IP Library › Granted Patent US 12,617,825
Granted Patent B2
US 12,617,825 · App. 17/716,636 · Granted May 5, 2026

Methods and compositions for reducing the immunogenicity of chimeric notch receptors

Inventors: Peter Emtage (Lafayette, CA); Amy E. Gilbert (San Francisco, CA); Anselm Levskaya (Oakland, CA); Spencer Scott (San Francisco, CA); Vladimir Slepushkin (Vallejo, CA)
Assignee: Cell Design Labs, Inc.
C07K14/4702A61K40/11A61K40/31A61K40/35A61K40/4202A61K40/4211A61K48/00C07K14/4705C07K14/705C07K14/70517C07K14/71C07K16/28C07K16/2803C07K16/30C07K19/00C12N5/0636C12N5/0645C12N5/10C12N15/63C12N15/85A61K2039/5156A61P35/04C07K16/462C07K2317/569C07K2317/622C07K2317/626C07K2317/70C07K2319/00C07K2319/02C07K2319/03C07K2319/09C07K2319/33C07K2319/41C07K2319/50C07K2319/70C07K2319/71C07K2319/80C07K2319/95C12N2740/16043C12N2830/15C12N2830/85
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Quick Facts
Patent No.
US 12,617,825
App. No.
17/716,636
Granted
May 5, 2026
Kind
B2
Abstract

The present invention relates to methods and compositions for reducing the immunogenicity of chimeric Notch receptors, and specifically to transcription factors useful for controlling gene expression delivered to tissues by such chimeric Notch receptors.

Claims (46)

1 . A method of treating a CD19-expressing cancer in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of a T cell expressing a chimeric Notch polypeptide comprising from N-terminal to C-terminal and in covalent linkage:

a) an extracellular domain comprising a binding agent that specifically binds to human CD19;

b) a human Notch 2 or human Notch 3 core domain comprising one or more proteolytic cleavage sites; and

c) an intracellular domain comprising a transcriptional regulator comprising a DNA binding domain of human origin and a transactivation domain of human origin; and

wherein said T cell also comprises a nucleic acid construct comprising a cognate DNA binding sequence for the DNA binding domain of human origin, a promoter sequence, and a nucleic acid sequence encoding either a cytokine that locally induces and recruits immune cells to the CD19-expressing cancer or a chimeric antigen receptor (CAR) that targets an antigen other than CD19 on cancer cells in the human subject.

2 . The method of claim 1 , wherein the DNA binding domain is from human Hepatocyte Nuclear Factor 1 α (HNF1α) or human Early Growth Response 1 α (EGR1 α).

3 . The method of claim 2 , wherein the DNA binding domain is from human HNF1α.

4 . The method of claim 3 , wherein the human HNF1α DNA-binding domain of the chimeric Notch polypeptide comprises the DNA-binding domain of any one of the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6 and SEQ ID NO: 7.

5 . The method of claim 3 , wherein the human HNF1α DNA-binding domain of the chimeric Notch polypeptide consists of the amino acid sequence of amino acids 1-283 of SEQ ID NO: 5.

6 . The method of claim 1 , wherein the polypeptide comprises a human Notch 3 core domain.

7 . The method of claim 6 , wherein the human Notch 3 core domain of the chimeric Notch polypeptide comprises the amino acid sequence of amino acids 1374-1734 of SEQ ID NO: 27.

8 . The method of claim 1 , wherein the transactivation domain is from human RelA (p65), human WWTR1 (TAZ), or human CREB3 (LZIP).

9 . The method of claim 1 , wherein the transactivation domain is from human RelA (p65).

10 . The method of claim 9 , wherein the transactivation domain of the chimeric Notch polypeptides comprises the transactivation domain from any one of SEQ ID NOs: 12-17.

11 . The method of claim 1 , wherein the binding agent is an scFv, a VHH, a bispecific antibody, or a BiTE.

12 . The method of claim 1 , wherein the intracellular domain further comprises a Nuclear Localization Sequence (NLS) upstream of the transcriptional regulator.

13 . The method of claim 12 , wherein the NLS is a native human Notch 3 NLS.

14 . The method of claim 1 , wherein the chimeric Notch polypeptide further comprises one or more linkers.

15 . The method of claim 14 , wherein the one or more linkers comprise the amino acid sequence of one or more of SEQ ID NO: 3 and SEQ ID NO: 4.

16 . The method of claim 1 , wherein the human Notch 2 or human Notch 3 core domain comprises three Lin-12 repeat regions (LNRs) and a transmembrane domain.

17 . The method of claim 1 , wherein the chimeric Notch polypeptide comprises from N-terminal to C-terminal and in covalent linkage:

a) an extracellular domain comprising a scFv that specifically binds to human CD19;

b) a human Notch 3 core domain comprising one or more proteolytic cleavage sites;

c) a first glycine serine linker; and

d) an intracellular domain comprising a transcriptional regulator comprising a DNA binding domain of human HNF1α, a second glycine serine linker, and a human RelA (p65) transactivation domain.

18 . The method of claim 17 , wherein:

the human Notch 3 core domain of the chimeric Notch polypeptide comprises the amino acid sequence of amino acids 1374-1734 or 1374-1738 of SEQ ID NO: 27;

the first glycine serine linker comprises the sequence set forth in SEQ ID NO:3;

the DNA binding domain of human HNF1α comprises the DNA-binding domain of any one of the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6 and SEQ ID NO: 7;

the second glycine serine linker comprises the sequence set forth in SEQ ID NO:4; and

wherein the human RelA transactivation domain is a transactivation domain from any one of the sequences of SEQ ID NOs: 12-17.

19 . The method of claim 17 , wherein the chimeric Notch polypeptide comprises a human CD8 alpha signal peptide immediately upstream of the scFv that specifically binds to human CD19.

20 . A method of treating a CD19-expressing cancer in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of a T cell expressing a chimeric Notch polypeptide comprising from N-terminal to C-terminal and in covalent linkage:

a) an extracellular domain comprising an scFv that specifically binds to human CD19;

b) a human Notch 3 core domain comprising one or more proteolytic cleavage sites; and

c) an intracellular domain comprising a transcriptional regulator comprising a human HNF1α DNA binding domain and a human RelA (p65) transactivation domain; and

wherein said T cell also comprises a nucleic acid construct comprising a cognate DNA binding sequence for the HNF1a DNA binding domain, a promoter sequence, and a nucleic acid sequence encoding either a cytokine that locally induces and recruits immune cells to the CD19-expressing cancer or a chimeric antigen receptor (CAR) that targets an antigen other than CD19 on cancer cells in the human subject.

21 . A method of treating a CD19-expressing cancer in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of a macrophage expressing a chimeric Notch polypeptide comprising from N-terminal to C-terminal and in covalent linkage:

a) an extracellular domain comprising a binding agent that specifically binds to human CD19;

b) a human Notch 2 or human Notch 3 core domain comprising one or more proteolytic cleavage sites;

c) an intracellular domain comprising a transcriptional regulator comprising a DNA binding domain of human origin and a transactivation domain of human origin; and

wherein said macrophage also comprises a nucleic acid construct comprising a cognate DNA binding sequence for the DNA binding domain of human origin, a promoter sequence, and a nucleic acid sequence encoding either a cytokine that locally induces and recruits immune cells to the CD19-expressing cancer or a chimeric antigen receptor (CAR) that targets an antigen other than CD19 on cancer cells in the human subject.

22 . The method of claim 21 , wherein the chimeric Notch polypeptide comprises from N-terminal to C-terminal and in covalent linkage:

a) an extracellular domain comprising an scFv that specifically binds to human CD19;

b) a human Notch 3 core domain comprising one or more proteolytic cleavage sites; and

c) an intracellular domain comprising a transcriptional regulator comprising a human HNF1α DNA binding domain and a human RelA (p65) transactivation domain.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 9, 2022
From: GILBERT, AMY; SLEPUSHKIN, VLADIMIR; EMTAGE, PETER; LEVSKAYA, ANSELM; SCOTT, SPENCER
To: CELL DESIGN LABS, INC.
Reel/Frame 059866/0662 →
Continuity (4)
Division 16010805 · Jun 18, 2018
Provisional Application 62603993 · Jun 19, 2017
Provisional Application 62556765 · Sep 11, 2017
Related Publication 20220363728A1 · Nov 17, 2022
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Office Action in Mexican Appln. No. MX/a/2019/015513, dated Jan. 11, 2024, 11 pages (with English translation). [cited by applicant]
Office Action in Mexican Appln. No. MX/a/2019/015513, dated Jun. 27, 2024, 7 pages (with English translation). [cited by applicant]
Office Action in New Zealand Appln. No. 759712, dated Feb. 18, 2022, 5 pages. [cited by applicant]
Office Action in Saudi Arabian Appln. No. 519410835, dated Feb. 2, 2022, 8 pages (with English translation). [cited by applicant]
Office Action in Saudi Arabian Appln. No. 522432612, dated Feb. 6, 2023, 5 pages (with English summary). [cited by applicant]
Office Action in Saudi Arabian Appln. No. 522432612, dated Sep. 10, 2023, 7 pages (with English translation). [cited by applicant]
Office Action in Saudi Arabian Appln. No. 522432612, dated Sep. 12, 2022, 6 pages (with English summary). [cited by applicant]
Office Action in Singapore Appln. No. 11201911639T, dated Sep. 11, 2024, 6 pages. [cited by applicant]
Office Action in Taiwanese Appln. No. 112144909, dated Dec. 17, 2024, 18 pages (with English translation). [cited by applicant]
Office Action in Taiwanese Appln. No. 112144909, dated May 21, 2025, 8 pages (with English translation). [cited by applicant]
Office Action issued in CA Application No. 3065549, dated Sep. 8, 2021. [cited by applicant]
Office Action, issued in related Japanese Application No. 2019-569872, dated Mar. 9, 2021. [cited by applicant]
Substantive Examination Report issued in SA Application No. 519410835, dated Aug. 31, 2021. [cited by applicant]
Communication pursuant to Article 94(3) EPC issued in EP Appln. No. 18745721.3, mailed on Dec. 15, 2025, 3 pages. [cited by applicant]