IP Library › Granted Patent US 12,502,421
Granted Patent B2
US 12,502,421 · App. 18/051,856 · Granted Dec 23, 2025

Engineered leucine decarboxylases

Inventors: Jonathan Benjamin Asfaha (Oakland, CA); Subhamoy Das (Menlo Park, CA); Faye Loan Du (San Jose, CA); Stephan Jenne (Foster City, CA); Nikki D. Kruse (San Carlos, CA); Joyce Liu (Fremont, CA); Kerryn McCluskie (Pacifica, CA); Roasa Mehmood (Fremont, CA); Adam P. Silverman (San Carlos, CA); Kristen Jean Vallieu (Las Vegas, NV)
Assignee: Syntis Bio, Inc.
A61K38/51A61P3/00C12N9/88C12Y401/01014
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Quick Facts
Patent No.
US 12,502,421
App. No.
18/051,856
Granted
Dec 23, 2025
Kind
B2
Abstract

The present invention provides engineered leucine decarboxylase (LDC) polypeptides and compositions thereof, as well as polynucleotides encoding the engineered leucine decarboxylase polypeptides. In some embodiments, the engineered leucine decarboxylase polypeptides display enhanced catalytic activity, as well as reduced sensitivity to proteolysis, and/or increased tolerance to low pH environments. In some embodiments, the engineered leucine decarboxylase polypeptides are optimized to provide improved storage stability. The present invention also provides methods for the use of the compositions comprising the engineered leucine decarboxylase polypeptides for therapeutic and industrial purposes.

Claims (20)

1 . An engineered leucine decarboxylase polypeptide comprising an amino acid sequence having at least 96% sequence identity to a reference sequence corresponding to SEQ ID NO: 828, wherein the amino acid sequence comprises at least one substitution according to 202H, 272A, 290I, or 383S, or combinations thereof, wherein the amino acid positions are relative to the reference sequence corresponding to SEQ ID NO: 828.

2 . The engineered leucine decarboxylase polypeptide of claim 1 , wherein the amino acid sequence of the engineered leucine decarboxylase polypeptide comprises the substitution according to 202H.

3 . The engineered leucine decarboxylase polypeptide of claim 1 , wherein the amino acid sequence of the engineered leucine decarboxylase polypeptide comprises the substitution according to 272A.

4 . The engineered leucine decarboxylase polypeptide of claim 1 , wherein the amino acid sequence of the engineered leucine decarboxylase polypeptide comprises the substitution according to 290I.

5 . The engineered leucine decarboxylase polypeptide of claim 1 , wherein the amino acid sequence of the engineered leucine decarboxylase polypeptide comprises the substitution according to 383S.

6 . The engineered leucine decarboxylase polypeptide of claim 1 , wherein the engineered leucine decarboxylase polypeptide exhibits increased leucine decarboxylase activity in a gastric environment compared to the leucine decarboxylase having the amino acid sequence corresponding to SEQ ID NO: 828.

7 . The engineered leucine decarboxylase polypeptide of claim 1 , wherein the amino acid sequence of the engineered leucine decarboxylase polypeptide comprises SEQ ID NO: 854, 860, 862, 864, 866, 868, 870, 872, 876, 880, 884, 886, 914, 950, 952, 954, 956, 958, 960, 962, 964, 966, 970, 972, 974, 982, 986, 988, 990, 994, 996, 998, 1000, 1002, 1004, 1008, 1014, 1018, 1020, 1022, 1024, 1028, 1030, 1032, 1034, 1036, 1042, 1044, 1048, 1052, 1054, 1058, 1060, 1062, or 1064.

8 . A composition comprising at least one engineered leucine decarboxylase polypeptide of claim 1 .

9 . A pharmaceutical composition comprising at least one engineered leucine decarboxylase polypeptide of claim 1 .

10 . The pharmaceutical composition of claim 9 , further comprising at least one pharmaceutically acceptable excipient and/or carrier.

11 . A method of reducing plasma leucine, isoleucine, alloisoleucine and/or ketoisocaproic acid levels in a subject, comprising administering to a subject in need thereof an effective amount of an engineered leucine decarboxylase of claim 1 .

12 . A method of treating and/or decreasing a symptom of a disease or condition associated with elevated plasma leucine, isoleucine, alloisoleucine, methionine, and/or ketoisocaproic acid levels, comprising administering to a subject in need thereof an effective amount of an engineered leucine decarboxylase of claim 1 to decrease levels of plasma leucine, isoleucine, alloisoleucine, methionine, and/or ketoisocaproic acid in the subject, wherein treating is palliative or prophylactic treatment.

13 . The method of claim 12 , wherein the disease or condition associated with elevated plasma leucine, isoleucine, alloisoleucine, and/or ketoisocaproic acid levels is maple syrup urine disease, isovaleric acidemia or 3-methylcrotonyl-CoA carboxylase deficiency.

14 . The method of claim 12 , wherein the engineered leucine decarboxylase is administered at a dose of 1 mg/kg to 500 mg/kg, 1 mg/kg to 400 mg/kg, 1 mg/kg to 200 mg/kg, or 5 mg/kg to 200 mg/kg.

15 . The method of claim 12 , wherein the engineered leucine decarboxylase is administered at a dose of 1 mg/kg to less than 25 mg/kg.

16 . The method of claim 12 , wherein the dose is about 6.25 mg/kg to about 12.5 mg/kg.

17 . The method of claim 12 , wherein the engineered leucine decarboxylase is administered in an effective amount to reduce plasma leucine, ketoisocaproic acid, and methionine levels.

18 . The method of claim 12 , wherein the engineered leucine decarboxylase is administered immediately before, concurrently with, and/or immediately following ingestion of a meal containing protein.

19 . The method of claim 12 , wherein the subject is able to eat a diet that is less restricted in protein content compared to diets required by subjects who are afflicted with the disease or condition.

20 . The method of claim 12 , wherein the treating is palliative treatment.

Assignments (5)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 10, 2025
From: CODEXIS, INC.
To: SYNTIS BIO, INC.
Reel/Frame 072535/0736 →
RELEASE OF SECURITY INTEREST Recorded Aug 21, 2024
From: INNOVATUS LIFE SCIENCES LENDING FUND I, LP, AS COLLATERAL AGENT
To: CODEXIS, INC.
Reel/Frame 068361/0757 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 13, 2024
From: ASFAHA, JONATHAN BENJAMIN; DU, FAYE LOAN; JENNE, STEPHAN; KRUSE, NIKKI D.; LIU, JOYCE; MCCLUSKIE, KERRYN; MEHMOOD, ROASA; SILVERMAN, ADAM P.; VALLIEU, KRISTEN JEAN; DAS, SUBHAMOY
To: CODEXIS, INC.
Reel/Frame 067717/0877 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 7, 2024
From: CODEXIS, INC.
To: SYNTIS BIO, INC.
Reel/Frame 067340/0445 →
SECURITY INTEREST Recorded Feb 15, 2024
From: CODEXIS, INC.
To: INNOVATUS LIFE SCIENCES LENDING FUND I, LP, AS COLLATERAL AGENT
Reel/Frame 066600/0650 →
Continuity (2)
Provisional Application 63274395 · Nov 1, 2021
Related Publication 20230277635A1 · Sep 7, 2023
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