Dual specific binding proteins directed against IL-1β and/or IL-17

Patent metadata

Field	Value
Publication number	US-8987418-B2
Application number	US-201414323627-A
Country	US
Kind code	B2
Filing date	Jul 3, 2014
Priority date	Mar 15, 2013
Publication date	Mar 24, 2015
Grant date	Mar 24, 2015

Abstract

Engineered multivalent and multispecific binding proteins that bind IL-1β and/or IL-17 are provided, along with methods of making and uses in the prevention, diagnosis, and/or treatment of disease.

First claim

We claim:

1. A binding protein comprising first and second polypeptide chains, each independently comprising VD1-(X1)n-VD2-C-X2, wherein
VD1 is a first variable domain;
VD2 is a second variable domain;
C is a constant domain;
X1 is a linker;
X2 is an Fc region that is either present or absent;
n is 0 or 1,

wherein the VD1 domains on the first and second polypeptide chains form a first functional target binding site and the VD2 domains on the first and second polypeptide chains form a second functional target binding site, and wherein the binding protein is capable of binding IL-1β and IL-17, wherein
(i) the variable domains that form a functional target binding site for IL-1β comprise:
CDRs 1-3 from SEQ ID NO: 32 and CDRs 1-3 from SEQ ID NO: 33,
CDRs 1-3 from SEQ ID NO: 34 and CDRs 1-3 from SEQ ID NO: 35,
CDRs 1-3 from SEQ ID NO: 36 and CDRs 1-3 from SEQ ID NO: 37,
CDRs 1-3 from SEQ ID NO: 38 and CDRs 1-3 from SEQ ID NO: 39, or
CDRs 1-3 from SEQ ID NO: 40 and CDRs 1-3 from SEQ ID NO: 41;

and
(ii) the variable domains that form a functional target binding site for IL-17 comprise CDRs 1-3 from SEQ ID NO: 44 and CDRs 1-3 from SEQ ID NO: 45.

2. The binding protein of claim 1 , wherein the first polypeptide chain comprises VD1-(X1)n-VD2-C-X2, wherein
VD1 is a first heavy chain variable domain;
VD2 is a second heavy chain variable domain;
C is a heavy chain constant domain;
X1 is a linker;
X2 is an Fc region that is either present or absent;
n is 0 or 1, and

wherein the second polypeptide chain comprises VD1-(X1)n-VD2-C, wherein
VD1 is a first light chain variable domain;
VD2 is a second light chain variable domain;
C is a light chain constant domain;
X1 is a linker;
n is 0 or 1,

wherein the VD1 domains on the first and second polypeptide chains form a first functional target binding site and the VD2 domains on the first and second polypeptide chains form a second functional target binding site.

3. The binding protein of claim 1 , wherein
(i) the binding protein is capable of binding IL-1β with a K D of about 5.1×10 −11 M, as measured by surface plasmon resonance, or capable of inhibiting IL-1β with an IC50 of about 2.563 nM, as measured in an IL-1β neutralization assay, and/or
(ii) the binding protein is capable of binding IL-17 with a K D of about 4.8×10 −12 M, as measured by surface plasmon resonance, or capable of inhibiting IL-17 with an IC50 of about 1.7 nM, as measured in an IL-17 neutralization assay.

4. The binding protein of claim 1 , wherein
(i) the variable domains that form a functional target binding site for IL-1β comprise:
(1) SEQ ID NO: 32 and SEQ ID NO: 33,
(2) SEQ ID NO: 34 and SEQ ID NO: 35,
(3) SEQ ID NO: 36 and SEQ ID NO: 37,
(4) SEQ ID NO: 38 and SEQ ID NO: 39, or
(5) SEQ ID NO: 40 and SEQ ID NO: 41;

and
(ii) the variable domains that form a functional target binding site for IL-17 comprise:
(1) SEQ ID NO: 44 and SEQ ID NO: 45.

5. The binding protein of claim 1 , comprising two first polypeptide chains and two second polypeptide chains and four functional target binding sites.

6. The binding protein of claim 1 , wherein X1 comprises any one of SEQ ID NO: 1-31.

7. The binding protein of claim 1 , wherein
(i) the variable domains that form a functional target binding site for IL-1β comprise CDRs 1-3 from SEQ ID NO: 32 and CDRs 1-3 from SEQ ID NO: 33, and
(ii) the variable domains that form a functional target binding site for IL-17 comprise CDRs 1-3 from SEQ ID NO: 44 and CDRs 1-3 from SEQ ID NO: 45.

8. The binding protein of claim 7 , wherein
(i) the variable domains that form a functional target binding site for IL-1β comprise SEQ ID NO: 32 and SEQ ID NO: 33, and
(ii) the variable domains that form a functional target binding site for IL-17 comprise SEQ ID NO: 44 and SEQ ID NO: 45.

9. The binding protein of claim 7 , wherein X1 on the first polypeptide chain comprises SEQ ID NO: 29 and X1 on the second polypeptide chain comprises SEQ ID NO: 30.

10. The binding protein of claim 7 , wherein the first polypeptide chain of the binding protein comprises SEQ ID NO: 98 and the second polypeptide chain of the binding protein comprises SEQ ID NO: 99.

11. The binding protein of claim 10 , wherein the binding protein comprises
(a) a heavy chain constant region on the first polypeptide chain comprising a human IgG1 heavy chain sequence modified by one or more amino acid changes, wherein the changes comprise substitution of leucines at positions 234 and 235 with alanines, wherein the amino acid positions are numbered using EU index numbering; and
(b) a light chain constant region on the second polypeptide chain comprising a human kappa light chain constant region sequence.

12. The binding protein of claim 10 , wherein:
(i) the binding protein is capable of binding IL-1β with a K D of about 5.1×10 −11 M, as measured by surface plasmon resonance, or capable of inhibiting IL-1β with an IC50 of about 0.027 nM, as measured in an IL-1β neutralization assay, and/or
(ii) the binding protein is capable of binding IL-17 with a K D of about 4.8×10 −12 M, as measured by surface plasmon resonance, or capable of inhibiting IL-17 with an IC50 of about 0.091 nM, as measured in an IL-17 neutralization assay.

13. The binding protein of claim 1 , wherein
(i) the variable domains that form a functional target binding site for IL-1β comprise CDRs 1-3 from SEQ ID NO: 34 and CDRs 1-3 from SEQ ID NO: 35, and
(ii) the variable domains that form a functional target binding site for IL-17 comprise CDRs 1-3 from SEQ ID NO: 44 and CDRs 1-3 from SEQ ID NO: 45.

14. The binding protein of claim 13 , wherein
(i) the variable domains that form a functional target binding site for IL-1β comprise SEQ ID NO: 34 and SEQ ID NO: 35, and
(ii) the variable domains that form a functional target binding site for IL-17 comprise SEQ ID NO: 44 and SEQ ID NO: 45.

15. The binding protein of claim 13 , wherein X1 on the first polypeptide chain comprises SEQ ID NO: 29 and X1 on the second polypeptide chain comprises SEQ ID NO: 30.

16. The binding protein of claim 13 , wherein the first polypeptide chain of the binding protein comprises SEQ ID NO: 104 and the second polypeptide chain of the binding protein comprises SEQ ID NO: 105.

17. The binding protein of claim 16 , wherein the binding protein comprises
(a) a heavy chain constant region on the first polypeptide chain comprising a human IgG1 heavy chain sequence modified by one or more amino acid changes, wherein the changes comprise substitution of leucines at positions 234 and 235 with alanines, wherein the amino acid positions are numbered using EU index numbering; and
(b) a light chain constant region on the second polypeptide chain comprising a human kappa light chain constant region sequence.

18. The binding protein of claim 16 , wherein:
(i) the binding protein is capable of binding IL-1β with a K D of about 3.4×10 −11 M, as measured by surface plasmon resonance, or capable of inhibiting IL-1β with an IC50 of about 0.018 nM, as measured in an IL-1β neutralization assay, and/or
(ii) the binding protein is capable of binding IL-17 with a K D of about 4.8×10 −12 M, as measured by surface plasmon resonance, or capable of inhibiting IL-17 with an IC50 of about 0.068 nM, as measured in an IL-17 neutralization assay.

19. A binding protein capable of binding IL-1β and IL-17, comprising first and second polypeptide chains, each independently comprising VD1-(X1)n-VD2-C-(X2)n, wherein
VD1 is a first variable

Assignees

• Abbvie Inc

Inventors

• Ghayur Tariq
• Gu Jijie
• Harris Maria
• Goodreau Carrie
• Saluja Sonal

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · 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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P5/18

  of the parathyroid hormones · CPC title

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title