Single Linker FabFv Antibodies and Methods of Producing Same

Patent metadata

Field	Value
Publication number	US-2016017057-A1
Application number	US-201314654240-A
Country	US
Kind code	A1
Filing date	Dec 20, 2013
Priority date	Dec 21, 2012
Publication date	Jan 21, 2016
Grant date	—

Abstract

The present disclosure relates to a multi-specific antibody molecule comprising or consisting of three polypeptides: a) a polypeptide chain of formula (I): (Vxx) n Vx-Cx-X—V 1 ; and b) a polypeptide chain of formula (II): (Vyy) n Vy-Cy c) a polypeptide of formula (III):V 2 wherein Vx represents a variable domain, Vxx represents a variable domain, Cx represents a constant region, X represents a linker, V represents a variable domain, Vy represents a variable domain, Vyy represents a variable domain, Cy represents a constant region, V 2 represents a variable domain, n independently represents 0 or 1, wherein the polypeptide chain of formula (I) and the polypeptide chain of formula (II) is aligned such that the constant regions Cx and Cy are paired and the variable domains Vx and Vy are paired to form a binding domain and optionally a disulphide bond is present between V and V 2 , in particular where a disulphide bond is present. The disclosure also extends to pharmaceutical formulation comprising the construct, DNA encoding the constructs and vectors comprising same. The disclosure further extends to a method of expressing the constructs, for example in a host cell and methods for formulating same as a pharmaceutical composition. The disclosure also relates to use of the constructs and formulations in treatment.

First claim

1 . A multi-specific antibody molecule comprising three polypeptides,
a) a polypeptide chain of formula (I)
(Vxx) n Vx-Cx-X—V 1 ,

b) a polypeptide chain of formula (II),
(Vyy) n Vy-C y , and
c) a polypeptide of formula (III),
V 2 ,
wherein Vx represents a variable domain, Vxx represents a variable domain, Cx represents a constant region, X represents a linker, V 1 represents a variable domain, Vy represents a variable domain, Vyy represents a variable domain, Cy represents a constant region, V 2 represents a variable domain, n independently represents 0 or 1, wherein the polypeptide chain of formula (I) and the polypeptide chain of formula (II) are aligned such that the constant regions Cx and Cy are paired and the variable domains Vx and Vy are paired to form a binding domain, and optionally a disulphide bond is present between V 1 and V 2 .

2 . A bi-specific antibody molecule comprising or consisting of three polypeptides,
a) a heavy chain of formula (Ia),
VH—CH 1 —X—V 1 ,

b) a light chain of formula (M),
VL-C L ,
c) a polypeptide of formula (III),
V 2 ,
wherein VH represents a heavy chain variable domain, CH 1 represents domain 1 of the heavy chain constant region, X represents a linker, V 1 represents a variable domain, VL represents a light chain variable domain, C L represents a constant region from a light chain, V 2 represents a variable domain, wherein optionally a disulphide bond is present between V 1 and V 2 .

3 . A bi-specific antibody molecule comprising three polypeptides,
a) a heavy chain of formula (Ib),
VH—CH 1 ,

b) a light chain of formula (IIb),
VL-C L —X—V 2 ,

c) a polypeptide of formula (III),
V 1 ,
wherein VH represents a heavy chain variable domain, CH 1 represents domain 1 of the heavy chain constant region, X represents a linker, V 1 represents a variable domain, VL represents a light chain variable domain, C L represents a constant region from a light chain, V 2 represents a variable region, wherein optionally a disulphide bond is present between V 1 and V 2 .

4 . The multi-specific antibody molecule according to claim 1 , wherein V1 represents a heavy chain variable domain and V2 represents a light chain variable domain.

5 . The multi-specific antibody molecule according to claim 1 , wherein the variable domain pair V 1 /V 2 are linked by a disulfide bond between two engineered cysteine residues, one in V 1 and one in V 2 , wherein the position of the pair of engineered cysteine residues is selected from the group consisting of VH37 and VL95, VH44 and VL100, VH44 and VL105, VH45 and VL87, VH100 and VL50, VH100b and VL49, VH98 and VL46, VH101 and VL46, VH105 and VL43 and VH106 and VL57.

6 . The multi-specific antibody molecule according to claim 1 wherein the variable domain pair V 1 /V 2 have specificity for a serum carrier protein.

7 . The multi-specific antibody molecule according to claim 6 wherein V1 comprises the sequence given in SEQ ID NO:87 for CDRH-1, the sequence given in SEQ ID NO:88 for CDRH2 and the sequence given in SEQ ID NO:89 for CDRH-3 and V2 comprises the sequence given in SEQ ID NO:90 for CDRL-1, the sequence given in SEQ ID NO:91 for CDRL2 and the sequence given in SEQ ID NO:92 for CDRL-3.

8 . The multi-specific antibody molecule according to claim 6 wherein V1 comprises the sequence given in SEQ ID NO:93 for CDRH-1, the sequence given in SEQ ID NO:94 for CDRH2 and the sequence given in SEQ ID NO:95 for CDRH-3 and V2 comprises the sequence given in SEQ ID NO:96 for CDRL-1, the sequence given in SEQ ID NO:97 for CDRL2 and the sequence given in SEQ ID NO:98 for CDRL-3.

9 . The multi-specific antibody molecule according to claim 1 , wherein X has the sequence given in SEQ ID NO:78.

10 . The bi-specific antibody molecule according to claim 3 wherein X has the sequence given in SEQ ID NO:103.

11 . The polynucleotide encoding a multi-specific antibody molecule according to claim 1 .

12 . The vector comprising a polynucleotide defined in claim 11 .

13 . A host cell comprising the polynucleotide of claim 11 .

14 . A host cell comprising three vectors each vector comprising a polynucleotide encoding a different polypeptide chain of the multi-specific antibody molecule according to claim 1 .

15 . A process comprising expressing the multi-specific molecule from a host cell defined in claim 13 .

16 . A pharmaceutical composition comprising the multi-specific molecule according to claim 1 and at least one excipient.

17 . (canceled)

18 . A method of treating a patient in need thereof comprising administering a therapeutically effective amount of the multi-specific antibody molecule according to claim 1 .

19 . A method of treating a patient in need thereof comprising administering a therapeutically effective amount of the bi-specific antibody molecule according to claim 2 .

20 . A method of treating a patient in need thereof comprising administering a therapeutically effective amount of the bi-specific antibody molecule according to claim 3 .

21 . A pharmaceutical composition comprising the bi-specific antibody molecule according to claim 2 and at least one excipient.

22 . A pharmaceutical composition comprising the bi-specific antibody molecule according to claim 3 and at least one excipient.

Assignees

• Ucb Biopharma Sprl

Inventors

• Dave Emma
• Heywood Sam Philip
• Humphreys David Paul

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title