IP Library › Granted Patent US 12,735,491

Granted Patent B2

US 12,735,491 · App. 19/011,114 · Granted Sep 15, 2026

Multi-domain CD1a antagonist/PD-1 agonist antibody molecules

Inventors: Adam Curnock (Abingdon, GB); David Overton (Abingdon, GB)

Assignee: Immunocore Limited

C07K16/2833 A61P37/04 C07K16/2818 C07K16/468 G01N33/6854 C07K2317/24 C07K2317/31 C07K2317/565 C07K2317/567 C07K2317/569 C07K2317/76 C07K2317/92 C07K2317/94 G01N2333/70521 G01N2333/70596

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 12,735,491
App. No.: 19/011,114
Granted: Sep 15, 2026
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

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).

Claims (136)

1 . A multi-domain molecule comprising:

(i) a first binding domain that binds to PD-1, wherein the first binding domain comprises a CDR1, a CDR2, and a CDR3 comprising the following sequences:

(SEQ ID NO: 1)

CDR1 - GFTFSSYA,

(SEQ ID NO: 2)

CDR2 - IASDGAST, and

(SEQ ID NO: 3)

CDR3 - CARGGYLTYDRY,

and

(ii) a second binding domain that binds to CD1a, wherein the second binding domain comprises a CDR1, a CDR2, and a CDR3 comprising the following sequences:

CDR1—GRTFNPGDLMG (SEQ ID NO: 4),

CDR2—AIKWGPTYYADSVKG (SEQ ID NO: 7), and

CDR3—GSGTFSSNYRDFEY (SEQ ID NO: 10),

wherein the C-terminus of the first binding domain is linked to the N-terminus of the second binding domain.

2 . The multi-domain molecule of claim 1 , wherein the first binding domain binds to an epitope in PD-1 comprising one or more or all of the following amino acids: E38, F59, P60, E61, T75, Q76, L77, P78, N79 and G80, numbered according to SEQ ID NO: 13.

3 . The multi-domain molecule of claim 1 , wherein the first binding domain comprises FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, wherein FR is a framework region, and wherein FR1, FR2, FR3 and FR4 comprise the following sequences:

FR1—AVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 14), with zero, one, two or three mutations therein,

FR2—MTWVRQAPGKGPEWVSA (SEQ ID NO: 15), with zero, one, two or three mutations therein,

FR3—SYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYY (SEQ ID NO: 16), with zero, one, two or three mutations therein, and

FR4—YLTYDRYGQGTLVTVSS (SEQ ID NO: 17), with zero, one, two or three mutations therein.

4 . The multi-domain molecule of claim 1 , wherein the first binding domain comprises:

(a) the amino acid sequence provided in SEQ ID NO: 18 or a humanized version thereof, or an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 18; or

(b) the amino acid sequence of SEQ ID NO: 20, or an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 20.

5 . The multi-domain molecule of claim 1 , wherein the second binding domain is a humanized llama anti-CD1a VHH.

6 . The multi-domain molecule of claim 5 , wherein the humanized llama anti-CD1a VHH comprises one or more or all of the following amino acids:

(a) P24, F38, E45, R46, F48, A50, Y73, R75, V78, and G97, numbered according to SEQ ID NO: 21;

(b) P24, F38, F48, Y73, R75, and V78, numbered according to SEQ ID NO: 25;

(d) F38, E45, R46, F48, A50, Y73, K75, V78, and G97, numbered according to SEQ ID NO: 29.

7 . The multi-domain molecule of claim 1 , wherein the second binding domain comprises FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, wherein FR is a framework region, and wherein FR1, FR2, FR3 and FR4 comprise the following sequences:

FR1—EVQLLESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 30), with zero, one, two or three mutations therein,

FR2—WVRQAPGKGLEWVS (SEQ ID NO: 31), with zero, one, two or three mutations therein,

FR3—RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAK (SEQ ID NO: 32), with zero, one, two or three mutations therein, and

FR4—WGQGTLVTVSS (SEQ ID NO: 33), with zero, one, two or three mutations therein.

8 . The multi-domain molecule of claim 7 , wherein the mutation(s) in the second binding domain framework regions are selected from:

(a) A24P, V38F, G45E, L46R, W48F, S50A, N73Y, K75R, L78V and A97G numbered according to SEQ ID NO: 21; or

(b) A24P, V38F, W48F, N73Y, K75R, and L78V numbered according to SEQ ID NO: 25.

9 . The multi-domain molecule of claim 1 , wherein the second binding domain comprises the amino acid sequence provided in SEQ ID NO: 34 or a humanized version thereof.

10 . The multi-domain molecule of claim 1 , further comprising (iii) a half-life extending domain, wherein the half-life extending domain comprises a first IgG Fc chain (FC1) and a second IgG Fc chain (FC2), wherein the FC1 chain and FC2 chain dimerise to form an Fc domain, and wherein the C-terminus of the second binding domain is linked to the N-terminus of FC1.

11 . The multi-domain molecule of claim 10 , wherein the half-life extending domain comprises:

(a) one or more amino acid substitutions which facilitate dimerisation of FC1 and FC2;

(b) one or more amino acid substitutions which prevent or reduce binding to FcγR;

(d) one or more amino acid substitutions which attenuate an effector function of the Fc domain.

12 . The multi-domain molecule of claim 1 , wherein, the first binding domain is linked to the N-terminus of the second binding domain by a linker and/or IgG hinge sequence.

13 . The multi-domain molecule of claim 1 , wherein the multi-domain molecule comprises the amino acid sequence of:

(a) (i) SEQ ID NO: 57; and (ii) SEQ ID NO: 58;

(b) (i) SEQ ID NO: 59; and (ii) SEQ ID NO: 58; or

14 . A nucleic acid encoding the multi-domain molecule of claim 1 , wherein the first and second binding domains are encoded within a single open reading frame, or within two distinct open reading frames.

15 . An expression vector comprising the nucleic acid of claim 14 .

16 . A cell comprising the expression vector of claim 15 .

17 . A purified and/or engineered cell presenting the multi-domain molecule of claim 1 .

18 . A pharmaceutical composition comprising the multi-domain molecule of claim 1 , together with one or more pharmaceutically acceptable carriers or excipients.

19 . A method of producing a multi-domain molecule, the method comprising a) maintaining a cell comprising the nucleic acid of claim 14 under optimal conditions for expression of the multi-domain molecule and b) isolating the multi-domain molecule.

20 . The multi-domain molecule of claim 1 , wherein the second binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 21.

21 . The multi-domain molecule of claim 1 , wherein the second binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 22.

22 . The multi-domain molecule of claim 1 , wherein the second binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 23.

23 . The multi-domain molecule of claim 1 , wherein the second binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 24.

24 . The multi-domain molecule of claim 1 , wherein the second binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 25.

25 . The multi-domain molecule of claim 1 , wherein the second binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 26.

26 . The multi-domain molecule of claim 1 , wherein the second binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 27.

27 . A method for treating an autoimmune disease in a subject, the method comprising administering the multi-domain molecule of claim 1 .

28 . A multi-domain molecule comprising: (i) a first binding domain that binds to PD-1, wherein the first binding domain comprises a CDR1, a CDR2, and a CDR3 comprising the following sequences:

(SEQ ID NO: 1)

CDR1 - GFTFSSYA,

(SEQ ID NO: 2)

CDR2 - IASDGAST, and

(SEQ ID NO: 3)

CDR3 - CARGGYLTYDRY,

and

(ii) a second binding domain that binds to CD1a, wherein the second binding domain comprises a CDR1, a CDR2, and a CDR3 comprising the following sequences:

(SEQ ID NO: 5)

CDR1 - GRAFRPHNVMA,

(SEQ ID NO: 8)

CDR2 - AARWSGIYYAESVKG ,

and

(SEQ ID NO: 11)

CDR3 - STAQDMTLALMSDYDY,

wherein the C-terminus of the first binding domain is linked to the N-terminus of the second binding domain.

29 . The multi-domain molecule of claim 28 , wherein the second binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 28.

30 . A method for treating an autoimmune disease in a subject, the method comprising administering the multi-domain molecule of claim 28 .

31 . A nucleic acid encoding the multi-domain molecule of claim 28 , wherein the first and second binding domains are encoded within a single open reading frame, or within two distinct open reading frames.

32 . An expression vector comprising the nucleic acid of claim 31 .

33 . A cell comprising the expression vector of claim 32 .

34 . A purified and/or engineered cell presenting the multi-domain molecule of claim 28 .

35 . A pharmaceutical composition comprising the multi-domain molecule of claim 28 , together with one or more pharmaceutically acceptable carriers or excipients.

36 . A method of producing a multi-domain molecule, the method comprising a) maintaining a cell comprising the nucleic acid of claim 31 under optimal conditions for expression of the multi-domain molecule and b) isolating the multi-domain molecule.

37 . A multi-domain molecule comprising:

(i) a first binding domain that binds to PD-1, wherein the first binding domain comprises a CDR1, a CDR2, and a CDR3 comprising the following sequences:

(SEQ ID NO: 1)

CDR1 - GFTFSSYA,

(SEQ ID NO: 2)

CDR2 - IASDGAST, and

(SEQ ID NO: 3)

CDR3 - CARGGYLTYDRY,

and

(ii) a second binding domain that binds to CD1a, wherein the second binding domain comprises a CDR1, a CDR2, and a CDR3 comprising the following sequences:

(SEQ ID NO: 6)

CDR1 - GRTFSPSDLMG,

(SEQ ID NO: 9)

CDR2 - AIKWGPTYYSDSVKG, and

(SEQ ID NO: 12)

CDR3 - GSSTFSANYRDYEY,

wherein the C-terminus of the first binding domain is linked to the N-terminus of the second binding domain.

38 . The multi-domain molecule of claim 37 , wherein the second binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 27.

39 . A method for treating an autoimmune disease in a subject, the method comprising administering the multi-domain molecule of claim 37 .

40 . A nucleic acid encoding the multi-domain molecule of claim 37 , wherein the first and second binding domains are encoded within a single open reading frame, or within two distinct open reading frames.

41 . An expression vector comprising the nucleic acid of claim 40 .

42 . A cell comprising the expression vector of claim 41 .

43 . A purified and/or engineered cell presenting the multi-domain molecule of claim 37 .

44 . A pharmaceutical composition comprising the multi-domain molecule of claim 37 , together with one or more pharmaceutically acceptable carriers or excipients.

45 . A method of producing a multi-domain molecule, the method comprising a) maintaining a cell comprising the nucleic acid of claim 40 under optimal conditions for expression of the multi-domain molecule and b) isolating the multi-domain molecule.

46 . A single domain antibody that binds to CD1a, comprising a CDR1, CDR2, and CDR3, comprising the following amino acid sequences:

(SEQ ID NO: 4)

(a) CDR1 - GRTFNPGDLMG,

(SEQ ID NO: 7)

CDR2 - AIKWGPTYYADSVKG,

and

(SEQ ID NO: 10)

CDR3 - GSGTFSSNYRDFEY;

(SEQ ID NO: 5)

(b) CDR1 - GRAFRPHNVMA,

(SEQ ID NO: 8)

CDR2 - AARWSGIYYAESVKG,

and

(SEQ ID NO: 11)

CDR3 - STAQDMTLALMSDYDY;

(SEQ ID NO: 6)

(SEQ ID NO: 9)

CDR2 - AIKWGPTYYSDSVKG,

and

(SEQ ID NO: 12)

CDR3 - GSSTFSANYRDYEY.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 21, 2025

From: CURNOCK, ADAM; OVERTON, DAVID

To: IMMUNOCORE LIMITED

Reel/Frame 070294/0518 →

Continuity (3)

Provisional Application 63716619 · Nov 5, 2024

Provisional Application 63618230 · Jan 5, 2024

Related Publication 20250333513A1 · Oct 30, 2025

References Cited (29)

US 20210206856A1 · Higginson-Scott et al. · 2021 [cited by applicant]

US 20210363216A1 · Bossi et al. · 2021 [cited by applicant]

US 20220112291A1 · Winau · 2022 [cited by examiner]

WO 2010029434A1 · 2010 [cited by applicant]

WO 2011110621A1 · 2011 [cited by applicant]

WO WO2017158176A1 · 2017 [cited by examiner]

WO 2018024237A1 · 2018 [cited by applicant]

WO 2020157211A1 · 2020 [cited by applicant]

WO 2024223842A1 · 2024 [cited by applicant]

Almagro et al., Front. Immunol. 2018; 8:1751 (Year: 2018). [cited by examiner]

Chiu ML et al., Antibodies 2019 8, 55, 1-80 (Year: 2019). [cited by examiner]

Noël et al. “Global analysis of VHHs framework regions with a structural alphabet.” Biochimie 131 (2016): 11-19 (Year: 2016). [cited by examiner]

Kim, Ji Hyung, et al. “CD1a on Langerhans cells controls inflammatory skin disease.” Nature immunology 17.10 (2016): 1159-1166 (Year: 2016). [cited by examiner]

Hardman, Clare S., et al. “CD1a promotes systemic manifestations of skin inflammation.” Nature Communications 13.1 (2022):7535 (Year: 2022). [cited by examiner]

Agata et al., “Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes,” Int Immunol 8:765-772 (1996). [cited by applicant]

Curnock et al., “Cell-targeted PD-1 agonists that mimic PD-L1 are potent T cell inhibitors,” JCI Insight 6(20): e152468 (2021). [cited by applicant]

Dong et al., “B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion,” Nat Med 5:1365-1369 (1999). [cited by applicant]

Freeman et al., “Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation,” J Exp Med 192:1027-1034 (2000). [cited by applicant]

International Search Report and Written Opinion issued in PCT/IB2025/050090, dated Apr. 11, 2025. [cited by applicant]

Keir et al., “PD-1 and its ligands in tolerance and immunity,” Annu Rev Immunol 26:677-704 (2008). [cited by applicant]

Latchman et al., “PD-L2 is a second ligand for PD-1 and inhibits T cell activation,” Nat Immunol 2:261-268 (2001). [cited by applicant]

Okazaki et al., “PD-1 and PD-1 ligands: from discovery to clinical application,” Int Immunol 19:813-824 (2007). [cited by applicant]

Otsuka et al., “Differentiation of Langerhans Cells from Monocytes and Their Specific Function in Inducing IL-22-Specific Th Cells,” J. Immunol 201(10): 3006-3016 (2018). [cited by applicant]

Paluch et al., “Immune Checkpoints as Therapeutic Targets in Autoimmunity,” Front Immunol 9:2306 (2018). [cited by applicant]

Ravetch et al., “Fc receptors,” Annu. Rev. Immunol. 9:457-492 (1991). [cited by applicant]

Schmitt et al., “Cyclosporin in the treatment of patients with atopic eczema—a systematic review and meta-analysis,” J Eur Acad Dermatol Venereol 21(5):606-619 (2007). [cited by applicant]

Sulea, “Humanization of Camelid Single-Domain Antibodies,” Methods in Molecular Biology 2446:299-312 (2022). [cited by applicant]

Uniprot: Q9NZQ7 ⋅ PD1L1_HUMAN, retrieved on Apr. 23, 2025 at: https://www.uniprot.org/uniprotkb/Q9NZQ7/. [cited by applicant]

Ye et al., “CD1a and skin T cells: a pathway for therapeutic intervention,” Clinical and Experimental Dermatology 49(5):450-458 (2024). [cited by applicant]