Compositions and methods related to engineered Fc constructs

Patent metadata

Field	Value
Publication number	US-11124573-B2
Application number	US-201916363846-A
Country	US
Kind code	B2
Filing date	Mar 25, 2019
Priority date	May 2, 2014
Publication date	Sep 21, 2021
Grant date	Sep 21, 2021

Abstract

The present invention relates to compositions and methods of engineered IgG Fc constructs, wherein said Fc constructs include one or more Fc domains.

First claim

The invention claimed is:

1. A method for treating rheumatoid arthritis comprising administering to a subject in need thereof an Fc construct comprising:
a). a first polypeptide having the formula A-L-B; wherein
i). A comprises a first Fc domain monomer;
ii). L is a linker; and
iii). B comprises a second Fc domain monomer;

b). a second polypeptide having the formula A′-L′-B′; wherein
i). A′ comprises a third Fc domain monomer;
ii). L′ is a linker; and
iii). B′ comprises a fourth Fc domain monomer;

c). a third polypeptide that comprises a fifth Fc domain monomer; and
d). a fourth polypeptide that comprises a sixth Fc domain monomer;
wherein A and A′ combine to form a first Fc domain, B and the fifth Fc domain monomer combine to form a second Fc domain, and B′ and the sixth Fc domain monomer combine to form a third Fc domain;
the first polypeptide comprises the same amino acid sequence as the second polypeptide, and the third polypeptide comprises the same amino acid sequence as the fourth polypeptide;
the second Fc domain monomer comprises a different amino acid sequence than the fifth Fc domain monomer, and the fourth Fc domain monomer comprises a different amino acid sequence than the sixth Fc domain monomer, and
each of the first, second, third, fourth, fifth, and sixth Fc domain monomers comprises a human IgG1 CH2 domain monomer and a human IgG1 CH3 domain monomer, wherein each CH3 domain monomer has no more than 10 single amino acid substitutions to promote complementary dimerization of Fc domain monomers.

2. The method of claim 1 , wherein
each of the CH3 domain monomers of the first and third Fc domain monomers comprises a complementary dimerization selectivity module that promote dimerization between the first Fc domain monomer and the third Fc domain monomer,
each of the CH3 domain monomers of the second and fifth Fc domain monomers comprises a complementary dimerization selectivity module that promote dimerization between the second Fc domain monomer and the fifth Fc domain monomer, and/or
each of the CH3 domain monomers of the fourth and sixth Fc domain monomers comprises a complementary dimerization selectivity module that promote dimerization between the fourth Fc domain monomer and the sixth Fc domain monomer.

3. The method of claim 2 , wherein the complementary dimerization selectivity modules of the first and third Fc domain monomers each comprise reverse charge mutations in at least two positions within a ring of charged residues at the interface between the CH3 domain monomers of the first and third Fc domain monomers.

4. The method of claim 3 , wherein the reverse charge mutations in at least two positions are K409D/D399K, K392D/D399K, E357K/K370E, D356K/K439D, K409E/D399K, K392E/D399K, E357K/K370D, or D356K/K439E (all positions by EU Kabat numbering sy stem).

5. The method of claim 2 , wherein the complementary dimerization selectivity modules of the first and third Fc domain monomers comprise quadruple reverse charge mutations in four positions at the interface between the C H 3 domain monomers of the first and third Fc domain monomers.

6. The method of claim 5 , wherein the quadruple reverse charge mutations combine any pair of double mutations selected from K409D/D399K, K392D/D399K, E357K/K370E, D356K/K439D, K409E/D399K, K392E/D399K, E357K/K370D, and D356K/K439E (all positions by EU Kabat numbering system).

7. The method of claim 2 , wherein one of the complementary dimerization selectivity modules of the second and fifth Fc domain monomers comprises an engineered protuberance and the other of the complementary dimerization selectivity modules of the second and fifth Fc domain monomers comprises an engineered cavity.

8. The method of claim 2 , wherein one of the complementary dimerization selectivity modules of the fourth and sixth Fc domain monomers comprises an engineered protuberance and the other of the complementary dimerization selectivity modules of the fourth and sixth Fc domain monomers comprises an engineered cavity.

9. The method of claim 2 , wherein the complementary dimerization selectivity modules of the second and fourth Fc domain monomers each comprise an engineered protuberance and the complementary dimerization selectivity modules of the fifth and sixth Fc domain monomers each comprise an engineered cavity.

10. The method of claim 9 , wherein the engineered protuberance comprises at least one mutation selected from the group consisting of S354C, T366W, T366Y, T394W, T394F, and F405W and the engineered cavity comprises at least one mutation selected from the group consisting of Y349C, T366S, L368A, Y407V, Y407T, Y407A, F405A, and T394S (all positions by EU Kabat numbering system).

11. The method of claim 2 , wherein the complementary dimerization selectivity modules of the second and fourth Fc domain monomers each comprise an engineered cavity and the complementary dimerization selectivity modules of the fifth and sixth Fc domain monomers each comprise an engineered protuberance.

12. The method of claim 11 , wherein the engineered cavity comprises at least one mutation selected from the group consisting of Y349C, T366S, L368A, Y407V, Y407T, Y407A, F405A, and T394S and the engineered protuberance comprises at least one mutation selected from the group consisting of S354C, T366W, T366Y, T394W, T394F, and F405W (all positions by EU Kabat numbering system).

13. The method of claim 1 , wherein the Fc construct contains no more than three Fc domains.

14. The method of claim 1 , wherein one or more linker in said Fc construct is a spacer.

15. The method of claim 2 , wherein the CH3 domain monomers of the first and the third Fc domain monomers dimerize and each of the complementary dimerization selectivity modules of the first and third Fc domain monomers comprises reverse charge mutations in at least two positions within a ring of charged residues at the interface between the CH3 domain monomers of the first and the third Fc domain monomers;
wherein the CH3 domain monomers of the second and the fifth Fc domain monomers dimerize, the complementary dimerization selectivity module of the second Fc domain monomer comprises an engineered protuberance, and the complementary dimerization selectivity module of the fifth Fc domain monomer comprises an engineered cavity;

and
wherein the CH3 domain monomers of the fourth and sixth Fc domain monomers dimerize, the complementary dimerization selectivity module of the fourth Fc domain monomer comprises an engineered protuberance, and the complementary dimerization selectivity module of the sixth Fc domain monomer comprises an engineered cavity.

16. The method of claim 2 ,
wherein the CH3 domain monomers of the first and the third Fc domain monomers dimerize, the complementary dimerization selectivity module of the first Fc domain monomer comprises an engineered protuberance, and the complementary dimerization selectivity module of the third Fc domain monomer comprises an engineered cavity;
wherein the CH3 domain monomers of the second and the fifth Fc domain monomers dimerize and each of the complementary dimerization selectivity modules of the second and fifth Fc domain monomers comprises reverse charge mutations in at least two positions within a ring of charged residues at the interface between the CH3 domains of the second and the fifth Fc domain monomers; and
wherein the CH3 domain monomers of the fourth and sixth Fc domain monomers dimerize and each of the complementary dimerization selectivity modules of the fourth and sixth Fc domain monomers comprises reverse charge mutations in at least two p

Assignees

• Momenta Pharmaceuticals Inc
• Janssen Biotech Inc

Inventors

• Bosques Carlos J
• Huston James S
• Lansing Jonathan C
• Ling Leona E
• Meador Iii James
• Ortiz Daniel
• Rutitzky Laura

Classifications

• C07K16/283 Primary

  against Fc-receptors, e.g. CD16, CD32, CD64 (CD23 C07K16/2851) · CPC title

• A61P1/04 Primary

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• A61K39/395

  Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum · CPC title

• C07K16/46 Primary

  Hybrid immunoglobulins (hybrids of an immunoglobulin with a peptide not being an immunoglobulin C07K19/00) · CPC title

• C07K2317/526

  CH3 domain · CPC title