Polynucleotides encoding IL-17/IL-23 bispecific, IL-17A/F and IL-23p19 antibodies

Patent metadata

Field	Value
Publication number	US-9783606-B2
Application number	US-201414576278-A
Country	US
Kind code	B2
Filing date	Dec 19, 2014
Priority date	May 22, 2012
Publication date	Oct 10, 2017
Grant date	Oct 10, 2017

Abstract

The present invention relates to antagonizing the activity of IL-17A, IL-17F and IL-23 using bispecific antibodies that comprise a binding entity that is cross-reactive for IL-17A and IL-17F and a binding entity that binds IL-23p19. The present invention relates to novel bispecific antibody formats and methods of using the same.

First claim

What is claimed is:

1. An isolated nucleic acid molecule encoding a bispecific antibody comprising an IL-17A/F binding entity and an IL-23 binding entity, wherein the IL-23 binding entity comprises two pairs of immunoglobulin chains, each pair having one light and one heavy chain, which light chain variable domain comprises a CDR1 having the amino acid sequence of SEQ ID NO:22, a CDR2 having the amino acid sequence of SEQ ID NO:23, and a CDR3 having the amino acid sequence of SEQ ID NO:24, and heavy chain variable domain comprises a CDR1 having the amino acid sequence of SEQ ID NO:19, a CDR2 having the amino acid sequence of SEQ ID NO:20, and a CDR3 having the amino acid sequence of SEQ ID NO:21, and wherein the IL-17A/F binding entity comprises two Fab fragments which are linked to the C-terminus of the heavy chain of the IL-23 binding entity, wherein each IL-17A/F Fab comprises a light chain variable domain comprising a CDR1 having the amino acid sequence of SEQ ID NO:22, a CDR2 having the amino acid sequence of SEQ ID NO:23, and a CDR3 having the amino acid sequence of SEQ ID NO:24; and a heavy chain variable domain comprising a CDR1 having the amino acid sequence of SEQ ID NO:25, a CDR2 having the amino acid sequence of SEQ ID NO:26, and a CDR3 having the amino acid sequence of SEQ ID NO:27.

2. The isolated nucleic acid molecule of claim 1 , wherein both light chain variable domains of the IL-17A/F binding entity and the IL-23 binding entity comprise the amino acid sequence of SEQ ID NO:9.

3. The isolated nucleic acid molecule of claim 1 , wherein the light chain constant domain of the IL-17A/F binding entity and the IL-23 binding entity comprises the amino acid sequence of SEQ ID NO:10.

4. The isolated nucleic acid molecule of claim 1 , wherein the light chain variable domain of the IL-17A/F binding entity and the IL-23 binding entity comprises the amino acid sequence of SEQ ID NO:9 and the light chain constant domain comprises the amino acid sequence of SEQ ID NO:10.

5. The isolated nucleic acid molecule of claim 1 , wherein both light chains of the IL-17A/F binding entity and the IL-23 binding entity comprise the amino acid sequence of SEQ ID NO:17.

6. The isolated nucleic acid molecule of claim 1 , wherein the light chain of the IL-17A/F binding entity and the IL-23 binding entity is kappa or lambda.

7. The isolated nucleic acid molecule of claim 1 , wherein the heavy chain variable domain of the IL-17A/F binding entity comprises the amino acid sequence of SEQ ID NO:13.

8. The isolated nucleic acid molecule of claim 1 , wherein the heavy chain C H1 of the IL-17A/F binding entity comprises the amino acid sequence of SEQ ID NO:14 or SEQ ID NO:15.

9. The isolated nucleic acid molecule of claim 1 , wherein the heavy chain variable domain of the IL-23 binding entity comprises the amino acid sequence of SEQ ID NO:7.

10. The isolated nucleic acid molecule of claim 1 , wherein the heavy chain constant domain of the IL-23 binding entity comprises the amino acid sequence of SEQ ID NO:8 or amino acid residues 1-326 of SEQ ID NO:8.

11. The isolated nucleic acid molecule of claim 1 , wherein the heavy chain constant domain of the IL-23 binding entity comprises the amino acid sequence of SEQ ID NO:11.

12. The isolated nucleic acid molecule of claim 1 , wherein the heavy chain of the bispecific antibody, which comprises the IL-23 binding entity and the IL-17A/F binding entity, comprises the amino acid sequence of SEQ ID NO:74.

13. The isolated nucleic acid molecule of claim 1 , wherein the heavy chain of the bispecific antibody comprises a human constant region.

14. The isolated nucleic acid molecule of claim 13 , wherein the isotype of the heavy chain is IgG1, IgG2, IgG3 or IgG4.

15. The isolated nucleic acid molecule of claim 14 , wherein the IgG4 heavy chain has a Serine to Proline mutation at position 241 according to Kabat.

16. The isolated nucleic acid molecule of claim 1 , wherein the light chain of the bispecific antibody comprises the amino acid sequence of SEQ ID NO:17 and the heavy chain of the bispecific antibody comprises the amino acid sequence of SEQ ID NO:74.

17. An expression vector comprising the following operably linked elements:
a transcription promoter;
a nucleic acid molecule encoding the light chain of the bispecific antibody of claim 1 , wherein the IL-23 binding entity and the IL-17A/F binding entity comprise the same light chain amino acid sequence; and
a transcription terminator.

18. An expression vector comprising the following operably linked elements:
a transcription promoter;
a nucleic acid molecule encoding the heavy chain of the bispecific antibody of claim 1 , which includes the heavy chain of the IL-23 binding entity and the IL-17A/F binding entity; and
a transcription terminator.

19. A recombinant host cell comprising the expression vector of claim 18 .

20. The recombinant host cell of claim 19 , further comprising an expression vector comprising:
a transcription promoter;
a nucleic acid molecule encoding the light chain of the bispecific antibody; wherein the IL-23 binding entity and the IL-17A/F binding entity share the light chain; and
a transcription terminator; and
wherein the cell expresses the heavy chain and light chain.

21. A method of producing a bispecific antibody comprising:
a) culturing the host cell of claim 20 , wherein the expressed heavy and light chains form the bispecific antibody; and
b) recovering the bispecific antibody.

22. An expression vector comprising the following operably linked elements:
a transcription promoter;
a first nucleic acid molecule encoding the heavy chain of the bispecific antibody of claim 1 , which includes the heavy chain of the IL-23 binding entity and the IL-17A/F binding entity;
a second nucleic acid molecule encoding the light chain of the bispecific antibody of claim 1 , wherein the IL-23 binding entity and the IL-17A/F binding entity comprise the same light chain amino acid sequence; and
a transcription terminator.

23. A recombinant host cell comprising the expression vector of claim 22 .

24. A method of producing the bispecific antibody encoded by the nucleic acid molecule in the expression vector of claim 22 comprising:
a) culturing a host cell comprising said vector under conditions wherein the encoded heavy and light chains are expressed and form the bispecific antibody; and
b) recovering the bispecific antibody.

25. An expression vector comprising the following operably linked elements:
a first transcription promoter;
a first nucleic acid molecule encoding the heavy chain of the bispecific antibody of claim 1 , which includes the heavy chain of the IL-23 binding entity and the IL-17A/F binding entity;
a first transcription terminator;
a second transcription promoter;
a second nucleic acid molecule encoding the light chain of the bispecific antibody of claim 1 , wherein the IL-23 binding entity and the IL-17A/F binding entity comprise the same light chain amino acid sequence; and
a second transcription terminator.

26. A recombinant host cell comprising the expression vector of claim 25 .

27. A method of producing the bispecific antibody encoded by the nucleic acid molecules in the expression vector of claim 25 comprising:
a) culturing a host cell comprising said vector under conditions wherein the encoded heavy and light chains are expressed and form the

Assignees

• Bristol Myers Squibb Co

Inventors

• Stevens Brenda L
• Witte Alison
• Rixon Mark W
• Cardarelli Josephine M
• Kempe Thomas D
• Presnell Scott R
• Srinivasan Mohan
• Wong Susan C
• Chen Guodong
• Wei Hui
• Krystek Stanley R
• Schneeweis Lumelle A
• Sheppard Paul O
• Chakraborty Indrani

Classifications

• 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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/02

  Immunomodulators · CPC title