IP Library › Granted Patent US 9,376,673
Granted Patent B1
US 9,376,673 · App. 15/019,474 · Granted Jun 28, 2016

Beta-lactamases with improved properties for therapy

Inventors: Michael Kaleko (Rockville, MD); Sheila Connelly (Rockville, MD)
Assignee: SYNTHETIC BIOLOGICS, INC.
C12N9/86C12Y305/02006
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 9,376,673
App. No.
15/019,474
Granted
Jun 28, 2016
Kind
B1
Abstract

This invention relates to, in part, compositions of beta-lactamases and methods of using these enzymes in, for example, gastrointestinal tract (GI tract) disorders such as C. difficile infection (CDI).

Claims (29)

1. A beta-lactamase comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 1 and having A232G, A237S, A238G, and S240D mutations according to Ambler classification.

2. The beta-lactamase of claim 1 , further comprising a D276R mutation according to Ambler classification.

3. The beta-lactamase of claim 1 , further comprising a D276K mutation according to Ambler classification.

4. The beta-lactamase of claim 1 , further comprising a Q135M mutation according to Ambler classification.

5. The beta-lactamase of any one of claims 1 - 4 , wherein the beta-lactamase hydrolyzes one or more of penicillins and cephalosporins.

6. The beta-lactamase of claim 5 , wherein the penicillin is ampicillin.

7. The beta-lactamase of claim 5 , wherein the cephalosporin is selected from ceftriaxone, cefotaxime, cefozolin, cefoperazone, cefepime, cefuroxime, and ceftazidime.

8. The beta-lactamase of any one of claims 1 - 4 , wherein the beta-lactamase has improved enzymatic activity against a cephalosporin as compared to SEQ ID NO: 1.

9. The beta-lactamase of claim 8 , wherein the cephalosporin is selected from cefotaxime, cefepime, and ceftriaxone.

10. The beta-lactamase of any one of claims 1 - 4 , wherein the beta-lactamase has improved catalytic efficiency against a cephalosporin as compared to SEQ ID NO: 1.

11. The beta-lactamase of claim 10 , wherein the beta-lactamase has about a 10-fold to about a 1000-fold improved catalytic efficiency against a cephalosporin as compared to SEQ ID NO: 1.

12. The beta-lactamase of claim 11 , wherein the cephalosporin is ceftriaxone.

13. The beta-lactamase of any one of claims 1 - 4 , wherein the beta-lactamase is active in the GI tract.

14. The beta-lactamase of claim 13 , wherein the beta-lactamase is stable in the small intestine, optionally selected from one or more of the duodenum, jejunum, and ileum.

15. A polynucleotide comprising a polynucleotide sequence encoding the beta-lactamase of any one of claims 1 - 4 .

16. A host cell comprising the polynucleotide of claim 15 .

17. A pharmaceutical composition, comprising the beta-lactamase of any one of claims 1 - 4 and a pharmaceutically acceptable carrier or excipient.

18. The pharmaceutical composition of claim 17 , wherein the composition is formulated for oral administration, optionally selected from a tablet, a multi-particulate sprinkle, and a multi-particulate capsule.

19. A method for preventing an antibiotic induced adverse effect in the GI tract, comprising administering an effective amount of a beta-lactamase to a patient in need thereof, wherein the beta-lactamase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:1 and having A232G, A237S, A238G, and S240D mutations according to Ambler classification.

20. The method of claim 19 , wherein the beta-lactamase further comprises a D276R mutation according to Ambler classification.

21. The method of claim 19 , wherein the beta-lactamase further comprises a D276K mutation according to Ambler classification.

22. The method of claim 19 , wherein the beta-lactamase further comprises a Q135M mutation according to Ambler classification.

23. The method of any one of claims 19 - 22 , wherein the subject is being administered or will be administered an antibiotic.

24. A method for treating or preventing an antibiotic induced C. difficile infection (CDI) and/or a C. difficile -associated disease, comprising administering an effective amount of a beta-lactamase to a patient in need thereof, wherein the beta-lactamase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 1 and having A232G, A237S, A238G, and S240D mutations according to Ambler classification.

25. The method of claim 24 , wherein the beta-lactamase further comprises a D276R mutation according to Ambler classification.

26. The method of claim 24 , wherein the beta-lactamase further comprises a D276K mutation according to Ambler classification.

27. The method of claim 24 , wherein the beta-lactamase further comprises a Q135M mutation according to Ambler classification.

28. The method of any one of claims 24 - 27 , wherein the wherein the subject is being administered or will be administered an antibiotic.

29. The method of any one of claims 24 - 27 , wherein the C. difficile -associated disease is antibiotic-associated diarrhea.

Assignments (2)
CHANGE OF NAME Recorded Feb 28, 2023
From: SYNTHETIC BIOLOGICS, INC.
To: THERIVA BIOLOGICS, INC.
Reel/Frame 062822/0493 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 11, 2016
From: KALEKO, MICHAEL; CONNELLY, SHEILA
To: SYNTHETIC BIOLOGICS, INC.
Reel/Frame 037713/0306 →
Continuity (3)
Continuation 14689877 · Apr 17, 2015
Provisional Application 61980844 · Apr 17, 2014
Provisional Application 62046627 · Sep 5, 2014