Molecules with altered neonate Fc receptor binding having enhanced therapeutic and diagnostic properties

Patent metadata

Field	Value
Publication number	US-11767369-B2
Application number	US-201916566280-A
Country	US
Kind code	B2
Filing date	Sep 10, 2019
Priority date	May 16, 2014
Publication date	Sep 26, 2023
Grant date	Sep 26, 2023

Abstract

The present invention provides molecules, including proteins, more particularly, immunoglobulins whose in vivo half-lives are altered (increased or decreased) by the presence of an IgG constant domain, or FcRn binding fragment thereof (e.g., an Fc region or hinge-Fc region) (e.g., from a human IgG, e.g., human IgG1), that have modifications of one or more of amino acid residues in at least the CH3 domain.

First claim

What is claimed is:

1. A modified human or humanized IgG1 comprising an Fc region wherein
(i) positions 432 and 437 are each substituted with cysteine,
(ii) position 433 is substituted with serine;
(iii) position 434 is substituted with tryptophan or tyrosine;
(iv) position 435 is histidine;
(v) position 436 is substituted with leucine;

numbered according to the EU numbering index of Kabat, relative to a human wild-type Fc region;
and wherein the modified human or humanized IgG1 has an increased half-life compared to the half-life of an IgG1 having the human wild-type Fc region.

2. The modified human or humanized IgG1 of claim 1 , wherein
position 434 is substituted with tyrosine.

3. The modified human or humanized IgG1 of claim 1 , wherein the binding affinity of the modified human or humanized IgG1 for FcRn at pH 6.0 is higher than the binding affinity of the IgG1 having the human wild-type Fc region for FcRn at pH 6.

4. The modified human or humanized IgG1 of claim 1 , wherein the binding affinity of the modified human or humanized IgG1 for FcRn at pH 7.4 is higher than the binding affinity of the IgG1 having the human wild-type Fc region for FcRn at pH 7.4.

5. The modified human or humanized IgG1 of claim 1 , wherein the modified human or humanized IgG1 exhibits increased pH dependence of binding affinity for FcRn compared to the IgG1 having the human wild-type Fc region.

6. The modified human or humanized IgG1 of claim 1 , wherein the modified human or humanized IgG1 exhibits decreased pH dependence of binding affinity for FcRn compared to the IgG1 having the wild-type Fc region.

7. The modified human or humanized IgG1 of claim 1 , selected from the group consisting of N3 defined by SEQ ID NO: 20 or N3E defined by SEQ ID NO: 16.

8. A polypeptide comprising an FcRn-binding portion of an Fc region of a human IgG1 molecule, wherein positions 432 and 437 of said FcRn-binding portion are each substituted with cysteine, position 433 is substituted with serine; position 434 is substituted with tryptophan or tyrosine; position 435 is histidine; and position 436 is substituted with leucine; numbered according to the EU numbering index of Kabat, relative to a wild-type human FcRn-binding portion.

9. The polypeptide of claim 8 , wherein the FcRn binding portion of the Fc region comprises from about amino acid residues 231-446 of a human IgG1 molecule according to the EU numbering index of Kabat.

10. The polypeptide of claim 8 , wherein the FcRn binding portion of the Fc region comprises from about amino acid residues 216-446 of a human IgG1 molecule according to the EU numbering index of Kabat.

11. A fusion protein comprising a non-IgG polypeptide covalently linked to at least an FcRn-binding portion of an Fc region of a human IgG1 molecule, wherein positions 432 and 437 of said FcRn-binding portion are each substituted with cysteine, position 433 is substituted with serine; position 434 is substituted with tryptophan or tyrosine; position 435 is histidine; and position 436 is substituted with leucine; numbered according to the EU numbering index of Kabat, relative to a wild-type human Fc region; and wherein said fusion protein has a longer in vivo half life than the non-IgG polypeptide.

12. The fusion protein of claim 11 , wherein the FcRn binding portion of the Fc region comprises from about amino acid residues 231-446 of a human IgG1 molecule according to the EU numbering index of Kabat.

13. The fusion protein of claim 11 , wherein the FcRn binding portion of the Fc region comprises from about amino acid residues 216-446 of a human IgG1 molecule according to the EU numbering index of Kabat.

14. The fusion protein of claim 11 wherein the non-IgG polypeptide is an immunomodulator, a receptor, a hormone or a drug.

15. A molecule comprising a non-protein agent conjugated to an FcRn-binding portion of an Fc region of a human IgG1 molecule, wherein positions 432 and 437 of said FcRn-binding portion are each substituted with cysteine, position 433 is substituted with serine; position 434 is substituted with tryptophan or tyrosine; position 435 is histidine; and position 436 is substituted with leucine; numbered according to the EU numbering index of Kabat, relative to a wild-type human Fc region; and wherein said molecule has a longer in vivo half life than the non-protein agent.

16. The molecule of claim 15 , wherein the FcRn binding portion of the Fc region comprises from about amino acid residues 231-446 of a human IgG1 molecule according to the EU numbering index of Kabat.

17. The molecule of claim 15 , wherein the FcRn binding portion of the Fc region comprises from about amino acid residues 216-446 of a human IgG1 molecule according to the EU numbering index of Kabat.

18. A pharmaceutical composition comprising the modified human or humanized IgG1 according to claim 1 , and a pharmaceutically acceptable carrier.

19. A kit comprising the modified human or humanized IgG1, according to claim 1 .

20. The fusion protein of claim 11 , wherein position 434 is substituted with tyrosine.

21. The molecule of claim 15 , wherein position 434 is substituted with tyrosine.

22. The modified human or humanized IgG1 of claim 1 , wherein position 434 is substituted with tryptophan.

23. The polypeptide of claim 8 , wherein position 434 is substituted with tyrosine.

24. The polypeptide of claim 8 , wherein position 434 is substituted with tryptophan.

25. The fusion protein of claim 11 , wherein position 434 is substituted with tryptophan.

26. The molecule of claim 15 , wherein position 434 is substituted with tryptophan.

Assignees

• Medimmune Llc

Inventors

• Tsui Ping
• Borrok Martin
• Dall'Acqua William
• Wu Yanli
• Beyaz-Kavuncu Nurten

Classifications

• C07K16/11

  Paramyxoviridae (F); Pneumoviridae (F), e.g. respiratory syncytial virus [RSV] · CPC title

• C07K16/40 Primary

  against enzymes · CPC title

• A61K47/68

  the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment · CPC title

• C07K16/00

  Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies · CPC title

• C07K16/005

  constructed by phage libraries · CPC title