MULTI-SPECIFIC ANTIBODY MOLECULES HAVING SPECIFICITY FOR TNF-ALPHA, IL-17A and IL-17F

Patent metadata

Field	Value
Publication number	US-2020277366-A1
Application number	US-201616063108-A
Country	US
Kind code	A1
Filing date	Dec 14, 2016
Priority date	Dec 18, 2015
Publication date	Sep 3, 2020
Grant date	—

Abstract

The invention relates to multi-specific antibody molecules having specificity for TNF alpha, IL-17A and IL-17F, therapeutic uses of the antibody molecules and methods for producing said antibody molecules.

First claim

1 . A multi-specific antibody molecule comprising a binding domain specific to human TNF-alpha and a binding domain specific to human IL-17A and human IL-17F, wherein the antibody molecule is capable of neutralising the biological activity of human TNF-alpha, human IL-17A and human IL-17F.

2 . A multi-specific antibody molecule according to claim 1 , wherein the antibody has a binding affinity for human TNF-alpha of 200 pM or better.

3 . A multi-specific antibody molecule according to claim 1 or claim 2 , wherein the antibody has a binding affinity for human IL-17A of 100 pM or better.

4 . A multi-specific antibody molecule according to claim 3 , wherein the antibody has a binding affinity for human IL-17A of 20 pM or better.

5 . A multi-specific antibody molecule according to any one of claims 1 to 4 , wherein the antibody has a binding affinity for IL-17F of 100 pM or better.

6 . A multi-specific antibody molecule according to claim 5 , wherein the antibody has a binding affinity for IL-17 F of 20 pM or better.

7 . A multi-specific antibody molecule according to any one of claims 1 to 6 , wherein the binding domain specific to human IL-17A and human IL-17F also binds the IL-17A/IL-17F heterodimer.

8 . A multispecific antibody molecule according to any one of claims 1 to 7 , wherein each binding domain comprises two antibody variable domains.

9 . A multispecific antibody molecule according to claim 8 , wherein the two antibody variable domains are a VH/VL pair.

10 . A multispecific antibody molecule according to any one of claims 1 to 9 , wherein the molecule format is selected from diabody, scdiabody, triabody, tandem scFv, FabFv, Fab′Fv, FabdsFv, Fab-scFv, Fab-dsscFv, Fab-(dsscFv) 2 diFab, diFab′, tribody, tandem scFv-Fc, scFv-Fc-scFv, scdiabody-Fc, scdiabody-CH3, Ig-scFv, scFv-Ig, V-Ig, Ig-V, Duobody and DVD-Ig.

11 . A multispecific antibody molecule according to any one of claims 1 to 9 wherein the binding domain which is specific to human TNF-alpha and the binding domain which is specific to IL-17A and human IL-17F are independently selected from a Fab, scFv, Fv, dsFv and dsscFv.

12 . A multi-specific antibody molecule according to any one of claims 1 to 9 comprising or consisting of:
V H1 -CH 1 -X-V 1 ; and  c) a polypeptide chain of formula (I):

V L1 -C L -Y-V 2 ;  d) a polypeptide chain of formula (II):

wherein:
V H1 represents a heavy chain variable domain;
CH 1 represents a domain of a heavy chain constant region, for example domain 1 thereof;
X represents a bond or linker;
Y represents a bond or linker;
V 1 represents a dsFv, a sdAb, a scFv or a dsscFv;
V L1 represents a light chain variable domain;
C L represents a domain from a light chain constant region, such as Ckappa;
V 2 represents dsFv, a sdAb, a scFv or a dsscFv.

13 . A multi-specific antibody molecule according to claim 12 , wherein at least one of V 1 and V 2 is a scFv or dsscFv.

14 . A multi-specific antibody molecule according to claim 13 , wherein V 1 is a scFv or dsscFv and V 2 is a scFv or dsscFv.

15 . A multi-specific antibody molecule according to claim 14 , wherein V1 is a dsscFv and V2 is a dsscFv.

16 . A multi-specific antibody molecule according to any one of claims 12 to 15 , wherein V1 is a scFv or dsscFv, and V1 comprises a polypeptide chain of:
a. formula (III): VH2-Z1-VL2 and VH2 is attached to X, for example through a peptide bond; or
b. formula (IV): VL2-Z1-VH2 and VL2 is attached to X, for example through a peptide bond;

wherein VH2 represents a heavy chain variable domain, Z1 represents a peptide linker and VL2 represents a light chain variable domain.

17 . A multispecific antibody molecule according to any one of claims 12 to 16 , wherein V2 is a scFv or dsscFv, and V2 comprises a polypeptide chain of:
a. formula (V): VH3-Z2-VL3 and VH3 is attached to Y, for example through a peptide bond; or
b. formula (VI): VL3-Z2-VH3 and VL3 is attached to Y, for example through a peptide bond;

wherein VH3 represents a heavy chain variable domain, Z2 represents a peptide linker and VL3 represents a light chain variable domain.

18 . A multispecific antibody according to claim 16 or 17 , wherein Z1 and/or Z2 are a peptide linker of 12 to 25 amino acids in length, for example the sequence given in SEQ ID NO: 68.

19 . A multi-specific antibody molecule according to any one of claims 12 to 18 , wherein X is a peptide linker, for example the sequence given in SEQ ID NO: 1 or 2.

20 . A multi-specific antibody molecule according to any one of claims 12 to 19 , wherein Y is a peptide linker, for example the sequence given in SEQ ID NO: 1 or 2.

21 . A multi-specific antibody molecule according to claim 19 or claim 20 , wherein X is the sequence given in SEQ ID NO: 2 and Y is the sequence given in SEQ ID NO:2.

22 . A multi-specific antibody molecule according to claim 19 or claim 20 , wherein X is the sequence given in SEQ ID NO: 1 and Y is the sequence given in SEQ ID NO:2.

23 . A multi-specific antibody molecule according to any one of claims 12 to 22 wherein at least one of V1 and V2 is a dsscFv or dsFv; and the light chain and heavy chain variable domains of V 1 and/or the light chain and heavy chain variable domains of V 2 are linked by a disulfide bond between two engineered cysteine residues.

24 . A multi-specific antibody molecule according to any one of claims 12 - 23 , wherein at least one of V1 and V2 is a dsscFv or dsFv; and the heavy chain and light chain variable domains of V 1 and/or V 2 are linked by a disulfide bond between two cysteine residues, wherein the position of the pair of cysteine residues is selected from the group comprising or consisting of: V H 37 and V L 95, V H 44 and V L 100, V H 44 and V L 105, V H 45 and V L 87, V H 100 and V L 50, V H 100b and V L 49, V H 98 and V L 46, V H 101 and V L 46, V H 105 and V L 43 and V H 106 and V L 57, wherein the V H and V L values are independently selected within a given V 1 or V 2 .

25 . A multi-specific antibody molecule according to claim 24 , wherein the position of the pair of engineered cysteine residues is V H 44 and V L 100.

26 . A multi-specific antibody molecule according to any one of claims 12 to 25 , wherein VH1 and VL1 comprise the binding domain specific to human IL-17A and human IL-17F and V1 and/or V2 comprise the binding domain specific to human TNF-alpha.

27 . A multi-specific antibody molecule according to any one of claims 1 to 26 which comprises three binding domains.

28 . A multi-specific antibody molecule according to claim 27 wherein each of the three binding domains bind different antigens.

29 . A multi-specific antibody molecule according to claim 28 , wherein the antibody molecule comprises a binding domain specific to a human serum carrier protein.

30 . A multi-specific antibody molecule according to claim 29 , wherein the human serum carrier protein is selected from the group consisting of thyroxine-binding protein, transthyretin, α1-acid glycoprotein, transferrin, fibrinogen and albumin, or a fragment of any thereof.

31 . A multi-specific antibody molecule according to any one of claims 12 to 30 , wherein:
a. VH1 and VL1 comprise the binding domain specific to human IL-17A and human IL-17F;

Assignees

• Ucb Biophrma Sprl
• Ucb Biopharma Sprl

Inventors

• Adams Ralph
• Bhatta Pallavi
• Dave Emma
• Heywood Sam Philip
• Humpherys David Taul
• Marshall Diane
• Shaw Stevan Graham
• Lightwood Daniel John

Classifications

• C07K16/241 Primary

  Tumor Necrosis Factors · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• C07K2317/60

  characterized by non-natural combinations of immunoglobulin fragments · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• C07K2317/55

  Fab or Fab' · CPC title