IP Library › Granted Patent US 9,340,618
Granted Patent B2
US 9,340,618 · App. 14/174,009 · Granted May 17, 2016

IL-11R binding proteins

Inventors: Kirsten Edwards (Parkville, AU); Matthew Hardy (Parkville, AU); Veronika Rayzman (Parkville, AU); Michael Wilson (Parkville, AU)
Assignee: CSL LIMITED
C07K16/2866G01N33/56966C07K2317/34C07K2317/55C07K2317/76C07K2317/92G01N2333/7155
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Quick Facts
Patent No.
US 9,340,618
App. No.
14/174,009
Granted
May 17, 2016
Kind
B2
Abstract

The present disclosure provides proteins comprising antigen binding sites of antibodies that bind to interleukin-11 (IL-11) receptor alpha (IL-11Rα) and uses thereof, e.g., in therapy.

Claims (112)

1. An isolated or recombinant IL-11Rα-binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain specifically binds to IL-11Rα and neutralizes IL-11 signaling, and the antigen binding domain binds to an epitope comprising residues within the first fibronectin III domain of IL-11Rα, wherein the first fibronectin III domain comprises amino acids 111-215 of SEQ ID NO: 1, and wherein the antigen binding domain comprises a heavy chain variable region (V H ) and a light chain variable region (V L ), the V H comprising:

(i) a complementarity determining region (CDR) 1 comprising a sequence set forth between amino acids 31-35 of SEQ ID NO: 37 optionally comprising three or fewer amino acid substitutions, a CDR2 comprising a sequence set forth between amino acids 50-66 of SEQ ID NO: 37 optionally comprising four or fewer amino acid substitutions and a CDR3 comprising a sequence set forth between amino acids 99-107 of SEQ ID NO: 37 optionally comprising four or fewer amino acid substitutions; or

(ii) a sequence at least about 95% identical to the sequence set forth in SEQ ID NO: 37.

2. The IL-11Rα-binding protein of claim 1 , wherein the amino acid substitution(s) in CDR2 of the V H are between amino acids 54 and 57 of SEQ ID NO: 37 and/or the amino acid substitution(s) of the V H are within the six N-terminal or the six C-terminal residues of the CDR3.

3. The IL-11Rα-binding protein of claim 1 , wherein the antigen binding domain comprises a V H comprising the sequence set forth in SEQ ID NO: 71.

4. The IL-11Rα-binding protein of claim 1 , wherein the antigen binding domain comprises a V H comprising the sequence set forth in SEQ ID NO: 72.

5. The IL-11Rα-binding protein of claim 1 , wherein the antigen binding domain comprises:

(i) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 5;

(ii) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 5;

(iii) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 6;

(iv) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 6;

(v) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 7;

(vi) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 7;

(vii) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 8;

(viii) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 8;

(ix) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 9;

(x) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 9;

(xi) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 10;

(xii) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 10;

(xiii) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 11;

(xiv) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 11;

(xv) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 12;

(xvi) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 12;

(xvii) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 13;

(xviii) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 13;

(xix) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 14;

(xx) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 14;

(xxi) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 15;

(xxii) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 15;

(xxiii) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 16;

(xxiv) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 16;

(xxv) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 17;

(xxvi) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 17;

(xxvii) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 18;

(xxviii) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 18;

(xxix) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 19;

(xxx) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 19;

(xxxi) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 20;

(xxxii) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 20;

(xxxiii) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 21;

(xxxiv) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 21;

(xxxv) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 22;

(xxxvi) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 22;

(xxxvii) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 23;

(xxxviii) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 23;

(xxxix)a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 24;

(xl) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 24;

(xli) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 25;

(xlii) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 25;

(xliii) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 26;

(xliv) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 26;

(xlv) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 27;

(xlvi) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 27;

(xlvii) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 28;

(xlviii) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 28;

(xlix) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 29;

(l) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 29;

(li) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 30;

(lii) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 30;

(liii) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 31;

(liv) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 31;

(lv) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 32;

(lvi) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 32;

(lvii) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 33;

(lviii) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 33;

(lix) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 34; or

(lx) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 34.

6. The IL-11Rα-binding protein of claim 1 , wherein the antigen binding domain comprises:

(i) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 8;

(ii) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 8;

(iii) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 15;

(iv) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 15;

(v) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 16;

(vi) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 16;

(vii) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 18;

(viii) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 18;

(ix) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 29; or

(x) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 29.

7. The IL-11Rα-binding protein of claim 1 , wherein the V H and V L bind to form a Fv comprising an antigen binding domain, and wherein the V H and V L are in a single polypeptide chain or the V H and V L are in separate polypeptide chains.

8. The IL-11Rα-binding protein of claim 7 , wherein if the V H and V L are in a single polypeptide chain, the protein is:

(i) a single chain Fv fragment (scFv);

(ii) a dimeric scFv (di-scFv);

(iii) one of (i) or (ii) linked to a constant region of an antibody, Fc or a heavy chain constant domain (C H )2 and/or C H 3; or

(iv) one of (i) or (ii) linked to a protein that binds to an immune effector cell, or if the V H and V L are in separate polypeptide chains the protein is:

(a) a diabody;

(b) a triabody;

(c) a tetrabody;

(d) a Fab;

(e) a F(ab′)2;

(f) a Fv;

(g) one of (a) to (f) linked to a constant region of an antibody, Fc or a heavy chain constant domain (C H )2 and/or C H 3;

(h) one of (a) to (f) linked to a protein that binds to an immune effector cell; or

(i) an antibody.

9. The IL-11Rα-binding protein of claim 8 , wherein the antigen binding domain comprises:

(i) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 8;

(ii) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 8;

(iii) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 15;

(iv) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 15;

(v) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 16;

(vi) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 16;

(vii) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 18;

(viii) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 18;

(ix) a V H comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 and a V L comprising CDRs 1, 2 and 3 of the sequence set forth in SEQ ID NO: 29; or

(x) a V H comprising the sequence set forth in SEQ ID NO: 37 and a V L comprising the sequence set forth in SEQ ID NO: 29.

10. The IL-11Rα-binding protein of claim 1 , which is conjugated to another compound.

11. A composition comprising the IL-11Rα-binding protein of claim 1 and a pharmaceutically acceptable carrier.

12. The IL-11Rα-binding protein of claim 1 , further comprising a constant region of an IgG4 antibody or a stabilized constant region of an IgG4 antibody comprising a proline at position 241 according to the numbering system of Kabat, wherein the constant region optionally lacks a C-terminal lysine residue.

13. The IL-11Rα-binding protein of claim 9 , further comprising a constant region of an IgG4 antibody or a stabilized constant region of an IgG4 antibody comprising a proline at position 241 according to the numbering system of Kabat, wherein the constant region optionally lacks a C-terminal lysine residue.

14. The IL-11Rα-binding protein of claim 1 , comprising:

(i) a heavy chain which comprises a V H comprising the sequence set forth in SEQ ID NO: 37 and a stabilized constant region of an IgG4 antibody comprising a proline at position 241 according to the numbering system of Kabat, wherein the constant region optionally lacks a C terminal lysine residue and a light chain which comprises a V L comprising the sequence set forth in SEQ ID NO: 18 and a human light chain constant region; or

(ii) a heavy chain which comprises the sequence set forth in SEQ ID NO: 37 and a stabilized constant region of an IgG4 antibody comprising a proline at position 241 according to the numbering system of Kabat, wherein the constant region optionally lacks a C-terminal lysine residue and a light chain which comprises a V L comprising the sequence set forth in SEQ ID NO: 18 and a human light chain constant region.

15. An isolated or recombinant IL-11Rα binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain specifically binds to IL-11Rα and neutralizes IL-11 signaling, and the antigen binding domain binds to an epitope comprising residues within the first fibronectin III domain of IL-11Rα, wherein the first fibronectin III domain comprises amino acids 111-215 of SEQ ID NO: 1, and wherein the antigen binding domain comprises a heavy chain variable region (V H ) comprising the sequence set forth in SEQ ID NO: 37 and a light chain variable region (V L ).

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 7, 2015
From: EDWARDS, KIRSTEN; HARDY, MATTHEW; RAYZMAN, VERONIKA; WILSON, MICHAEL
To: CSL LIMITED
Reel/Frame 036279/0338 →
Priority Claims (1)
AU 2013900389 · Feb 7, 2013 · national
Continuity (2)
Provisional Application 61764756 · Feb 14, 2013
Related Publication 20140219919A1 · Aug 7, 2014