IMMUNOCORE LIMITED

The present invention relates to specific binding molecules that bind the HLA-A*02 restricted peptide GLSPTVWLSV (SEQ ID NO: 1) derived from HBV envelope protein. The specific binding molecules may comprise alpha and/or beta TCR variable domains and may comprise non-natural mutations within the alpha and/or beta variable domains relative to a native TCR. The specific binding molecules of the invention are particularly suitable for use as novel immunotherapeutic reagents for the treatment of infectious or malignant disease.

The present invention relates to T cell receptors (TCRs) that bind the HLA-A*02 restricted peptide GVYDGREHTV (SEQ ID NO: 1) derived from the germline cancer antigen MAGE A4. Said TCRs may comprise non-natural mutations within the alpha and/or beta variable domains relative to a native MAGE A4 TCR. The TCRs of the invention are particularly suitable for use as novel immunotherapeutic reagents for the treatment of malignant disease.

The present invention relates to specific binding molecules which bind to CD3, particularly antibodies and fragments thereof, with improved properties.

The present invention relates to multi-domain binding molecules. The molecules comprise i) a peptide-major histocompatibility complex (pMHC) binding domain comprising a first variable region linked to a constant region (VC1) and a second variable region linked to a constant region (VC2), wherein VC1 and VC2 dimerise to form the pMHC binding domain; ii) an immune cell engaging domain comprising an antibody light chain variable domain (TCE-VL) linked to an antibody heavy chain variable domain (TCE-VH); and iii) a half-life extending domain comprising a first portion of an IgG Fc region (FC1) and a second portion of an IgG1 Fc region (FC2); wherein the multi-domain binding molecule comprises: a first polypeptide chain in which the immune cell engaging domain is linked to the N terminus of VC1; a second polypeptide chain in which VC2 is linked via its C terminus to the N terminus of FC1; and a third polypeptide chain comprising FC2; and wherein the pMHC binding domain and the immune cell engaging domain are capable of binding to a pMHC complex and a T cell respectively. The binding molecules can be used to treat diseases such as cancer, autoimmune diseases and infectious diseases.

The present invention relates to the treatment of melanoma in a patient, where the method includes administering to a patient who has or is suspected of having melanoma a therapeutically effective amount of tebentafusp; and a therapeutically effective amount of an immune checkpoint inhibitor. In particular, patients may have metastatic melanoma that is refractory to treatment with an anti-PD(L)1 inhibitor in the metastatic setting or where the patient's melanoma is relapsed following treatment with an anti-PD(L)1 inhibitor.

The present disclosure provides multi-domain molecules comprising, (i) a first binding domain that binds to PD-1, (ii) a second binding domain that binds to CD1a, and optionally, (iii) a half-life extending domain. Such multi-domain molecules are particularly useful in the development of soluble immunotherapeutic reagents for the treatment of autoimmune diseases, such as atopic dermatitis (AD).

Methods are presented for the administration of a TCR-anti-CD3 fusion molecule to treat patients who have a PRAME positive cancer. The methods comprise administering an TCR-anti-CD3 fusion molecule to a patient intravenously and comprise administration of (a) at least one first dose in the range of from 5-40 μg; (b) at least one second dose in the range of from 15-80 μg; and then (c) at least one third dose in the range of from 60-400 μg, wherein the second dose is higher than the first dose and the third dose is higher than the second dose, and wherein doses are administered every 6-8 days.

The present invention relates to soluble multi-domain binding molecules comprising T cell receptors (TCR) having specificity for an antigen, an immunoglobulin Fc domain or an albumin-binding moiety; and an immune effector domain. Such multi-domain binding molecules are advantageous because they display improved half-life while retaining function.

The present invention relates to specific binding molecules which bind to the HLA-E restricted peptide RLPAKAPLL (SEQ ID NO: 1) derived from Mycobacterium tuberculosis enoyl-ACP reductase. Said specific binding molecules may comprise CDR sequences embedded within a framework sequence. The CDRs and framework sequences may correspond to a T cell receptor (TCR) variable domain and may further comprise non-natural mutations relative to a native TCR variable domain. The specific binding molecules of the invention are particularly suitable for use as novel immunotherapeutic reagents for the treatment of infectious disease.

The present invention relates to multi-domain, single-chain binding molecules. The molecules comprise i) a peptide-major histocompatibility complex (pMHC) binding domain which binds to a SLLQHLIGL (SEQ ID NO: 1) HLA-A*02 complex, the pMHC domain comprising a first variable region linked to a constant region (VC1) and a second variable region linked to a constant region (VC2); ii) a T cell engaging immune effector domain comprising an antibody light chain variable region (TCE-VL) and an antibody heavy chain variable region (TCE-VH); and iii) a half-life extending domain comprising a first IgG Fc region (FC1) and a second IgG Fc region (FC2), wherein the FC1 region and FC2 region dimerise to form an Fc domain. The binding molecules can be used to treat diseases such as cancer.