Molecules with reduced effector function and extended half-lives, compositions, and uses thereof

Patent metadata

Field	Value
Publication number	US-10011660-B2
Application number	US-201314397958-A
Country	US
Kind code	B2
Filing date	Apr 17, 2013
Priority date	Apr 30, 2012
Publication date	Jul 3, 2018
Grant date	Jul 3, 2018

Abstract

Provided are polypeptides comprising a variant IgG Fc domain, wherein the polypeptides exhibit reduced or ablated effector functions (e.g., ADCC and/or CDC) and increased stability and plasma half-life compared to a parent polypeptide. Also provided are compositions, methods of treatment, and methods to diminish Fc-induced effector function in a parent polypeptide.

First claim

What is claimed is:

1. An isolated polypeptide comprising a human immunoglobulin G class 1 (IgG 1 ) Fc domain, wherein the IgG 1 Fc domain comprises:
(a) a Phenylalanine (F) amino acid at position 234;
(b) a Glutamine (Q) at position 235; and,
(c) a Glutamine (Q) amino acid at position 322,

wherein the amino acid numbering is according to the EU index as in Kabat.

2. The polypeptide of claim 1 , further comprising a Glycine (G) amino acid at position 331, wherein the amino acid numbering is according to the EU index as in Kabat.

3. The polypeptide of claim 1 , further comprising:
(a) a Tyrosine (Y) amino acid at position 252, or a Serine (S) amino acid at position 252, or a Tryptophan (W) amino acid at position 252 or a Threonine (T) amino acid at position 252; and/or
(b) a Threonine (T) amino acid at position 254; and/or
(c) a Glutamic acid (E) amino acid at position 256, or a Serine (S) amino acid at position 256, or a Arginine (R) amino acid at position 256, or a Glutamine (Q) amino acid at position 256, or an Aspartate (D) amino acid at position 256,

wherein the amino acid numbering is according to the EU index as in Kabat.

4. The polypeptide of claim 1 , further comprising:
(a) a Tyrosine (Y) amino acid at position 252; and/or
(b) a Threonine (T) amino acid at position 254; and/or
(c) a Glutamic acid (E) amino acid at position 256,

wherein the amino acid numbering is according to the EU index as in Kabat.

5. The polypeptide of claim 1 , further comprising:
(a) a Tyrosine (Y)amino acid at position 252 or a Threonine (T) amino acid at position 252; and
(b) a Threonine (T) amino acid at position 254,

wherein the amino acid numbering is according to the EU index as in Kabat.

6. The polypeptide of claim 1 , further comprising:
(a) a Threonine (T) amino acid at position 254; and
(b) a Glutamic acid (E) amino acid at position 256, or a Serine (S) amino acid at position 256, or a Arginine (R) amino acid at position 256, or a Glutamine (Q) amino acid at position 256, or an Aspartate (D) amino acid at position 256,

wherein the amino acid numbering is according to the EU index as in Kabat.

7. The polypeptide of claim 1 , further comprising:
(a) a Tyrosine (Y) amino acid at position 252, or a Serine (S) amino acid at position 252, or a Tryptophan (W) amino acid at position 252 or a Threonine (T) amino acid at position 252; and
(b) a Glutamic acid (E) amino acid at position 256, or a Serine (S) amino acid at position 256, or a Arginine (R) amino acid at position 256, or a Glutamine (Q) amino acid at position 256, or an Aspartate (D) amino acid at position 256,

wherein the amino acid numbering is according to the EU index as in Kabat.

8. The polypeptide of claim 1 , further comprising:
(a) a Tyrosine (Y) amino acid at position 252, and a Threonine (T) amino acid at position 254; or,
(b) a Threonine (T) amino acid at position 254 and a Glutamic acid (E) amino acid at position 256; or,
(c) a Tyrosine (Y) amino acid at position 252 and a Glutamic acid (E) amino acid at position 256

wherein the amino acid numbering is according to the EU index as in Kabat.

9. The polypeptide of claim 1 , further comprising a Tyrosine (Y) amino acid at position 252, a Threonine (T) amino acid at position 254, and, a Glutamic acid (E) amino acid at position 256, wherein the amino acid numbering is according to the EU index as in Kabat.

10. The polypeptide of claim 1 , comprising:
(a) a Phenylalanine (F) amino acid at position 234;
(b) a Glutamine (Q) amino acid at position 235;
(c) a Glutamine (Q) amino acid at position 322;
(d) a Tyrosine (Y) amino acid at position 252;
(e) a Threonine (T) amino acid at position 254; and,
(f) a Glutamic acid (E) amino acid at position 256,

wherein the amino acid numbering is according to the EU index as in Kabat.

11. The polypeptide of claim 1 , further comprising:
(a) a Glycine (G) amino acid at position 331;
(b) a Tyrosine (Y) amino acid at position 252;
(c) a Threonine (T) amino acid at position 254; and,
(d) a Glutamic acid (E) amino acid at position 256,

wherein the amino acid numbering is according to the EU index as in Kabat.

12. The polypeptide of claim 1 , wherein the polypeptide has an improved pharmacokinetic (PK) property when compared to the same polypeptide comprising a wild-type IgG 1 Fc domain.

13. The polypeptide of claim 12 , wherein the PK property is half-life.

14. The polypeptide of claim 1 , wherein the polypeptide has improved FcRn binding when compared to the same polypeptide comprising a wild-type IgG 1 Fc domain.

15. The polypeptide of claim 1 , wherein the polypeptide further comprises an antigen binding domain.

16. The polypeptide of claim 15 , wherein the antigen-binding domain is derived from a monoclonal antibody or an antigen-binding fragment thereof.

17. The polypeptide of claim 15 , wherein the antigen-binding domain is derived from a human antibody, a humanized antibody, or a chimeric antibody.

18. The polypeptide of claim 15 , wherein the antigen-binding domain comprises:
(a) a single chain antibody;
(b) a diabody;
(c) a polypeptide chain of an antibody;
(d) an F(ab′) 2 fragment; or,
(e) and F(ab) fragment.

19. The polypeptide of claim 1 , wherein the polypeptide has reduced Fc-mediated effector function when compared to the same polypeptide comprising a wild-type IgG 1 Fc domain.

20. The polypeptide of claim 19 , wherein the effector function is antibody-dependent cell-mediated cytotoxicity (ADCC).

21. The polypeptide of claim 19 , wherein the effector function is complement-dependent cytotoxicity (CDC).

22. The polypeptide of claim 1 , wherein the polypeptide has lower affinity for an Fc gamma receptor (FcγR) when compared to the same polypeptide comprising a wild-type IgG 1 Fc domain.

23. The polypeptide of claim 22 , wherein the FcγR is a human FcγR.

24. The polypeptide of claim 22 , wherein the FcγR is selected from the group consisting of FcγRI, FcγRII, and FcγRIII.

25. The polypeptide of claim 24 , wherein the FcγRI is FcγRIa.

26. The polypeptide of claim 24 , wherein the FcγRII is FcγRIIa or FcγRIIb.

27. The polypeptide of claim 24 , wherein the FcγRIII is FcγRIII (158V) or FcγRIII (158F).

28. The polypeptide of claim 1 , wherein the polypeptide binds with improved affinity to FcRn when compared to the same polypeptide comprising a wild-type IgG 1 Fc domain.

29. The polypeptide of claim 28 , wherein the polypeptide has a higher affinity for FcRn at pH 6.0 than at pH 7.4.

30. The polypeptide of claim 1 , wherein the polypeptide binds with reduced affinity to C1q when compared to the same polypeptide comprising a wild-type IgG 1 Fc domain.

31. The polypeptide of claim 1 , wherein the polypeptide displays an increase in thermal stability when compared to the same polypeptide comprising a Phenylalanine-Glutamic acid-Serine (FES)-YTE IgG 1 Fc domain.

32. The polypeptide of claim 31 , wherein thermal stability is measured by Differential Scanning Calorimetry (DSC).

33. The polypeptide of claim 32 , wherein the increase in thermal stability is at least 4° C.

34. The polypeptide of claim 31 , wherein thermal stability is measured by Differential Scanning Fluorime

Assignees

• Medimmune Llc

Inventors

• Tsui Ping
• Borrok Ii Martin
• Dall'Acqua William

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07K16/11

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

• C07K2317/71

  Decreased effector function due to an Fc-modification · CPC title

• C07K2317/55

  Fab or Fab' · CPC title

• C07K2317/54

  F(ab')2 · CPC title