO: 16, a CDR2-beta of SEQ ID NO:

[0027] 25 and a CDR3-beta of SEQ ID NO: 34; or e) an alpha chain variable domain comprising a variable segment encoded by the TRAV29DV5 gene, a Joining segment encoded by the TRAJ49 gene, a CDR1- alpha of SEQ ID NO: 1, a CDR2-alpha of SEQ ID NO: 4 and a CDR3-alpha of SEQ ID NO: 7; and / or a beta chain variable region comprising a variable segment encoded by the TRBV5-1 gene, a Joining segment encoded by the TRBJ1-2 gene, a CDRl-beta of SEQ ID NO: 17, a CDR2-beta of SEQ ID NO:

[0028] 26 and a CDR3-beta of SEQ ID NO: 35; or f) an alpha chain variable domain comprising a variable segment encoded by the TRAV29DV5 gene, a Joining segment encoded by the TRAJ49 gene, a CDR1- alpha of SEQ ID NO: 1, a CDR2-alpha of SEQ ID NO: 4 and a CDR3-alpha of SEQ ID NO: 8; and / or a beta chain variable region comprising a variable segment encoded by the TRBV5-6 gene, a Joining segment encoded by the TRBJ2-1 gene, a CDRl-beta of SEQ ID NO: 14, a CDR2-beta of SEQ ID NO: 23 and a CDR3-beta of SEQ ID NO: 36; or g) an alpha chain variable domain comprising a variable segment encoded by the TRAV29DV5 gene, a Joining segment encoded by the TRAJ49 gene, a CDR1- alpha of SEQ ID NO: 1, a CDR2-alpha of SEQ ID NO: 4 and a CDR3-alpha of SEQ ID NO: 8; and / or a beta chain variable region comprising a variable segment encoded by the TRBV7-9 gene, a Joining segment encoded by the TRBJ2-7 gene, a CDRl-beta of SEQ ID NO: 18, a CDR2-beta of SEQ ID NO:

[0029] 27 and a CDR3-beta of SEQ ID NO: 37; or h) an alpha chain variable domain comprising a variable segment encoded by the TRAV29DV5 gene, a Joining segment encoded by the TRAJ43 gene, a CDR1- alpha of SEQ ID NO: 1, a CDR2-alpha of SEQ ID NO: 4 and a CDR3-alpha of SEQ ID NO: 9; and / or a beta chain variable region comprising a variable segment encoded by the TRBV10-3 gene, a Joining segment encoded by the TRBJ1-2 gene, a CDRl-beta of SEQ ID NO: 19, a CDR2-beta of SEQ ID NO:

[0030] 28 and a CDR3-beta of SEQ ID NO: 38; or i) an alpha chain variable domain comprising a variable segment encoded by the TRAV29DV5 gene, a Joining segment encoded by the TRAJ43 gene, a CDR1- alpha of SEQ ID NO: 1, a CDR2-alpha of SEQ ID NO: 4 and a CDR3-alpha of SEQ ID NO: 9; and / or a beta chain variable region comprising a variable segment encoded by the TRBV3-1 gene, a Joining segment encoded by the TRBJ1-2 gene, a CDRl-beta of SEQ ID NO: 20, a CDR2-beta of SEQ ID NO:

[0031] 29 and a CDR3-beta of SEQ ID NO: 39; or j) an alpha chain variable domain comprising a variable segment encoded by the TRAV29DV5 gene, a Joining segment encoded by the TRAJ35 gene, a CDR1- alpha of SEQ ID NO: 1, a CDR2-alpha of SEQ ID NO: 4 and a CDR3-alpha of SEQ ID NO: 10; and / or a beta chain variable region comprising a variable segment encoded by the TRBV7-9 gene, a Joining segment encoded by the TRBJ1-2 gene, a CDRl-beta of SEQ ID NO: 18, a CDR2-beta of SEQ ID NO: 27 and a CDR3-beta of SEQ ID NO: 40. k) an alpha chain variable domain comprising a variable segment encoded by the TRAV39 gene, a Joining segment encoded by the TRAJ48 gene, a CDRl-alpha of SEQ ID NO: 2, a CDR2-alpha of SEQ ID NO: 5 and a CDR3-alpha of SEQ ID NO: 11; and / or a beta chain variable region comprising a variable segment encoded by the TRBV28 gene, a Joining segment encoded by the TRBJ2-1 gene, a CDRl-beta of SEQ ID NO: 21, a CDR2-beta of SEQ ID NO: 30 and a CDR3- beta of SEQ ID NO: 41; or l) an alpha chain variable domain comprising a variable segment encoded by the TRAV26-1 gene, a Joining segment encoded by the TRAJ36 gene, a CDRl-alpha of SEQ ID NO: 3, a CDR2-alpha of SEQ ID NO: 6 and a CDR3-alpha of SEQ ID NO: 12; and / or a beta chain variable region comprising a variable segment encoded by the TRBV3-1 gene, a Joining segment encoded by the TRBJ2-1 gene, a CDRl-beta of SEQ ID NO: 20, a CDR2-beta of SEQ ID NO: 29 and a CDR3- beta of SEQ ID NO: 42; or m) an alpha chain variable domain comprising a variable segment encoded by the TRAV26-1 gene, a Joining segment encoded by the TRAJ20 gene, a CDR1 -alpha of SEQ ID NO: 3, a CDR2-alpha of SEQ ID NO: 6 and a CDR3-alpha of SEQ ID NO: 43; and / or a beta chain variable region comprising a variable segment encoded by the TRBV7-7 gene, a Joining segment encoded by the TRBJ1-4 gene, a CDRl-beta of SEQ ID NO: 44, a CDR2-beta of SEQ ID NO: 45 and a CDR3- beta of SEQ ID NO: 46; or n) a gamma chain variable domain comprising a variable segment encoded by the TRGV9 gene, a joining segment encoded by the TRGJP*01 gene, a CDR1- gamma of SEQ ID NO: 47, a CDR2 -gamma of SEQ ID NO: 49 and a CDR3- gamma of SEQ ID NO: 51; and / or a delta chain variable region comprising a variable segment encoded by the TRDV2 gene, a joining segment encoded by the TRDJ1 gene, a CDRl-delta of SEQ ID NO: 55, a CDR2- delta of SEQ ID NO: 58 and a CDR3- delta of SEQ ID NO: 61; or o) a gamma chain variable domain comprising a variable segment encoded by the TRGV9 gene, a joining segment encoded by the TRGJP1 gene, a CDRl-gamma of SEQ ID NO: 47, a CDR2 -gamma of SEQ ID NO: 49 and a CDR3-gamma of SEQ ID NO: 52; and / or a delta chain variable region comprising a variable segment encoded by the TRDV2 gene, a joining segment encoded by the TRDJ1 gene, a CDRl-delta of SEQ ID NO: 55, a CDR2-delta of SEQ ID NO: 58 and a CDR3-delta of SEQ ID NO: 62; or p) a gamma chain variable domain comprising a variable segment encoded by the TRGV5 or TRGV3 gene or with shared variable segment encoded by SEQ ID NO: 65, a joining segment encoded by the TRGJ2 gene, a CDRl-gamma of SEQ ID NO: 48, a CDR2 -gamma of SEQ ID NO: 50 and a CDR3-gamma of SEQ ID NO: 53; and / or a delta chain variable region comprising a variable segment encoded by the TRDV1 gene, a joining segment encoded by the TRDJ1 gene, a CDRl-delta of SEQ ID NO: 56, a CDR2-delta of SEQ ID NO: 59 and a CDR3- delta of SEQ ID NO: 63; or q) a gamma chain variable domain comprising a variable segment encoded by the TRGV5 or TRGV3 gene or with shared variable segment encoded by SEQ ID NO: 65, a joining segment encoded by the TRGJ2 gene, a CDRl-gamma of SEQ ID NO: 48, a CDR2 -gamma of SEQ ID NO: 50 and a CDR3-gamma of SEQ ID NO: 54; and / or a delta chain variable region comprising a variable segment encoded by the TRDV3 gene, a joining segment encoded by the TRDJ1 gene, a diversity segment encoded by the TRDD3 gene, a CDRl-delta of SEQ ID NO: 57, a CDR2-delta of SEQ ID NO: 60 and a CDR3-delta of SEQ ID NO: 64; or r) an alpha chain variable domain comprising a variable segment encoded by the TRAV9-2gene, a Joining segment encoded by the TRAJ33 gene, a CDRl-alpha of SEQ ID NO: 105, a CDR2-alpha of SEQ ID NO: 106 and a CDR3-alpha of SEQ ID NO: 107; and / or a beta chain variable region comprising a variable segment encoded by the TRBV11-3 gene, a Joining segment encoded by the TRBJ1-1 gene, a CDRl-beta of SEQ ID NO: 108, a CDR2-beta of SEQ ID NO: 109 and a CDR3-beta of SEQ ID NO: 110.

[0032] The TCR may comprise: a) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 71; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 72; or b) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 73; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 74; or c) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 75; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 76; or d) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 77; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 78; or e) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 79; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 80; or f) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 81; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 82; or g) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 83; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 84; or h) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 85; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 86; or i) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 87; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 88; or j) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 89; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 90; or k) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 91; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 92; or l) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 93; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 94; or m) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 95; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 96; or n) a gamma chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 97; and / or a delta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 98; or o) a gamma chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 99; and / or a delta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 100; or p) a gamma chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 101; and / or a delta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 102; or q) a gamma chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 103; and / or a delta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 104; or r) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 111; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 112.

[0033] The TCR may also comprise an alpha chain TRAC constant domain sequence and a beta chain TRBC1 or TRBC2 constant domain sequence. Alternatively, the TCR may also comprise a gamma TRGC1 or TRGC2 constant domain sequence and a delta chain TRDC constant domain sequence.

[0034] The constant domain may be from another species, such as mouse TRAC and / or TRBC and / or TRGC and / or TRDC, or from a human. A mouse constant domain may allow for monitoring of the survival of T cells comprising such a TCR when injected in vivo, for example. The hybrid TCRs can be engineered to only pair together, which avoids hybrid TCR alpha or beta (or gamma or delta) chain molecules pairing with the host cell TCRs alpha or beta (or gamma or delta) chain molecules. Alternatively, the endogenous TCRs can be knocked out or knocked down.

[0035] The TCR may be a recombinant TCR. The TCR may be a soluble TCR. The TCR may be isolated.

[0036] Any TCR referred to herein may be modified by the conventional technique of affinity maturation, whereby relatively few or chemically minor mutations are introduced into a TCR referred to herein in order to improve binding or functional characteristics. Such affinity maturation may result in a TCR with one, two, three or more mutations, for example in the alpha or gamma CDR3, such as in the central motif referred to above.

[0037] In another aspect, there is provided a nucleic acid encoding one or more TCR disclosed herein. The nucleic acid may be a recombinant nucleic acid. The nucleic acid may be isolated.

[0038] The recombinant nucleic acid may be a DNA or RNA molecule. The DNA may be a cDNA. The nucleic acid may be non-naturally occurring and / or purified and / or engineered.

[0039] In another aspect, there is provided a vector comprising a nucleic acid disclosed herein. The vector may be a TCR expression vector. The vector may be a plasmid. The vector may be a viral vector, such as a retroviral vector, lentiviral vector or adenoviral vector. The vector may comprise nucleic acid disclosed herein, encoding in a single open reading frame, or two distinct open reading frames, the alpha chain and the beta chain respectively, or the gamma chain and delta chain, respectively.

[0040] In another aspect, there is provided a cell or population of cells comprising and / or encoding one or more TCR, nucleic acid or vector disclosed herein. The cell or population of cells may harbour a first expression vector which comprises nucleic acid encoding the alpha chain of a TCR disclosed herein, and a second expression vector comprising nucleic acid encoding the beta chain of a TCR disclosed herein; or a first expression vector which comprises nucleic acid encoding the gamma chain of a TCR disclosed herein, and a second expression vector comprising nucleic acid encoding the delta chain of a TCR disclosed herein.

[0041] The cell may be a T-cell. The T-cell may be a CD4+ T cell. The T-cell may be a CD8+ T cell. The T-cell may be a Mucosal associated invariant T cell (MAIT cell), The cell may be a natural killer cell, myeloid or monocyte cell. The cell or population of cells may include a non-naturally occurring and / or purified and / or or engineered cell, especially a T-cell such as a CD8+ T-cell, expressing / presenting a TCR disclosed herein. There are a number of methods suitable for the transfection of T cells with nucleic acid (such as DNA, cDNA or RNA) encoding the TCRs disclosed herein (see for example Robbins et al., (2008) J Immunol. 180: 6 116-61 3 1). T-cells expressing the TCRs disclosed herein will be suitable for use in adoptive therapy-based treatment of or prevention of cancer. As will be known to those skilled in the art, there are a number of suitable methods by which adoptive therapy can be carried out (see for example Rosenberg et al, (2008) Nat Rev Cancer 8(4): 299-308).

[0042] The cells or population of cells may be isolated and / or recombinant and / or non-naturally occurring and / or engineered.

[0043] In another aspect, there is provided a pharmaceutical composition comprising one or more TCR, nucleic acid, vector, cell or population of cells of the invention.

[0044] In another aspect, there is provided a TCR, nucleic acid, vector, cell or population of cells, or pharmaceutical composition of the invention for use in medicine.

[0045] In another aspect, there is provided a TCR, nucleic acid, vector, cell or population of cells, or pharmaceutical composition of the invention for use in treating or preventing a disease or disorder in a subject.

[0046] In another aspect, there is provided a method of treating or preventing a disease or disorder in a subject, comprising administering to the subject one or more TCR, nucleic acid, vector, cell or population of cells, or composition of the invention.

[0047] In another aspect, there the use of one or more TCR, nucleic acid, vector, cell or population of cells, or pharmaceutical composition of the invention in the manufacture of a medicament for treating or preventing a disease or disorder in a subject.

[0048] The disease or disorder may be associated with increased CD la expression and / or function, such as an inflammatory disease or cancer.

[0049] The one or more disease or disorder may be one or more inflammatory skin or mucosal disorder, or disease or one or more associated systemic disease or disorder, or one or more inflammatory drug reaction which manifests systemically, or a CD la-expressing malignancy or a malignancy wherein CD la is altered in expression or function. An inflammatory skin or mucosal disease or disorder may be selected from: a) a predominantly neutrophilic skin disease, such as acne, generalized pustular psoriasis, plaque psoriasis, guttate psoriasis, palmoplantar pustulosis, SAPHO syndrome, acute febrile neutrophilic dermatosis (Sweet syndrome), histiocytoid neutrophilic dermatitis, neutrophilic dermatosis of the dorsal hands, pyoderma gangrenosum, neutrophilic eccrine hidradenitis, hidradenitis suppurativa, erythema elevatum diutinum, Behcet disease, bowel-associated dermatitisarthritis syndrome, other infection-associated inflammation, neutrophilic urticarial dermatosis, palisading neutrophilic granulomatous dermatitis, erythema gyratum repens, neutrophilic annular erythema, acute generalised exanthematous pustulosis (AGEP), vasculitis, and others; b) an autoimmune disorder, such as connective tissue disease (eg lupus, dermatomyositis, scleroderma / systemic sclerosis, Churg Strauss syndrome), panniculitis, vasculitides, autoimmune blistering conditions (eg bullous pemphigoid, pemphigus, linear IgA disease), dermatitis herpetiformis, coeliac disease, some auto-inflammatory disease, vitiligo, alopecia areata, alopecia universalis, alopecia totalis, panniculitis, lichen planus, erythema multiforme, lichen sclerosis, other lichenoid and erythema multiforme-like diseases, vesiculation psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, Guillain-Barre syndrome, thyroiditis, transverse myelitis, neurodegeneration and others; c) mast cell disorders and eosinophilic disorders, such as Muckle Wells syndrome, eosinophilia and systemic symptoms syndrome, urticaria, angioedema, keratoconjunctivitis, food allergy, other allergy or atopy including atopic dermatitis, rhinitis, conjunctivitis, asthma, eosinophilic oesophagitis and other eosinophilic mucosal diseases, contact dermatitis, chronic obstructive airways disease and others. d) adverse drug reactions which manifest as an inflammatory skin or mucosal disease or disorder, such as Stevens Johnsons syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms syndrome (DRESS) and acute generalised exanthematous pustulosis (AGEP), erythema multiforme, bullous, fixed drug eruption, checkpoint inhibitor-associated skin and other inflammation and others; e) Graft vs host disease f) Pruritus and pruritic conditions including nodular prurigo; g) non-cutaneous lupus erythematosus;. or h) Conditions where altered frequency and / or phenotype of CD la-expressing cells can occur.

[0050] A CD la-expressing malignancy as referred to herein may be any malignancy where CD la expression can be detected. Such malignancies may include Langerhans cell histiocytosis, Langerhans cell sarcoma, subsets of T cell lymphomas, subsets of thymomas or rarely-occurring instances of other malignancies, such as subsets of mastocytosis. Preferably, the CD la-expressing malignancy is subsets of T cell lymphomas. The malignancy may have associated infiltration of CD la-expressing cells.

[0051] Preferably the one or more disease or disorder comprises or consists of psoriasis, dermatitis, lupus erythematosus, neutrophilic dermatoses, an associated systemic disease or disorder, and / or or an inflammatory drug reaction which manifests systemically, or a CD la-expressing malignancy or a malignancy wherein CD la is altered in expression or function.

[0052] An associated systemic disease or disorder as used herein may refer to any non- cutaneous site involvement that may be associated with an inflammatory skin or mucosal disease or disorder as defined herein. This may include non-cutaneous lupus erythematosus.

[0053] An inflammatory drug reaction which manifests systemically, may be at a non- cutaneous site such as the spleen. An associated systemic disease or disorder, or inflammatory drug reaction which manifests systemically, may be as a result of an inflammatory response. The inflammatory response may be for example to a drug such as Aldara (5% imiquimod cream). The inflammatory response may result in increased numbers or activity of CD4 T-cells, CD8 T-cells, neutrophils or eosinophils, and / or increased levels of IL-23, IL-12, IL-ip and / or MCP-1, and / or decreased IL-10 and / or IL-27.

[0054] In any aspect, the subject may be a mammal. The mammal may express a CD la orthologue. Preferably, the subject is a human.

[0055] Furthermore, a TCR, nucleic acid, vector, host cell or pharmaceutical composition of the invention may be administered alone or in combination with one or more other therapeutic agent, either simultaneously, sequentially or separately, dependent upon the condition to be treated. The one or more other therapeutic agent may be selected from the group comprising cytotoxic agents, immune activation or immune suppression agents such as checkpoint inhibitors / agonists or TLR agonists, anti-inflammatory agents such as steroids, anti -mitotic s, CAR-T cells such as regulatory or cytolytic CAR-T cells. An example of an immunosuppressive agent is a PD-1 agonist, other checkpoint agonist or IL-2 mutein or others.

[0056] The one or more other therapeutic agent may be directly linked to the TCR, or host cell expressing the TCR.

[0057] In another aspect, any TCR of the invention may be a bispecific molecule or multispecific molecule. The bispecific or multi-specific molecule will comprise a TCR of the invention, and may bind, in addition to a CD la peptide, a second or further target. For example, the bispecific or multi-specific molecule may in addition to a TCR of the invention, further comprise one or more of a CD3 targeting moiety, a PD-1 targeting moiety, an IL-2 receptor family targeting moiety, a CD2 targeting moiety, a CTLA4 targeting moiety, a CD28 targeting moiety, an ICOS targeting moiety, and / or a TNF receptor superfamily member targeting moiety. The targeted moiety may be on the same cell as the CD la (cis) and / or on a different cell (trans).

[0058] In another aspect, there is provided a method of monitoring treatment efficacy or disease status in a subject diagnosed with a CD la-expressing malignancy or a malignancy wherein CD la is altered in expression or function, comprising: i. providing a biological sample obtained from the subject; ii. determining the level of binding of one or more TCRs of the invention to CD la-expressing cells in the sample obtained from the subject before treatment, or at intervals between treatments, or at time intervals in the absence of treatment; iii. determining that the treatment is effective, or that the disease status is improving, if the tumour volume, or level of binding of one or more TCRs of the invention to CD la-expressing cells, is reduced after treatment or between treatment intervals or at time intervals in the absence of treatment. A biological sample as referred to herein may be a blood or serum sample, tissue biopsy, cerebrospinal fluid, saliva, or urine sample. Preferably, the biological sample may be a blood or serum sample.

[0059] The level of binding of one or more TCRs of the invention to CD la-expressing cells in the sample may be determined using any method known to the skilled person. One such method is for example using flow cytometry or any other technique utilising a detectable label, to be able to determine the number of CDla expressing cells in the sample.

[0060] Tumour volume may be determined by any suitable technique known to the skilled person.

[0061] The reduction in tumour volume or level of binding of one or more TCR of the invention to CD la-expressing cells may be by 10% or more, such as 25% or more, 50% or more, 75% or more, or 90% or more.

[0062] The treatment intervals or time intervals in the absence of treatment may be two weeks or more, such as four weeks or more, 8 weeks or more, 12 weeks or more, six months or more, or 12 months or more.

[0063] In another aspect, there is provided a method of diagnosing a subject with an inflammatory skin and mucosal disease or disorder, or associated systemic disease or disorder, or inflammatory drug reaction which manifests systemically, or CD la- expressing malignancy, or a malignancy wherein CDla is altered in expression or function, comprising: i. providing a biological sample obtained from the subject; ii. using one or more TCR of the invention to determine the level of expression of CDla in the sample obtained from the subject; iii. comparing the level of expression of CD la in the sample obtained from the subject with the level of expression of CDla in a positive or negative reference sample; iv. determining that the subject has an inflammatory skin and mucosal disease or disorder, or associated systemic disease or disorder, or inflammatory drug reaction which manifests systemically, or CD la-expressing malignancy, or a malignancy wherein CDla is altered in expression or function, if the level of expression of CDla in the sample obtained from the subject is higher than the level of expression of CD la in the negative reference sample, or equal to or higher than the level of expression of CD la positive reference sample.

[0064] Alternatively, in step iv, the subject may be determined to not have has an inflammatory skin and mucosal disease or disorder, or associated systemic disease or disorder, or inflammatory drug reaction which manifests systemically, or CD la-expressing malignancy, or a malignancy wherein CD la is altered in expression or function, if the level of expression of CD la in the sample obtained from the subject is equal to or lower than the level of expression of CD la in the negative reference sample, or lower than the level of expression of CDla the positive reference sample.

[0065] A negative reference sample may refer to a biological sample taken from a healthy subject, known not to have an inflammatory skin and mucosal disease or disorder, or associated systemic disease or disorder, or inflammatory drug reaction which manifests systemically, or CD la-expressing malignancy, or a malignancy wherein CDla is altered in expression or function. A positive reference sample may refer to a biological sample taken from a subject already diagnosed with an inflammatory skin and mucosal disease or disorder, or associated systemic disease or disorder, or inflammatory drug reaction which manifests systemically, or CD la-expressing malignancy, or a malignancy wherein CDla is altered in expression or function.

[0066] The level of expression of CDla in the method of diagnosing may refer to the level of CDla molecules expressed on a given cell or cells in a population, or the percentage of cells in a population or sample which are determined to express CD la.

[0067] DETAILED DESCRIPTION

[0068] Within the scope of the invention are phenotypically silent variants of any TCR disclosed herein. As used herein the term "phenotypically silent variants" is understood to refer to a TCR which incorporates one or more further amino acid changes, in which a TCR has a similar phenotype to the corresponding TCR without said change(s). As is known to those skilled in the art, it may be possible to produce TCRs that incorporate changes in the constant and / or variable domains thereof compared to those detailed above without altering the affinity for the interaction with a CDla peptide in complex with an MHC Class I molecule. In particular, such silent mutations may be incorporated within parts of the sequence that are known not to be directly involved in antigen binding (e.g., outside the CDRs). Such trivial variants are included in the scope of this invention. Those TCRs in which one or more conservative substitutions have been made also form part of this invention.

[0069] Mutagenesis can be carried out using any appropriate method including, but not limited to, those based on polymerase chain reaction (PCR), restriction enzyme-based cloning, or ligation independent cloning (LIC) procedures. These methods are detailed in many of the standard molecular biology texts. For further details regarding polymerase chain reaction (PCR) and restriction enzyme-based cloning, see Sambrook & Russell, (2001) Molecular Cloning - A Laboratory Manual (3rd Ed.) CSHL Press. Further information on ligation independent cloning (LIC) procedures can be found in Rashtchian, (1995) Curr Opin Biotechnol 6(1): 30-6.

[0070] The TCR may be an alpha-beta heterodimer, or gamma-delta heterodimer, or may be in single chain format. Single chain formats may include aP TCR polypeptides of the Va- L-V , Vp-L-Va, Va-Ca-L-Vp, Va-L-Vp-Cp or Va-Ca-L-Vp-Cp or Vp-Cp-L-Va-Ca types, or other types, wherein Va and VP are TCR a and P variable regions respectively, Ca and Cp are TCR a and P constant regions respectively, and L is a linker sequence. Or the single chain format may include y8 TCr polypeptides of the Vy-L-V8, V8-L-Vy, Vy-Cy-L-V8, Vy-L-V8-C8 or Vy-Cy-L-V8-C8 or V8-C8-L-Vy-Cy types, or other types, wherein Vy and V8 are TCR delta and P variable regions respectively, Cy and C8 are TCR y and 8 constant regions respectively, and L is a linker sequence. For use as a targeting agent for delivering therapeutic agents to the antigen presenting cell the TCR may be in soluble form (i.e. having no transmembrane or cytoplasmic domains). For stability, soluble P heterodimeric TCRs preferably have an introduced disulphide bond between residues of the respective constant domains, as described, for example, in WO 03 / 020763. One or both of the constant domains present in an aP or gamma-delta heterodimer of a TCR disclosed herein may be truncated at the C terminus or C termini, for example by up to 15, or up to 10 or up to 8 or fewer amino acids. For use in adoptive therapy, an aP or gamma-delta heterodimeric TCR may, for example, be transfected as full-length chains having both cytoplasmic and transmembrane domains. TCRs for use in adoptive therapy may contain a disulphide bond corresponding to that found in nature between the respective alpha and beta (or gamma and delta) constant domains, additionally or alternatively a non-native disulphide bond may be present. As will be obvious to those skilled in the art, it may be possible to truncate the sequences provided at the C-terminus and / or N-terminus thereof, by 1, 2, 3, 4, 5 or more residues, without substantially affecting the binding characteristics of the TCR. All such trivial variants are encompassed by the present invention.

[0071] A TCR disclosed herein may also be part of a multivalent complex of the TCR. Such multivalent TCR complexes may be particularly useful for tracking or targeting cells presenting particular antigens in vitro or in vivo and are also useful as intermediates for the production of further multivalent TCR complexes having such uses.

[0072] Any sequence referred to herein may also encompass a sequence which has at least 90% identity, such as 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to the specific SEQ ID NO referred to.

[0073] "Identity" as known in the art is the relationship between two or more polypeptide sequences or two or more polynucleotide sequences, as determined by comparing the sequences. In the art, identity also means the degree of sequence relatedness between polypeptide or polynucleotide sequences, as the case may be, as determined by the match between strings of such sequences. While there exist a number of methods to measure identity between two polypeptide or two polynucleotide sequences, methods commonly employed to determine identity are codified in computer programs. Preferred computer programs to determine identity between two sequences include, but are not limited to, GCG program package (Devereux, et al., Nucleic Acids Research, 12, 387 (1984), BLASTP, BLASTN, and FASTA (Atschul et al., J. Molec. Biol. 215, 403 (1990)).

[0074] A program such as the CLUSTAL program can be used to compare amino acid sequences. This program compares amino acid sequences and finds the optimal alignment by inserting spaces in either sequence as appropriate. It is possible to calculate amino acid identity or similarity (identity plus conservation of amino acid type) for an optimal alignment. A program like BLASTx will align the longest stretch of similar sequences and assign a value to the fit. It is thus possible to obtain a comparison where several regions of similarity are found, each having a different score. Both types of identity analysis are suitable. The percent identity of two amino acid sequences or of two nucleic acid sequences is determined by aligning the sequences for optimal comparison purposes (e.g., gaps can be introduced in the first sequence for best alignment with the sequence) and comparing the amino acid residues or nucleotides at corresponding positions. The "best alignment" is an alignment of two sequences which results in the highest percent identity. The percent identity is determined by the number of identical amino acid residues or nucleotides in the sequences being compared (i.e., % identity = number of identical positions / total number of positions x 100).

[0075] The determination of percent identity between two sequences can be accomplished using a mathematical algorithm known to those of skill in the art. An example of a mathematical algorithm for comparing two sequences is the algorithm of Karlin and Altschul (1990) Proc. Natl. Acad . Sci. USA 87:2264-2268, modified as in Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873- 5877. The NBUAST and XBUAST programs of Altschul, et al. (1990) J. Mol. Biol. 2 15:403-41 0 have incorporated such an algorithm. BUAST nucleotide searches can be performed with the NBUAST program, score = 100, wordlength = 12 to obtain nucleotide sequences homologous to nucleic acid molecules. BUAST protein searches can be performed with the XBUAST program, score = 50, wordlength = 3 to obtain amino acid sequences homologous to protein molecules for use in the invention. To obtain gapped alignments for comparison purposes, Gapped BUAST can be utilised as described in Altschul et al. (1997) Nucleic Acids Res. 25:3389-3402. Alternatively, PSI-Blast can be used to perform an iterated search which detects distant relationships between molecules (Id.). When utilising BUAST, Gapped BUAST, and PSI-Blast programs, the default parameters of the respective programs (e.g., XBUAST and NBUAST) can be used. See http: / / www.ncbi.nlm.nih.gov. Another example of a mathematical algorithm utilised for the comparison of sequences is the algorithm of Myers and Miller, CABIOS (1989). The AUIGN program (version 2.0) which is part of the CGC sequence alignment software package has incorporated such an algorithm. Other algorithms for sequence analysis known in the art include ADVANCE and ADAM as described in Torellis and Robotti (1994) Comput. Appl. Biosci., 10 :3-5; and FASTA described in Pearson and Eipman (1988) Proc. Natl. Acad. Sci. 85:2444-8. Within FASTA, ktup is a control option that sets the sensitivity and speed of the search. TCR specificity can be measured in vitro, for example, in cellular assays known to the skilled person, such as by measuring the binding of multimer (eg tetramer) HLA:peptide complexes. To test specificity the TCRs may be in soluble form and / or may be expressed on the surface of T cells, either naturally as with the T cell clones or expressed on third party T cells after transfer of DNA encoding the TCRs (eg by retrovirus or lentivirus transduction). Recognition by T cells bearing the TCRs disclosed herein may be determined by measuring the level of T cell activation after exposure to HLA plus CDla peptide on cells or other antigen.

[0076] For soluble TCRs, a therapeutically relevant concentration may be defined as a TCR concentration of 10~9M or below, and / or a concentration of up to 100 times, preferably up to 1000 fold, greater than the corresponding EC50 value. Antigen positive cells may be obtained by peptide-pulsing using a suitable peptide concentration to obtain a low level of antigen presentation (for example, 10’9M peptide, as described in Bossi et al. (2013) Oncoimmunol. 1;2 (l l):e26840) or, they may naturally present said peptide. Preferably, antigen negative cells are human cells.

[0077] For administration to patients, a TCR disclosed herein (which may be associated with a detectable label or therapeutic agent or expressed on a transfected T cell) or a cell or population of cells disclosed herein may be provided in a pharmaceutical composition together with one or more pharmaceutically acceptable carriers or excipients.

[0078] For example, an excipient can give form or consistency, or act as a diluent. Suitable excipients include, but are not limited to, stabilizing agents, wetting and emulsifying agents, salts for varying osmolarity, encapsulating agents, buffers, and skin penetration enhancers. The compositions of the invention will preferably be administered intravenously, for example comprising cells bearing one or more TCR of the invention, or soluble bispecific TCRs as defined herein.

[0079] Suitable formulations for intravenous administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts.

[0080] The compositions may be provided in unit dosage form, a sealed container, or as part of a kit, which may include instructions for use and / or a plurality of unit dosage forms. Suitable dose range for a TCR disclosed herein may ultimately determined by a physician.

[0081] Where more than one agent is to be administered, the agents may be formulated together in the same formulation or may be formulated into separate pharmaceutical compositions. The separate compositions may be administered concurrently, sequentially, or separately.

[0082] As used herein, the term “therapeutically effective amount” refers to the total amount of the agent or each active component of the pharmaceutical composition or method that is sufficient to provide patient benefit, i.e., prevention or amelioration of the condition to be treated, a reduction in symptoms, an increase in rate of healing, or a detectable change in the levels of a substance in the treated or surrounding tissue. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in concurrently, sequentially, or separately.

[0083] The agents or compositions may be delivered at intervals ranging from about 24 hours to about 2 days, to about 1 week, to about 2 weeks, to about 3 weeks to about 1 month to about 2 months, to about 3 months, to about 4 months, to about 5 months, to about 6 months, to about 12 months, or more. The scheduling of such dosage regimens can be optimized by the practitioner.

[0084] The agents or compositions may be administered using a treatment regimen comprising one or more doses, wherein the treatment regimen is administered over 2 days, 3 days, 4 days, 5 days, 6 days or 7 days, 14 days, 30 days, 1 month, 2 months, 3 months, 6 months, 12 months or more.

[0085] The term “patient” or “subject,” as used interchangeably herein, refers to any mammal, preferably a human.

[0086] The method of any aspect of the invention may be in vivo, ex vivo or in vitro. The skilled person will appreciate that preferred features of any one embodiment and / or aspect of the invention may be applied to all other embodiments and / or aspects of the invention. Table 1. TCR alpha-beta and gamma-delta T cell clones showing shared and related motifs within the alpha chain. The sequences correspond to 12 of 33 sequences obtained.

[0087]

[0088] BRIEF DESCRIPTION OF THE DRAWINGS

[0089] Figure 1 - shows CDla dextramer staining of a clonal population of CDla-reactive T cells showing the purity of the isolated T cell clones. Peripheral blood mononuclear cells were stained with fluorescent multimeric (dextramer) complexes of CDla containing endogenous lipids and sorted using fluorescence guided flow cytometry. After bulk sorting, the cells were resorted to clonality and further selected for cytokine production. Final T cell clones were expanded in vitro and stained with CDla dextrameric complexes and anti-CD2.

[0090] Figure 2 - demonstrates high IL13 production from CDla reactive T-cell clones. T cell clones were incubated overnight with K562 cells transduced with CDla or empty vector. Supernatant was harvested for cytokine concentration using ELISA. Figure 3 - demonstrates that reactive TCR clones are able to induce activation of T-cells with CDla and beta TCR knocked out. After sequencing the TCR of T cell clones, the TCR was expressed in Jurkat cells using CRISPR-mediated homology directed repair and then tested for functionality through determining CD69 and NFkB- GFP expression with flow cytometry after incubation with beads expressing CD la (or controls).

[0091] Figure 4 - demonstrates functionality of gamma-delta expressing T cells. (A) Primary gamma-delta (delta 1) T cell clones (AK17 and AK18) were co-incubated overnight with K562 cells expressing CD la (K562-CD la) or empty vector controls and cytokine production was measured by ELISA. (B) gamma-delta TCRs (delta 2) were deployed to orthotopically replace endogenous TCR in primary recipient T cells which were co-incubated with K562 cells expressing CD la or CD lb or empty vector controls. Cytokine production was measured by ELISA. Effector:target ratio (E:T) 1 :3.

[0092] Figure 5 - demonstrates functionality of Jurkat T cells expressing alpha-beta CDla-reactive TCR sharing the same alpha chain (AFGN motif) but different beta chain. The Jurkat cells were co-incubated with a titration of beads coated with CD la loaded with endogenous lipids (endo) or lysophophatidylcholine (LPC 18: 1) or sphingomyelin 42:2 (SM42:2). Activation was detected using flow cytometry for NFKB reporter and CD69 co-expression.

[0093] Figure 6 - Characteristics of further TCRs identified (TCRsl3-17).

[0094] Figure 7 - demonstrates binding of TCR18 to CDla and cytokine production in clones expressing this. (A) CD la tetramer staining of the primary D 10A T cell clone (and a control clone) detected by flow cytometry. (B) Cytokine production of the primary D 10A T cell clone after co-incubation with K562 cells expressing CD lb, CD la minor, or CD la major alleles or parental K562 cells (neg). *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

[0095] Figure 8 - shows CDla tetramer and anti-CD3 expression of primary T cells in which the endogenous TCR has been knocked out (upper panel) or replaced by the D10A TCR. Analysed by flow cytometry. MATERIALS AND METHODS

[0096] CD la-coated bead or K562-CDla activation assay

[0097] PureProteome Streptavidin Magnetic Beads (2 pl per condition; Millipore) were washed 3x with wash buffer (2 mM EDTA; Thermo Fisher Scientific; and 2% fetal bovine serum; Sigma-Aldrich; in phosphate buffered saline) using DynaMag™-2 Magnet (Thermo Fisher Scientific). Beads were then resuspended in wash buffer and biotinylated CD la protein produced in-house was added at 0.2 pg / pl final concentration for bead coating. Uncoated beads served as a negative control. Following 16 h of incubation at 4oC with rotation, beads were washed 3x with wash buffer as before and resuspended in complete Takara medium (LymphoONE T-Cell Expansion Xeno-Free Medium; Takara Bio; supplemented with 10% fetal bovine serum; Sigma-Aldrich). Beads were plated in a 96-well round bottom plate (Corning). CD la-reactive TCR- expressing NF-KB / GFP Jurkat cell lines or T cell clones were washed once in complete Takara medium, added to the plated beads (or K562-CDla or control) at for example, 150,000 cells per well and incubated at 37oC, 5% CO2 for 16 h. Then, cells were harvested, labelled with an anti-CD69 antibody (BioLegend) and their CD la-dependent activation was determined for example by measuring the expression of NF-KB and CD69 by flow cytometry (LSRFortessa X-20; BD Biosciences). Data analysis was performed in FlowJo 10.10.0 (BD Biosciences).

[0098] Cytokine measurement by LEGENDplex

[0099] Cytokines present in conditioned medium from CD la-reactive T cell clone activation assays were measured using LEGENDplex HU Th Cytokine Panel (12-plex) w / VbP V02 (BioLegend) according to manufacturer’s instructions. Briefly, Assay Buffer, conditioned media (or standards) and Pre-mixed Beads were incubated together in a 96- well V-bottom plate (Corning) for 2 h at RT with shaking. Then, beads were washed once and Detection Antibodies were added for a 1 h hour incubation at RT with shaking. Next, Streptavidin-PE was added without prior washing and incubated for further 30 min at RT with shaking. Finally, beads were washed once, resuspended in Wash Buffer and acquired by flow cytometry (LSRFortessa X-20; BD Biosciences). Cytokine concentrations were calculated by analyzing the data in LEGENDplex Data Analysis Software Suite (BioLegend). Cytokine detection by ELISA

[0100] Alternatively, cytokines in conditioned medium from CD la-reactive T cell clone activation assays were quantified by enzyme-linked immunosorbent assay (ELISA) kits (Thermo Fisher Scientific) according to manufacturer’s instructions. Briefly, a 96-Well Half-Area Microplate (Corning) was coated with Coating Antibody overnight at 4oC. Next, the plate was washed 3x and blocked with ELISA / ELISPOT Diluent for 1 h at RT followed by another wash. Samples and standards were added onto the plate and incubated for 2 h at RT. After 3x wash, Detection antibody was added and the plate was incubated for 1 hour at RT. Following 3 washes, Streptavidin-HRP was added to the wells for a 30 min incubation at RT and then the plate was washed 5x. After incubation with IX TMB Solution for 15 min at RT, Stop Solution was added and the plate absorbance was read at 450 nm (cytokine signal) and 570 nm (background) with CLARIOstar R440 (BMG Labtech). Background was subtracted from cytokine signal and linear regression was used to fit the standard curve from which cytokine concentrations in samples were calculated in Microsoft Excel (Microsoft Corporation).

[0101] EXAMPLES

[0102] Example 1 - Clonal CD la-reactive T cell isolation and expansion

[0103] CD la-reactive T cell clones were isolated using CD la multimeric complexes and cytokine capture. Cells were sorted to single cell populations and expanded in vitro and then stained with CD la multimeric (“dextramer”) complexes containing endogenous lipid antigens. Figure 1 shows CD la dextramer staining of a clonal population of CD la- reactive T cells showing the purity of the isolated T cell clones.

[0104] Example 2 - CD la-reactive T cell cytokine production

[0105] Multiple CDla-reactive T cell clones were tested for cytokine (IL-13) production after overnight incubation with K562 cells transduced to express CD la (or empty vector controls). Supernatants were harvested and IL-13 concentration measured by ELISA (figure 2). It was noted that the CD la-reactive T cells could produce large amounts of many different cytokines, but often with a type 2 cytokine bias. Such extraordinarily high levels of cytokine production demonstrate that the T cell clones have high functional avidity, with likely relevance to disease. T cell clones that bound CD la multimers and showed functionality were progressed towards next step analyses of TCR sequence and function. Example 3 - Transfer of reactivity by TCR homology directed repair

[0106] In order to confirm that the CD la multimer and functionality was explained by TCR reactivity, the TCRs expressed by the T cell clones were sequenced and transferred by CRISPR-mediated homology directed repair (HDR) into the alpha TCR locus of Jurkat cells that had endogenous CDla and beta TCR knocked out. The CDla-reactive TCR- expressing Jurkat cells responded to beads coated with CDla (figure 3). These data show that the reactivity is explained by the TCR expressed by the CDla-reactive T cell clones.

[0107] Example 4 - TCR sequence analysis

[0108] (V) and joining (J) and CDR3 regions of the alpha and beta chains of T cell clones sharing the invariant alpha chain (CDR3 CAASAFGNQFYF) are described, as well as examples of closely related motifs. Specifically, it was noted there was a motif within the alpha CDR3 comprised “AFGN” (most common), or the closely related “AWGN”, “AFNN”, “VFGN”. Furthermore, it was noted that the alpha CDR3 most commonly started with “CAAS” through the combination of TRAV29DV5 with TRAJ49 (most common) or TRAJ43. A related motif was also obtained through a combination of TRAV39 and TRAJ48 (TCR LC6). Of 29 alpha-beta TCR-expressing T cell clones isolated and characterised in this way, 12 were found to express the invariant (or closely related) alpha CDR3 from 4 unrelated healthy donors. It was noted that the beta chain TCR showed no common patterns implicating a role for the beta chain in determining antigen specificity, with the alpha chain perhaps supporting CDla binding. Such a common conserved alpha chain suggests strong selective pressure for the motifs and would be compatible with the high functional avidity shown for the T cell clones.

[0109] Example 5 - identification and characterisation of further CDla-reactive TCRs. including gamma-delta TCRs.

[0110] It was further noted that T cells expressing gamma-delta TCR could respond to CDla. Sequences of gamma-delta TCR and their associated TCR chain usage were identified, which includes deltal (TRDV1) or delta2 (TRDV2) or delta3 (TRDV3) regions. Although it is noted that a subset of gamma-delta T cells expressing the deltal (TRDV1) region have been previously known to be able to respond to CDla (eg Wegrecki et al. Nat Comms 2022, PMID: 35790773), this has not been documented for gamma-delta T cells expressing the delta2 (TRDV2) region. Therefore, this invention is of importance for defining CD la as a new ligand of delta2 (TRDV2) T cell receptors which has been a source of much debate in the literature. The sequences also show that the deltal (TRDV1) expressing T cells from different donors can surprisingly share a virtually identical gamma chain, while expressing different delta chains, implicating conserved / public / invariant gamma chains conferring CD la reactivity. This suggests strong selective pressure for the unusual gamma variable chain allele (predominant matching to the TRGV5 allele but with some features described for TRGV3) and gamma CDR3 motif for CDla engagement. Specifically, the TCR16 TRGV CDR3 is CATWDRPGYYKKLF; and the TCR17 TRGV CDR3 is CATWDRPLRYKKLF. The sequences also show that the delta2 (TRDV2) expressing T cells from different donors can surprisingly share a virtually identical gamma chain, implicating conserved / public / invariant gamma chains conferring CDla reactivity. Specifically the TRDV2 expressing T cells, expressed TRGV9 paired with either TRGJP*01 or TRGJP1 to yield shared gCDRl and gCDR2 and remarkably similar gCDR3 of CALWEPQELGKKIKVF for TCR14 and CALWDHQELGKKIKVF for TCR15.

[0111] Furthermore, gamma-delta T cells have conventionally been seen as relatively functionally quiescent, but we show in figure 4 that our approach for discovery yields T cells with surprisingly marked type 1 and type 2 functionality, including primary T cell clones (Figure 4a) and also recipient T cells which have received the gamma-delta TCR through orthotopic TCR replacement (Figure 4b).

[0112] In addition, the inventors discovered a further alpha-beta TCR reactive to endogenous lipids presented by CDla and expressing a related CDR3 alpha central motif shared by the conserved / public / invariant sequences in Table 1. This new discovery (‘XYXN’) extends the patterns of the central alpha CDR3 motif which confers reactivity to CDla. The inventors also provide further data confirming functionality of the alpha-beta TCR through using TCR-transduced Jurkat cells bearing TCR containing the shared “AFGN” central alpha CDR3 motif in response to CD la-coated beads (figure 5). Notably, the TCR-transduced cells express different TCR beta chains and show different functional avidity, confirming earlier findings (Figure 3) that the beta chain also contributes to functionality. The cells were able to respond to a known CDla agonist lysophosphatidylcholine (LPC 18: 1), but inhibited by the known endogenous blocker, very long chain sphingomyelin (SM42:2) (Cotton et al. JExpMed 2021, PMID: 33961028). Collectively, these additional data expand the invention to gamma-delta TCR and extend the shared alpha CDR3 motif; and add further exemplification of functionality, both for alpha-beta TCR and gamma-delta TCR.

[0113] Example 6 - further characterisation of TCR18

[0114] The inventors also surprisingly noted that other CDR3 alpha sequences were occasionally observed, which show some shared features with the common central alpha motif and the central gamma motif, for example “CALDSNYQLIW” (TCR 18), where aspartate (D) can be a feature of the gamma CDR3 motif and the underlined amino acids LDSN are more in keeping with the central alpha CDR3 motif. Such an alpha / gamma CDR3 motif combination is the first observation of its kind and suggests strong selective pressure on the CD la-reactive motif.

[0115] The TCR18 T cell clone was able to bind CD la tetrameric complexes (figure 7A) and produced diverse cytokines after co-incubation with K562 cells expressing CD la (minor and major variants), but not when the K562 cells expressed CD lb (figure IB). It was noted that although the clone produced different cytokines, there was a strong type 2 cytokine bias.

[0116] Orthotopic transfer of the D10A TCR into recipient primary T cells maintained CD la tetramer staining (lower panel, figure 8) compared to the primary T cells in which the endogenous TCR was knocked out (upper panel, figure 8). Of note, knockout of the endogenous TCR associated with reduction in CD3 cell surface expression which was rescued by the D10A TCR transfer.

[0117] Conclusion

[0118] Knowledge of the invariant or shared CD la-reactive alpha chain and gamma chains and associated motifs now allows further mechanistic studies of the nature and degree of lipid specificity. The TCR characteristics will now also support the discovery of lipid antigens and blockers with associated relevance to disease, opening new biology to treatment. In addition, large TCR datasets can now be probed where CD la had not been previously considered to play a role, unlocking their scientific value. For example, the existence of the invariant sequence or related motifs would point to a role for CD la in diseases of the skin and also at other tissue sites including the gut, lungs, joints, kidneys, nervous system, liver and other organs. This can carry diagnostic and / or prognostic utility. Furthermore, the evolutionary selection of such a conserved TCR sequence suggests functional importance which may be capitalized upon within TCR or T cellbased therapeutics for inflammation, infection and cancer.

Claims

CLAIMS1. A CD la-reactive T-cell receptor (TCR).

2. The CD la-reactive TCR of claim 1, wherein the TCR comprises a CDR3 alpha comprising a central motif of amino acid sequence: a) AXGN wherein X is F or W (SEQ ID NO: 66 or 67); b) VFGN (SEQ ID NO: 68); c) AFNN (SEQ ID NO: 69), or d) LWANN (SEQ ID NO: 70).

3. The CDla-reactive TCR of claim 1, wherein the TCR comprises a) a CDR3-alpha of amino acid sequence CAASAXGNQFYF (SEQ ID NO: 7 or 8), wherein X is F or W; or b) a CDR3 -gamma of amino acid sequence CALWX1X2QELGKKIKVF, where X1is E or D, and where X2is P or H, and optionally a delta chain comprising a TRDV2 variable region; or c) CDR3-gamma of amino acid sequence CATWDRPXIX2YI<KLF. where X1is G or L, and where X2is Y or R.

4. The TCR of any of claims l-3(a), wherein the TCR comprises CDRl-alpha of amino acid sequence NSMFDY (SEQ ID NO: 1), and / or a CDR2-alpha of amino acid sequence ISSIKDK (SEQ ID NO: 4).

5. The TCR of any of claims l-3a and or 4, wherein the TCR comprises a CDR3-beta in which the first four amino acids are CASS (SEQ ID NO: 113).

6. The TCR of claim 1, wherein the TCR comprises an alpha chain variable domain and a beta chain variable domain, or a gamma chain variable domain and a delta chain variable domain, comprising: a) a CDR3-alpha of amino acid sequence CAASAFGNQFYF (SEQ ID NO: 7), and / or a CDR3-beta of amino acid sequence CASSLDRGAEAFF (SEQ ID NO: 32); orb) a CDR3-alpha of amino acid sequence CAASAFGNQFYF (SEQ ID NO:7), and / or a CDR3-beta of amino acid sequence CASSYRGNIQETQYF (SEQ ID NO: 31); or c) a CDR3-alpha of amino acid sequence CAASAFGNQFYF (SEQ ID NO:7), and / or a CDR3-beta of amino acid sequence CASSEGSSNQPQHF (SEQ ID NO: 33); or d) a CDR3-alpha of amino acid sequence CAASAFGNQFYF (SEQ ID NO: 7), and / or a CDR3-beta of amino acid sequence CASSPLWGGETQYF (SEQ ID NO: 34); or e) a CDR3-alpha of amino acid sequence CAASAFGNQFYF (SEQ ID NO:7), and / or a CDR3-beta of amino acid sequence CASSSPTEAYGYTF (SEQ ID NO: 35); or f) a CDR3-alpha of amino acid sequence CAASAWGNQFYF (SEQ ID NO:8), and / or a CDR3-beta of amino acid sequence CASSFLSSSVEQFF (SEQ ID NO: 36); or g) a CDR3-alpha of amino acid sequence CAASAWGNQFYF (SEQ ID NO:8), and / or a CDR3-beta of amino acid sequence CASSPVDRAYEQYF (SEQ ID NO: 37); or h) a CDR3-alpha of amino acid sequence CAASAFNNDMRF (SEQ ID NO:9), and / or a CDR3-beta of amino acid sequence CAISEGGSYYGYTF (SEQ ID NO: 38); or i) a CDR3-alpha of amino acid sequence CAASAFNNDMRF (SEQ ID NO:9), and / or a CDR3-beta of amino acid sequence CASSPRDDYGYTF (SEQ ID NO: 39); or j) a CDR3-alpha of amino acid sequence CAASAFGNVLHC (SEQ ID NO:10), and / or a CDR3-beta of amino acid sequence CASSRPGPGYGYTF (SEQ ID NO: 40); or k) a CDR3-alpha of amino acid sequence CAVDVFGNEKLTF (SEQ ID NO: 11), and / or a CDR3-beta of amino acid sequence CASSLSDGRWGQGAAYNEQFF (SEQ ID NO: 41); or l) a CDR3 -alpha of amino acid sequence CIVRTLWANNLFF (SEQ ID NO: 12), and / or a CDR3-beta of amino acid sequence CASSPSYNEQFF (SEQ ID NO: 42); orm) a CDR3 -alpha of amino acid sequence CIVRYYNDYKLSF (SEQ ID NO: 43), and / or a CDR3-beta of amino acid sequence CASSPLGGNEKLFF (SEQ ID NO:46); or n) a CDR3-gamma of amino acid sequence CALWEPQELGKKIKVF (SEQ ID NO: 51), and / or a CDR3-delta of amino acid sequence CACDAMELGDKVTDKLIF (SEQ ID NO: 61); or o) a CDR3 -gamma of amino acid sequence CALWDHQELGKKIKVF (SEQ ID NO: 52), and / or a CDR3-delta of amino acid sequence CACDTVPESGDSPPEYTDKLIF (SEQ ID NO: 62); or p) a CDR3 -gamma of amino acid sequence CATWDRPGYYKKLF (SEQ IDNO: 53), and / or a CDR3-delta of amino acid sequenceCALGALWHPQTQPWYTDKLIF (SEQ ID NO: 63); or q) a CDR3 -gamma of amino acid sequence CATWDRPLRYKKLF (SEQ IDNO: 54), and / or a CDR3-delta of amino acid sequenceCAYNWPPFLQHWGIPDPMTKPDKLIF (SEQ ID NO: 64); or r) a CDR3- alpha of amino acid sequence CALDSNYQLIW (SEQ ID NO: 107), and / or a CDR3-beta of amino acid sequence CASSLEEGVRGALNTEAFF (SEQ ID NO: 110).

7. The TCR of claim 1 or claim 6, wherein the TCR comprises an alpha chain variable domain and a beta chain variable domain, or a gamma chain variable domain and a delta chain variable domain, comprising: a)a CDRl-alpha of amino acid sequence NSMFDY (SEQ ID NO: 1), a CDR2- alpha of amino acid sequence ISSIKDK (SEQ ID NO: 4), and a CDR3-alpha of amino acid sequence CAASAFGNQFYF (SEQ ID NO: 7), and / or a CDRl-beta of amino acid sequence SGHDT (SEQ ID NO: 14), a CDR2-beta of amino acid sequence YYEEEE (SEQ ID NO: 23), and a CDR3-beta of amino acid sequence CASSLDRGAEAFF (SEQ ID NO: 32); or b) a CDRl-alpha of amino acid sequence NSMFDY (SEQ ID NO: 1), a CDR2- alpha of amino acid sequence ISSIKDK (SEQ ID NO: 4), and a CDR3-alpha of amino acid sequence CAASAFGNQFYF (SEQ ID NO: 7), and / or a CDRl-beta of amino acid sequence SGHNT (SEQ ID NO: 13), a CDR2-beta of amino acid sequence YYREEE (SEQ ID NO: 22), and a CDR3-beta of amino acid sequence CASSYRGNIQETQYF (SEQ ID NO: 31); orc) a CDRl-alpha of amino acid sequence NSMFDY (SEQ ID NO: 1), a CDR2- alpha of amino acid sequence ISSIKDK (SEQ ID NO: 4), and a CDR3-alpha of amino acid sequence CAASAFGNQFYF (SEQ ID NO: 7), and / or a CDRl-beta of amino acid sequence SGDLS (SEQ ID NO: 15), a CDR2-beta of amino acid sequence YYNGEE (SEQ ID NO: 24), and a CDR3-beta of amino acid sequence CASSEGSSNQPQHF (SEQ ID NO: 33); or d) a CDRl-alpha of amino acid sequence NSMFDY (SEQ ID NO: 1), a CDR2- alpha of amino acid sequence ISSIKDK (SEQ ID NO: 4), and a CDR3-alpha of amino acid sequence CAASAFGNQFYF (SEQ ID NO: 7), and / or a CDRl-beta of amino acid sequence SGHAT (SEQ ID NO: 16), a CDR2-beta of amino acid sequence FQNNGV (SEQ ID NO: 25), and a CDR3-beta of amino acid sequence CASSPLWGGETQYF (SEQ ID NO: 34); or e) a CDRl-alpha of amino acid sequence NSMFDY (SEQ ID NO: 1), a CDR2- alpha of amino acid sequence ISSIKDK (SEQ ID NO: 4), and a CDR3-alpha of amino acid sequence CAASAFGNQFYF (SEQ ID NO: 7), and / or a CDRl-beta of amino acid sequence SGHRS (SEQ ID NO: 17), a CDR2-beta of amino acid sequence YFSETQ (SEQ ID NO: 26), and a CDR3-beta of amino acid sequence CASSSPTEAYGYTF (SEQ ID NO: 35); or f) a CDRl-alpha of amino acid sequence NSMFDY (SEQ ID NO: 1), a CDR2- alpha of amino acid sequence ISSIKDK (SEQ ID NO: 4), and a CDR3-alpha of amino acid sequence CAASAWGNQFYF (SEQ ID NO: 8), and / or a CDRl-beta of amino acid sequence SGHDT (SEQ ID NO: 14), a CDR2-beta of amino acid sequence YYEEEE (SEQ ID NO: 23), and a CDR3-beta of amino acid sequence CASSFLSSSVEQFF (SEQ ID NO: 36); or g) a CDRl-alpha of amino acid sequence NSMFDY (SEQ ID NO: 1), a CDR2- alpha of amino acid sequence ISSIKDK (SEQ ID NO: 4), and a CDR3-alpha of amino acid sequence CAASAWGNQFYF (SEQ ID NO: 8), and / or a CDRl-beta of amino acid sequence SEHNR (SEQ ID NO: 18), a CDR2-beta of amino acid sequence FQNEAQ (SEQ ID NO: 27), and a CDR3-beta of amino acid sequence CASSPVDRAYEQYF (SEQ ID NO: 37); or h) a CDRl-alpha of amino acid sequence NSMFDY (SEQ ID NO: 1), a CDR2- alpha of amino acid sequence ISSIKDK (SEQ ID NO: 4), and a CDR3-alpha of amino acid sequence CAASAFNNDMRF (SEQ ID NO: 9), and / ora CDRl-beta of amino acid sequence ENHRY (SEQ ID NO: 19), a CDR2-beta of amino acid sequence SYGVKD (SEQ ID NO: 28), and a CDR3-beta of amino acid sequence CAISEGGSYYGYTF (SEQ ID NO: 38); or i) a CDRl-alpha of amino acid sequence NSMFDY (SEQ ID NO: 1), a CDR2- alpha of amino acid sequence ISSIKDK (SEQ ID NO: 4), and a CDR3-alpha of amino acid sequence CAASAFNNDMRF (SEQ ID NO: 9), and / or a CDRl-beta of amino acid sequence LGHDT (SEQ ID NO: 20), a CDR2-beta of amino acid sequence YNNKEL (SEQ ID NO: 29), and a CDR3-beta of amino acid sequence CASSPRDDYGYTF (SEQ ID NO: 39); or j) a CDRl-alpha of amino acid sequence NSMFDY (SEQ ID NO: 1), a CDR2- alpha of amino acid sequence ISSIKDK (SEQ ID NO: 4), and a CDR3-alpha of amino acid sequence CAASAFGNVLHC (SEQ ID NO: 10), and / or a CDRl-beta of amino acid sequence SEHNR (SEQ ID NO: 18), a CDR2-beta of amino acid sequence FQNEAQ (SEQ ID NO: 27), and a CDR3-beta of amino acid sequence CASSRPGPGYGYTF (SEQ ID NO: 40); or k) a CDRl-alpha of amino acid sequence TTSDR (SEQ ID NO: 2), a CDR2- alpha of amino acid sequence LLSNGAV (SEQ ID NO: 5), and a CDR3-alpha of amino acid sequence CAVDVFGNEKLTF (SEQ ID NO: 11), and / or a CDRl-beta of amino acid sequence MDHEN (SEQ ID NO: 21), a CDR2-beta of amino acid sequence SYDVKM (SEQ ID NO: 30), and a CDR3-beta of amino acid sequence CASSLSDGRWGQGAAYNEQFF (SEQ ID NO: 41); or l) a CDRl-alpha of amino acid sequence TISGNEY (SEQ ID NO: 3), a CDR2- alpha of amino acid sequence GLKNN (SEQ ID NO: 6), and a CDR3-alpha of amino acid sequence CIVRTLWANNLFF (SEQ ID NO: 12), and / or a CDRl-beta of amino acid sequence LGHDT (SEQ ID NO: 20), a CDR2-beta of amino acid sequence YNNKEL (SEQ ID NO: 29), and a CDR3-beta of amino acid sequence CASSPSYNEQFF (SEQ ID NO: 42); or m) a CDRl-alpha of amino acid sequence TISGNEY (SEQ ID NO: 3), a CDR2- alpha of amino acid sequence GLKNN (SEQ ID NO: 6), and a CDR3-alpha of amino acid sequence CIVRYYNDYKLSF (SEQ ID NO: 43), and / or a CDRl-beta of amino acid sequence SSHAT (SEQ ID NO: 44), a CDR2-beta of amino acid sequence FNYEAQ (SEQ ID NO: 45), and a CDR3-beta of amino acid sequence CASSPLGGNEKLFF (SEQ ID NO: 46); orn) a CDRl-gamma of amino acid sequence GITISATS (SEQ ID NO: 47), a CDR2-gamma of amino acid sequence ISYDGTV (SEQ ID NO: 49), and a CDR3- gamma of amino acid sequence CALWEPQELGKKIKVF (SEQ ID NO: 51), and / or a CDRl-delta of amino acid sequence GEAIGNYY (SEQ ID NO: 55), a CDR2- delta of amino acid sequence EKD (SEQ ID NO: 58), and a CDR3-delta of amino acid sequence CACDAMELGDKVTDKLIF (SEQ ID NO: 61); or o) a CDRl-gamma of amino acid sequence GITISATS (SEQ ID NO: 47), a CDR2-gamma of amino acid sequence ISYDGTV (SEQ ID NO: 49), and a CDR3- gamma of amino acid sequence CALWDHQELGKKIKVF (SEQ ID NO: 52), and / or a CDRl-delta of amino acid sequence GEAIGNYY (SEQ ID NO: 55), a CDR2- delta of amino acid sequence EKD (SEQ ID NO: 58), and a CDR3-delta of amino acid sequence CACDTVPESGDSPPEYTDKLIF (SEQ ID NO: 62); or p) a CDRl-gamma of amino acid sequence VINAFY (SEQ ID NO: 48), a CDR2- gamma of amino acid sequence YDVSNSKD (SEQ ID NO: 50), and a CDR3-gamma of amino acid sequence CATWDRPGYYKKLF (SEQ ID NO: 53), and / or a CDRl-delta of amino acid sequence TSWWSYY (SEQ ID NO: 56), a CDR2- delta of amino acid sequence QGS (SEQ ID NO: 59), and a CDR3-delta of amino acid sequence CALGALWHPQTQPWYTDKLIF (SEQ ID NO: 63); or q) a CDRl-gamma of amino acid sequence VINAFY (SEQ ID NO: 48), a CDR2- gamma of amino acid sequence YDVSNSKD (SEQ ID NO: 50), and a CDR3-gamma of amino acid sequence CATWDRPLRYKKLF (SEQ ID NO: 54), and / or a CDRl-delta of amino acid sequence TVYSNPD (SEQ ID NO: 57), a CDR2- delta of amino acid sequence GDNSR (SEQ ID NO: 60), and a CDR3-delta of amino acid sequence CAYNWPPFLQHWGIPDPMTKPDKLIF (SEQ ID NO: 64); or r) a CDRl-alpha of amino acid sequence ATGYPS (SEQ ID NO: 105), a CDR2- alpha of amino acid sequence ATKADDK (SEQ ID NO: 106), and a CDR3-alpha of amino acid sequence CALDSNYQLIW (SEQ ID NO: 107), and / or a CDRl-beta of amino acid sequence SGHNT (SEQ ID NO: 108), a CDR2-beta of amino acid sequence YENEEA (SEQ ID NO: 109), and a CDR3-beta of amino acid sequence CASSLEEGVRGALNTEAFF (SEQ ID NO: 110).

8. The TCR of any of claims 1 or 6-7, wherein the TCR comprises: a) an alpha chain variable domain comprising a variable segment encoded by the TRAV29DV5 gene, a Joining segment encoded by the TRAJ49 gene, a CDRl- alpha of SEQ ID NO: 1, a CDR2-alpha of SEQ ID NO: 4 and a CDR3-alpha of SEQ IDNO: 7; and / or a beta chain variable region comprising a variable segment encoded by the TRBV5-6 gene, a Joining segment encoded by the TRBJ1-1 gene, a CDRl-beta of SEQ ID NO: 14, a CDR2-beta of SEQ ID NO: 23 and a CDR3-beta of SEQ ID NO: 32; or b) an alpha chain variable domain comprising a variable segment encoded by the TRAV29DV5 gene, a Joining segment encoded by the TRAJ49 gene, a CDRl-alpha of SEQ ID NO: 1, a CDR2-alpha of SEQ ID NO: 4 and a CDR3-alpha of SEQ ID NO: 7; and / or a beta chain variable region comprising a variable segment encoded by the TRBV5-4 gene, a Joining segment encoded by the TRBJ2-5 gene, a CDRl-beta of SEQ ID NO: 13, a CDR2-beta of SEQ ID NO: 22 and a CDR3-beta of SEQ ID NO: 31; or c) an alpha chain variable domain comprising a variable segment encoded by the TRAV29DV5 gene, a Joining segment encoded by the TRAJ49 gene, a CDRl- alpha of SEQ ID NO: 1, a CDR2-alpha of SEQ ID NO: 4 and a CDR3-alpha of SEQ ID NO: 7; and / or a beta chain variable region comprising a variable segment encoded by the TRBV9 gene, a Joining segment encoded by the TRBJ1-5 gene, a CDRl-beta of SEQ ID NO: 15, a CDR2-beta of SEQ ID NO: 24 and a CDR3-beta of SEQ ID NO: 33; or d) an alpha chain variable domain comprising a variable segment encoded by the TRAV29DV5 gene, a Joining segment encoded by the TRAJ49 gene, a CDRl- alpha of SEQ ID NO: 1, a CDR2-alpha of SEQ ID NO: 4 and a CDR3-alpha of SEQ ID NO: 7; and / or a beta chain variable region comprising a variable segment encoded by the TRBV11-2 gene, a Joining segment encoded by the TRBJ2-5 gene, a CDRl-beta of SEQ ID NO: 16, a CDR2-beta of SEQ ID NO: 25 and a CDR3-beta of SEQ ID NO: 34; or e) an alpha chain variable domain comprising a variable segment encoded by the TRAV29DV5 gene, a Joining segment encoded by the TRAJ49 gene, a CDRl- alpha of SEQ ID NO: 1, a CDR2-alpha of SEQ ID NO: 4 and a CDR3-alpha of SEQ ID NO: 7; and / or a beta chain variable region comprising a variable segment encoded by the TRBV5-1 gene, a Joining segment encoded by the TRBJ1-2 gene, a CDRl-beta of SEQ ID NO: 17, a CDR2-beta of SEQ ID NO: 26 and a CDR3-beta of SEQ ID NO: 35; or f) an alpha chain variable domain comprising a variable segment encoded by the TRAV29DV5 gene, a Joining segment encoded by the TRAJ49 gene, a CDRl- alpha of SEQ ID NO: 1, a CDR2-alpha of SEQ ID NO: 4 and a CDR3-alpha of SEQ ID NO: 8; and / or a beta chain variable region comprising a variable segment encoded bythe TRBV5-6 gene, a Joining segment encoded by the TRBJ2-1 gene, a CDRl-beta of SEQ ID NO: 14, a CDR2-beta of SEQ ID NO: 23 and a CDR3-beta of SEQ ID NO: 36; or g) an alpha chain variable domain comprising a variable segment encoded by the TRAV29DV5 gene, a Joining segment encoded by the TRAJ49 gene, a CDR1- alpha of SEQ ID NO: 1, a CDR2-alpha of SEQ ID NO: 4 and a CDR3-alpha of SEQ ID NO: 8; and / or a beta chain variable region comprising a variable segment encoded by the TRBV7-9 gene, a Joining segment encoded by the TRBJ2-7 gene, a CDRl-beta of SEQ ID NO: 18, a CDR2-beta of SEQ ID NO: 27 and a CDR3-beta of SEQ ID NO: 37; or h) an alpha chain variable domain comprising a variable segment encoded by the TRAV29DV5 gene, a Joining segment encoded by the TRAJ43 gene, a CDR1- alpha of SEQ ID NO: 1, a CDR2-alpha of SEQ ID NO: 4 and a CDR3-alpha of SEQ ID NO: 9; and / or a beta chain variable region comprising a variable segment encoded by the TRBV10-3 gene, a Joining segment encoded by the TRBJ1-2 gene, a CDRl-beta of SEQ ID NO: 19, a CDR2-beta of SEQ ID NO: 28 and a CDR3-beta of SEQ ID NO: 38; or i) an alpha chain variable domain comprising a variable segment encoded by the TRAV29DV5 gene, a Joining segment encoded by the TRAJ43 gene, a CDR1- alpha of SEQ ID NO: 1, a CDR2-alpha of SEQ ID NO: 4 and a CDR3-alpha of SEQ ID NO: 9; and / or a beta chain variable region comprising a variable segment encoded by the TRBV3-1 gene, a Joining segment encoded by the TRBJ1-2 gene, a CDRl-beta of SEQ ID NO: 20, a CDR2-beta of SEQ ID NO: 29 and a CDR3-beta of SEQ ID NO: 39; or j) an alpha chain variable domain comprising a variable segment encoded by the TRAV29DV5 gene, a Joining segment encoded by the TRAJ35 gene, a CDR1- alpha of SEQ ID NO: 1, a CDR2-alpha of SEQ ID NO: 4 and a CDR3-alpha of SEQ ID NO: 10; and / or a beta chain variable region comprising a variable segment encoded by the TRBV7-9 gene, a Joining segment encoded by the TRBJ1-2 gene, a CDRl-beta of SEQ ID NO: 18, a CDR2-beta of SEQ ID NO: 27 and a CDR3-beta of SEQ ID NO:

40. k) an alpha chain variable domain comprising a variable segment encoded by the TRAV39 gene, a Joining segment encoded by the TRAJ48 gene, a CDRl-alpha of SEQ ID NO: 2, a CDR2-alpha of SEQ ID NO: 5 and a CDR3-alpha of SEQ ID NO: 11; and / or a beta chain variable region comprising a variable segment encoded by theTRBV28 gene, a Joining segment encoded by the TRBJ2-1 gene, a CDRl-beta of SEQ ID NO: 21, a CDR2-beta of SEQ ID NO: 30 and a CDR3-beta of SEQ ID NO: 41; or l) an alpha chain variable domain comprising a variable segment encoded by the TRAV26-1 gene, a Joining segment encoded by the TRAJ36 gene, a CDRl-alpha of SEQ ID NO: 3, a CDR2-alpha of SEQ ID NO: 6 and a CDR3-alpha of SEQ ID NO: 12; and / or a beta chain variable region comprising a variable segment encoded by the TRBV3-1 gene, a Joining segment encoded by the TRBJ2-1 gene, a CDRl-beta of SEQ ID NO: 20, a CDR2-beta of SEQ ID NO: 29 and a CDR3-beta of SEQ ID NO: 42; or m) an alpha chain variable domain comprising a variable segment encoded by the TRAV26-1 gene, a Joining segment encoded by the TRAJ20 gene, a CDRl-alpha of SEQ ID NO: 3, a CDR2-alpha of SEQ ID NO: 6 and a CDR3-alpha of SEQ ID NO: 43; and / or a beta chain variable region comprising a variable segment encoded by the TRBV7-7 gene, a Joining segment encoded by the TRBJ1-4 gene, a CDRl-beta of SEQ ID NO: 44, a CDR2-beta of SEQ ID NO: 45 and a CDR3-beta of SEQ ID NO: 46; or n) a gamma chain variable domain comprising a variable segment encoded by the TRGV9 gene, a joining segment encoded by the TRGJP*01 gene, a CDR1- gamma of SEQ ID NO: 47, a CDR2 -gamma of SEQ ID NO: 49 and a CDR3-gamma of SEQ ID NO: 51; and / or a delta chain variable region comprising a variable segment encoded by the TRDV2 gene, a joining segment encoded by the TRDJ1 gene, a CDR1- delta of SEQ ID NO: 55, a CDR2- delta of SEQ ID NO: 58 and a CDR3- delta of SEQ ID NO: 61; or o) a gamma chain variable domain comprising a variable segment encoded by the TRGV9 gene, a joining segment encoded by the TRGJP1 gene, a CDRl-gamma of SEQ ID NO: 47, a CDR2 -gamma of SEQ ID NO: 49 and a CDR3-gamma of SEQ ID NO: 52; and / or a delta chain variable region comprising a variable segment encoded by the TRDV2 gene, a joining segment encoded by the TRDJ1 gene, a CDR1 -delta of SEQ ID NO: 55, a CDR2-delta of SEQ ID NO: 58 and a CDR3-delta of SEQ ID NO: 62; or p) a gamma chain variable domain comprising a variable segment encoded by the TRGV5 or TRGV3 gene or with shared variable segment encoded by SEQ ID NO: 65, a joining segment encoded by the TRGJ2 gene, a CDRl-gamma of SEQ ID NO: 48, a CDR2 -gamma of SEQ ID NO: 50 and a CDR3-gamma of SEQ ID NO: 53; and / or a delta chain variable region comprising a variable segment encoded by the TRDV1 gene, a joining segment encoded by the TRDJ1 gene, a CDRl-delta of SEQ ID NO: 56, a CDR2-delta of SEQ ID NO: 59 and a CDR3-delta of SEQ ID NO: 63; orq) a gamma chain variable domain comprising a variable segment encoded by the TRGV5 or TRGV3 gene or with shared variable segment encoded by SEQ ID NO: 65, a joining segment encoded by the TRGJ2 gene, a CDRl-gamma of SEQ ID NO: 48, a CDR2 -gamma of SEQ ID NO: 50 and a CDR3-gamma of SEQ ID NO: 54; and / or a delta chain variable region comprising a variable segment encoded by the TRDV3 gene, a joining segment encoded by the TRDJ1 gene, a diversity segment encoded by the TRDD3 gene, a CDRl-delta of SEQ ID NO: 57, a CDR2-delta of SEQ ID NO: 60 and a CDR3-delta of SEQ ID NO: 64; or r) an alpha chain variable domain comprising a variable segment encoded by the TRAV9-2gene, a Joining segment encoded by the TRAJ33 gene, a CDRl-alpha of SEQ ID NO: 105, a CDR2-alpha of SEQ ID NO: 106 and a CDR3-alpha of SEQ ID NO: 107; and / or a beta chain variable region comprising a variable segment encoded by the TRBV11-3 gene, a Joining segment encoded by the TRBJ1-1 gene, a CDRl-beta of SEQ ID NO: 108, a CDR2-beta of SEQ ID NO: 109 and a CDR3-beta of SEQ ID NO: 110.

9. The TCR of any of claims 1-8, wherein the TCR comprises: a) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 73; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 74; or b) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 71; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 72; or c) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 75; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 76; or d) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 77; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 78; or e) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 79; and / or a beta chain variableregion comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 80; or f) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 81; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 82; or g) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 83; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 84; or h) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 85; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 86; or i) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 87; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 88; or j) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 89; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 90; or k) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 91; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 92; or l) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 93; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 94; or m) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 95; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 96; orn) a gamma chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 97; and / or a delta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 98; or o) a gamma chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 99; and / or a delta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 100; or p) a gamma chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 101; and / or a delta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 102; or q) a gamma chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 103; and / or a delta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 104; or r) an alpha chain variable domain comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 111; and / or a beta chain variable region comprising a variable segment comprising or consisting of an amino acid sequence of SEQ ID NO: 112.

10. The TCR of any of claims 1-9, wherein the TCR is bispecific or multi-specific, or a TCR-drug conjugate.

11. The TCR of claim 10, wherein the bispecific or multi-specific TCR or TCR-drug conjugate further comprises one or more of a CD3 targeting moiety, a PD-1 targeting moiety, an IL-2 receptor family targeting moiety, a CD2 targeting moiety, a CTLA4 targeting moiety, a CD28 targeting moiety, an ICOS targeting moiety, and / or a TNF receptor superfamily member targeting moiety and / or a small molecule drug conjugate such as a steroid or antimitotic.

12. A nucleic acid encoding a TCR of any of claims 1-11.

13. A vector comprising the nucleic acid of claim 12.

14. A cell comprising one or more TCR of any of claims 1-10, nucleic acid of claim 10 or vector of claim 11; optionally wherein the cell is CD4+ T cell, a CD8+ T cell, a mucosal associated invariant T cell (MAIT cell), natural killer cell (NK cell), myeloid cell or monocyte cell.

15. A pharmaceutical composition comprising one or more TCR, nucleic acid, vector or cell of any of claims 1-14.

16. The TCR nucleic acid, vector, cell, or pharmaceutical composition of any of claims 1-15, for use in treating or preventing a disease or disorder in a subject.

17. A method of treating or preventing a disease or disorder in a subject, comprising administering to the subject one or more TCR, nucleic acid, vector, cell or composition of any of claims 1-15.

18. Use of one or more TCR, nucleic acid, vector, cell or composition of any of claims 1-15, in the manufacture of a medicament for treating or preventing a disease or disorder in a subject.

19. The TCR, nucleic acid, vector, cell, or composition for use according to claim 16, wherein the disease or disorder is associated with increased CD la expression and / or function.

20. The TCR, nucleic acid, vector, cell, or composition for use according to claim 16 or 19, wherein the disease or disorder is an inflammatory skin or mucosal disorder or disease or one or more associated systemic disease or disorder, one or more inflammatory drug reaction which manifests systemically, a CD la-expressing malignancy or a malignancy wherein CD la is altered in expression or function.

21. The TCR, nucleic acid, vector, cell, or composition for use according to claim 20, wherein the inflammatory skin or mucosal disease or disorder is selected from: a) a predominantly neutrophilic skin disease, such as acne, generalized pustular psoriasis, plaque psoriasis, guttate psoriasis, palmoplantar pustulosis, SAPHO syndrome, acute febrile neutrophilic dermatosis (Sweet syndrome), histiocytoid neutrophilic dermatitis, neutrophilic dermatosis of the dorsal hands, pyodermagangrenosum, neutrophilic eccrine hidradenitis, hidradenitis suppurativa, erythema elevatum diutinum, Behcet disease, bowel-associated dermatitis-arthritis syndrome, other infection-associated inflammation, neutrophilic urticarial dermatosis, palisading neutrophilic granulomatous dermatitis, erythema gyratum repens, neutrophilic annular erythema, acute generalised exanthematous pustulosis (AGEP), vasculitis; b) an autoimmune disorder, such as connective tissue disease (eg lupus, dermatomyositis, scleroderma / systemic sclerosis, Churg Strauss syndrome), panniculitis, vasculitides, autoimmune blistering conditions (eg bullous pemphigoid, pemphigus, linear IgA disease), dermatitis herpetiformis, coeliac disease, some auto- inflammatory disease, vitiligo, alopecia areata, alopecia universalis, alopecia totalis, panniculitis, lichen planus, erythema multiforme, lichen sclerosis, other lichenoid and erythema multiforme-like diseases, vesiculation psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, Guillain-Barre syndrome, thyroiditis, transverse myelitis; c) mast cell disorders and eosinophilic disorders, such as Muckle Wells syndrome, eosinophilia and systemic symptoms syndrome, urticaria, angioedema, keratoconjunctivitis, food allergy, other allergy or atopy including atopic dermatitis, rhinitis, conjunctivitis, asthma, eosinophilic oesophagitis and other eosinophilic mucosal diseases, contact dermatitis, chronic obstructive airways disease; d) adverse drug reactions which manifest as an inflammatory skin or mucosal disease or disorder, such as Stevens Johnsons syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms syndrome (DRESS) and acute generalised exanthematous pustulosis (AGEP), erythema multiforme, bullous, fixed drug eruption, checkpoint inhibitor-associated skin and other inflammation; e) Graft vs host disease; f) Pruritus and pruritic conditions including nodular prurigo; g) non-cutaneous lupus erythematosus; or h) Conditions where altered frequency and / or phenotype of CD la- expressing cells can occur.

22. The TCR, nucleic acid, vector, cell, or composition for use according to claim 20, wherein the CD la-expressing malignancy or a malignancy wherein CD la is altered in expression or function is selected from Langerhans cell histiocytosis, Langerhans cell sarcoma, a T cell lymphoma, a thymoma, or mastocytosis.

23. The TCR, nucleic acid, vector, cell, or composition for use according to any of claims 16 or 19-22, wherein the TCR, nucleic acid, vector, cell, or composition is to be administered with one or more other therapeutic agent; optionally wherein the one or more other therapeutic agent may be selected from cytotoxic agents, immune activation or immune suppression agents such as checkpoint inhibitors / agonists or TLR agonists, anti-inflammatory agents such as steroids, CAR-T cells such as regulatory or cytolytic CAR-T cells. An example of an immunosuppressive agent is a PD-1 agonist, other checkpoint agonist or IL-2 mutein.

24. The TCR or composition for use according to claim 23, wherein the one or more other therapeutic agent is directly linked to the TCR, or host cell expressing the TCR.

25. A method of monitoring treatment efficacy or disease status in a subject diagnosed with a CD la-expressing malignancy or a malignancy wherein CD la is altered in expression or function, comprising: i. providing a biological sample obtained from the subject; ii. determining the level of binding of one or more TCRs of any of claims 1-11 to CD la-expressing cells in the sample obtained from the subject before treatment, or at intervals between treatments, or at time intervals in the absence of treatment; iii. determining that the treatment is effective, or that the disease status is improving, if the tumour volume, or level of binding of the one or more TCRs to CD la- expressing cells, is reduced after treatment or between treatment intervals or at time intervals in the absence of treatment.

26. A method of diagnosing a subject with an inflammatory skin and mucosal disease or disorder, or associated systemic disease or disorder, or inflammatory drug reaction which manifests systemically, or CD la-expressing malignancy, or a malignancy wherein CD la is altered in expression or function, comprising: i. providing a biological sample obtained from the subject; ii. using one or more TCR of any of claims 1-11 to determine the level of expression of CD la in the sample obtained from the subject; iii. comparing the level of expression of CD la in the sample obtained from the subject with the level of expression of CD la in a positive or negative reference sample; iv. determining that the subject has an inflammatory skin and mucosal disease or disorder, or associated systemic disease or disorder, or inflammatory drug reactionwhich manifests systemically, or CD la-expressing malignancy, or a malignancy or other condition wherein CD la is altered in expression or function, if the level of expression of CD la in the sample obtained from the subject is higher than the level of expression of CD la in the negative reference sample, or equal to or higher than the level of expression of CDla positive reference sample.

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