IP Library › Granted Patent US 12,435,322
Granted Patent B2
US 12,435,322 · App. 17/696,364 · Granted Oct 7, 2025

Therapeutic nuclease compositions and methods

Inventors: Jeffrey A. Ledbetter (Seattle, WA); Martha Hayden-Ledbetter (Seattle, WA); Keith Elkon (Seattle, WA); Xizhang Sun (Seattle, WA)
Assignee: University Of Washington
C12N9/22C07K16/18C12N9/96C12N11/06A61K38/00C07K2319/30C12Y301/27005Y02P20/582
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Quick Facts
Patent No.
US 12,435,322
App. No.
17/696,364
Granted
Oct 7, 2025
Kind
B2
Abstract

Hybrid nuclease molecules and methods for treating an immune-related disease or disorder in a mammal, and a pharmaceutical composition for treating an immune-related disease in a mammal.

Claims (35)

1. A method for treating lupus nephritis in a subject in need thereof, comprising administering to the subject a composition comprising:

a polypeptide comprising human RNase 1 operatively coupled with or without a linker to the N-terminus of an Fc domain, and DNase operatively coupled with or without a linker to the C-terminus of the Fc domain, wherein the Fc domain is a human immunoglobulin Fc domain or a mutant human immunoglobulin Fc domain, and wherein the human immunoglobulin Fc domain or mutant human immunoglobulin Fc domain comprises at least one hinge region; and

a pharmaceutically acceptable carrier,

such that treatment occurs.

2. The method of claim 1 , wherein the Fc domain is a mutant human IgG1 Fc domain comprising one or more of the mutations selected from P238S, P331S, K322S, N297S, wherein numbering is according to the EU index.

3. The method of claim 1 , wherein the Fc domain comprises a mutant human IgG1 Fc domain comprising a substitution of one or more of three hinge region cysteine residues with serine.

4. The method of claim 1 , wherein the human RNase 1 comprises the amino acid sequence set forth in SEQ ID NO:149, with or without a leader sequence.

5. The method of claim 1 , wherein the Fc domain comprises a human IgG1 Fc domain.

6. The method of claim 1 , wherein the Fc domain is a mutant Fc domain that has reduced binding to Fc receptors on human cells.

7. The method of claim 1 , wherein the Fc domain comprises the amino acid sequence set forth in SEQ ID NO:145.

8. The method of claim 1 , wherein the DNase comprises:

(a) the amino acid sequence set forth in SEQ ID NO: 143; or

(b) a G105R mutation as set forth in SEQ ID NO: 142; or

(c) mutations G105R and A114F as set forth in SEQ ID NO: 139.

9. The method of claim 1 , wherein the polypeptide comprises a first linker domain, a second linker domain, or both, wherein when the polypeptide comprises a first linker domain, the human RNase 1 is operatively coupled to the Fc domain by the first linker domain, and when the polypeptide comprises a second linker domain, the DNase is operatively coupled to the Fc domain by the second linker domain.

10. The method of claim 9 , wherein the first linker domain, the second linker domain, or both, comprise a gly/ser peptide.

11. The method of claim 9 , wherein the first linker domain, the second linker domain, or both, comprise an NLG peptide comprising the amino acid sequence set forth in SEQ ID NO: 168.

12. The method of claim 1 , wherein the polypeptide comprises a dimeric polypeptide.

13. The method of claim 1 , wherein the composition is formulated for intravenous administration.

14. A method for treating lupus nephritis in a subject in need thereof, comprising administering to the subject a composition comprising:

(a) a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 151, SEQ ID NO: 152, or SEQ ID NO: 153, with or without a leader sequence; or

(b) a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 151, SEQ ID NO: 152, or SEQ ID NO: 153, with or without a leader sequence and comprising one or more Fc mutations selected from P238S, P331S, K322S, and N297S, numbering according to EU index; and

a pharmaceutical carrier,

such that treatment occurs.

15. The method of claim 14 , wherein the Fc domain comprises a mutant human IgG1 Fc domain comprising a substitution of one or more of three hinge region cysteine residues with serine.

16. The method of claim 14 , wherein the polypeptide comprises a dimeric polypeptide.

17. The method of claim 14 , wherein the composition is formulated for intravenous administration.

18. A method for treating lupus nephritis in a subject in need thereof, comprising administering to the subject a composition comprising:

a polypeptide comprising human RNase 1 operatively linked with or without a linker to the N-terminus of a mutant human IgG1 Fc domain, and DNase operatively linked with or without a linker to the C-terminus of the mutant Fc domain, wherein the human RNase 1 comprises the amino acid sequence set forth in SEQ ID NO: 149, with or without a leader sequence, and wherein the DNase comprises the amino acid sequence set forth in SEQ ID NO: 139, and wherein the mutant human IgG1 Fc domain comprises at least one hinge region; and

a pharmaceutically acceptable carrier,

such that treatment occurs.

19. The method of claim 18 , wherein the mutant Fc domain comprises one or more of the mutations selected from P238S, P331S, K322S, and N297S, numbering is according to the EU index.

20. The method of claim 19 , wherein the mutant Fc domain comprises a substitution of one or more of three hinge region cysteine residues with serine.

21. The method of claim 18 , wherein the polypeptide comprises a dimeric polypeptide.

22. The method of claim 18 , wherein the composition is formulated for intravenous administration.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 16, 2022
From: LEDBETTER, JEFFREY A.; HAYDEN-LEDBETTER, MARTHA; ELKON, KEITH; SUN, XIZHANG
To: UNIVERSITY OF WASHINGTON
Reel/Frame 059288/0235 →
Continuity (8)
Continuation 15679746 · Aug 17, 2017
Continuation 14516161 · Oct 16, 2014
Division 13799843 · Mar 13, 2013
Division 13197731 · Aug 3, 2011
Continuation PCTUS2010055131 · Nov 2, 2010
Provisional Application 61370752 · Aug 4, 2010
Provisional Application 61257458 · Nov 2, 2009
Related Publication 20230057085A1 · Feb 23, 2023
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