US 2026/0285984 A1 · TCR WITH HIGH AFFINITY AND SPECIFICITY SPECIFIC FOR PREPROINSULIN PEPTIDE ALWGPDPAAA BOUND TO HLA-A2*02

Abstract

The present invention relates to binding molecules comprising a peptide-major histocompatibility complex (pMHC)-binding domain which binds to a ALWGPDPAAA (SEQ ID NO: 1) peptide (derived from human pre-pro insulin (PPI) protein) presented as a peptide-HLA-A*02 complex. Said 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 binding molecules of the invention have high affinity and high specificity for the ALWGPDPAAA (SEQ ID NO: 1)-HLA-A*02 complex. The binding molecules may further comprise an immune suppressor and/or a half-life extending domain. Such binding molecules are particularly useful in the development of soluble immunotherapeutic reagents for the treatment of autoimmune diseases, such as diabetes.

Claims51

Dependent claims

A binding molecule comprising a peptide-major histocompatibility complex (pMHC)-binding domain that has the property of binding to a ALWGPDAAA (SEQ ID NO:

1) HLA-A*02 complex, wherein the pMHC-binding domain comprises (i) an alpha chain, comprising at least a TCR alpha chain variable domain, and (ii) a beta chain, comprising at least a TCR beta chain variable domain, wherein
(a) the TCR alpha chain variable domain comprises a CDR1, a CDR2 and a CDR3 comprising the following sequences:
CDR1—DKHSQG (SEQ ID NO:
23), optionally with one, two or three mutations therein,
CDR2—IYSQGD (SEQ ID NO:
27), optionally with one, two or three mutations therein,
CDR3—AVRGNEKLT (SEQ ID NO:
7), optionally with one, two or three mutations therein, and/or
(b) the TCR beta chain variable domain comprises a CDR1, a CDR2 and a CDR3 comprising the following sequences:
CDR1—LQHSY (SEQ ID NO:
35), optionally with one, two or three mutations therein,
CDR2—SVGVGF (SEQ ID NO:
29), optionally with one, two or three mutations therein,
CDR3—ASAYMTGELF (SEQ ID NO:
30), optionally with one, two or three mutations therein.

12 more elements

The binding molecule of any preceding claim, wherein the TCR alpha chain variable domain comprises framework regions, FR1, FR2, FR3 and FR4, comprising the following sequences:

FR1—AKEVEQNSGPLSVPEGAIASLQCTYS (SEQ ID NO:
25), optionally with one, two or three mutations therein,
FR2—FFWYRQYSGKSPELIMS (SEQ ID NO:
9), optionally with one, two or three mutations therein,
FR3—KEDGRFTAQLNKASQYVSLLIRDSQPSDSATYLC (SEQ ID NO:
10), optionally with one, two or three mutations therein,
FR4—FGTGTRLTIIP (SEQ ID NO:
11), optionally with one, two or three mutations therein, and/or the TCR beta chain variable domain comprises framework regions, FR1, FR2, FR3 and FR4, comprising the following sequences:
FR1—NAGVTQTPKFRILKIGQSMTLQCAQD (SEQ ID NO:
18), optionally with one, two or three mutations therein,
FR2—MYWYRQDPGMGLKPIYY (SEQ ID NO:
19), optionally with one, two or three mutations therein,
FR3—TDKGEVPQGYQVSRSTTEDFPLRLESAAPSQTSVYFC (SEQ ID NO:
75), optionally with one, two or three mutations therein,
FR4—FGEGSRLTVL (SEQ ID NO:
21), optionally with one, two or three mutations therein.

13 more elements

The binding molecule of any one of the preceding claims, comprising one of the following combinations of TCR alpha and beta chain variable domains:

(a) a TCR alpha chain variable domain comprising the amino acid sequence provided in SEQ ID NO:
22 and a TCR beta chain variable domain comprising the amino acid sequence provided in SEQ ID NO:
68;
(b) a TCR alpha chain variable domain comprising the amino acid sequence provided in SEQ ID NO:
24 and a TCR beta chain variable domain comprising the amino acid sequence provided in SEQ ID NO:
31;
(c) a TCR alpha chain variable domain comprising the amino acid sequence provided in SEQ ID NO:
26 and a TCR beta chain variable domain comprising the amino acid sequence provided in SEQ ID NO:
34;
(d) a TCR alpha chain variable domain comprising the amino acid sequence provided in SEQ ID NO:
26 and a TCR beta chain variable domain comprising the amino acid sequence provided in SEQ ID NO:
74;
(e) a TCR alpha chain variable domain comprising the amino acid sequence provided in SEQ ID NO:
26 and a TCR beta chain variable domain comprising the amino acid sequence provided in SEQ ID NO:
76;
or
(f) a TCR alpha chain variable domain comprising the amino acid sequence provided in SEQ ID NO:
26 and a TCR beta chain variable domain comprising the amino acid sequence provided in SEQ ID NO:
78.

16 more elements

The binding molecule of any preceding claim, wherein

(a) the alpha chain comprises the amino acid sequence provided in any one of SEQ ID NOs:
2, 70, 36, and 40, or an amino acid sequence that has at least 90%, at least 95%, or at least 98% identity to an amino acid sequence provided in any one of SEQ ID NOs:
2, 70, 36, and 40, and
(b) the beta chain comprises the amino acid sequence provided in any one of SEQ ID NOs:
12, 69, 38, 41, 80, 81 and 82, or an amino acid sequence that has at least 90%, at least 95%, or at least 98% identity to the amino acid sequence provided in any one of SEQ ID NOs:
12, 69, 38, 41, 80, 81 and 82.

3 more elements

The binding molecule of any preceding claim, wherein

(a) the alpha chain comprises the amino acid sequence of SEQ ID NO:
70 and the beta chain comprises the amino acid sequence of SEQ ID NO:
69;
(b) the alpha chain comprises the amino acid sequence of SEQ ID NO:
36 and the beta chain comprises the amino acid sequence of SEQ ID NO:
38;
(c) the alpha chain comprises the amino acid sequence of SEQ ID NO:
40 and the beta chain comprises the amino acid sequence of SEQ ID NO:
41;
(d) the alpha chain comprises the amino acid sequence of SEQ ID NO:
40 and the beta chain comprises the amino acid sequence of SEQ ID NO:
80;
(e) the alpha chain comprises the amino acid sequence of SEQ ID NO:
40 and the beta chain comprises the amino acid sequence of SEQ ID NO:
81;
or
(f) the alpha chain comprises the amino acid sequence of SEQ ID NO:
40 and the beta chain comprises the amino acid sequence of SEQ ID NO:
82.

16 more elements

The binding molecule of any preceding claim, further comprising a half-life extending domain, optionally comprising a first portion of an IgG Fc region (FC1) and a second portion of an IgG Fc region (FC2).

A single domain antibody that binds to PD-1 comprising a CDR1, CDR2 and CDR3, having the following amino acid sequences:

CDR1—GFTFSSYA (SEQ ID NO:
43), optionally with one, two or three mutations therein;
CDR2—IASDGAST (SEQ ID NO:
44), optionally with one, two or three mutations therein;
and
CDR3—CARGGYLTYDRY (SEQ ID NO:
45), optionally with one, two or three mutations therein.

4 more elements

Dependencies are inferred from the claim text.

Tcr with high affinity and specificity specific for preproinsulin peptide alwgpdpaaa bound to hla-a2*02

Life of this patent

Tcr with high affinity and specificity specific for preproinsulin peptide alwgpdpaaa bound to hla-a2*02

Life of this patent

Abstract

Claims51