Chimeric receptors with diverse co-regulatory sequences

Patent metadata

Field	Value
Publication number	US-2023312673-A1
Application number	US-202118043716-A
Country	US
Kind code	A1
Filing date	Sep 1, 2021
Priority date	Sep 2, 2020
Publication date	Oct 5, 2023
Grant date	—

Abstract

This disclosure relates to chimeric receptors (CRs) and their signaling components for the regulation of an immune response. Also provided are nucleic acids encoding the disclosed CRs, recombinant immune cells expressing the same, and pharmaceutical compositions containing the disclosed nucleic acids and/or recombinant cells. Further provided are methods useful for modulating an activity of an immune cell, methods for modulating an immune response in an individual, as well as methods for treating a health condition in an individual in needed thereof

First claim

What is claimed is:

1 . A chimeric receptor comprising:
a) an extracellular antigen-binding domain capable of binding to a target antigen; b) a transmembrane domain; and c) an intracellular signal transduction domain comprising an intracellular signaling domain (SD) derived from a signaling molecule selected from the group consisting of 4-1BB, BAFF-R, BCMA, BTLA, CD2, CD200R, CD244, CD28, CD300a, CD300f, CD40, CD7, CD72, CD96, CRACC, CRTAM, CTLA4, CXADR, DC-SIGN, GITR, HAVCR2, ICOS, ILT2, ILT3, ILT4, KIR2DL1, KIR3DL1, KLRG1, LAG3, LAIR1, NKG2D, NKR-P1A, NTB-A, PD1, Siglec-3, TACI, TIGIT, TLT-1, and TNR8 (CD30).

2 . The receptor of claim 1 , wherein the intracellular signal transduction domain comprises a modulatory SD capable of mediating a co-stimulatory signal derived from a signaling molecule selected from the group consisting of BAFF-R, CD40, TACI, CD2, CD7, TNR8 (CD30), and NTB-A.

3 . The receptor of claim 2 , wherein the modulatory SD is derived from:
a) BAFF-R and comprises the amino acid sequence of SEQ ID NO: 24 or a variant thereof having at least about 80% sequence identity to SEQ ID NO: 24; b) CD40 and comprises the amino acid sequence of SEQ ID NO: 10 or a variant thereof having at least about 80% sequence identity to SEQ ID NO: 10; c) TACI and comprises the amino acid sequence of SEQ ID NO: 25 or a variant thereof having at least about 80% sequence identity to SEQ ID NO: 25; d) CD2 and comprises the amino acid sequence of SEQ ID NO: 19 or a variant thereof having at least about 80% sequence identity to SEQ ID NO: 19; e) CD7 and comprises the amino acid sequence of SEQ ID NO: 3 or a variant thereof having at least about 80% sequence identity to SEQ ID NO: 3; f) CD30 and comprises the amino acid sequence of SEQ ID NO: 21 or a variant thereof having at least about 80% sequence identity to SEQ ID NO: 21; or g) NTB-A and comprises the amino acid sequence of SEQ ID NO: 29 or a variant thereof having at least about 80% sequence identity to SEQ ID NO: 29.

4 . The chimeric receptor of claim 2 or 3 , wherein the intracellular signal transduction domain further comprises an activation domain.

5 . The chimeric receptor of claim 4 , wherein the activation domain comprises one or more immunoreceptor tyrosine-based activation motifs (ITAMs).

6 . The chimeric receptor of claim 5 , wherein the activation domain is 80, 85, 90, 95, 96, 97, 98, 99, or 100% identical to a CD3 activation domain.

7 . The chimeric receptor of any one of claims 2 to 6 , wherein the extracellular antigen-binding domain comprises an antibody moiety capable of binding to the target antigen.

8 . The chimeric receptor of claim 7 , wherein the antibody moiety is a scFv.

9 . The chimeric receptor of any one of claims 2 to 8 , wherein the target antigen is CD19, CD20, or MAGE.

10 . The chimeric receptor of any one of claims 2 to 6 , wherein the extracellular antigen-binding domain comprises an extracellular domain derived from an inhibitory immune checkpoint molecule or a binding moiety capable of binding to a ligand of the inhibitory immune checkpoint molecule.

11 . The chimeric receptor of claim 1 , wherein the intracellular signal transduction domain comprises a modulatory SD capable of mediating an inhibitory signal derived from a signaling molecule selected from the group consisting of KLRG1, DC-SIGN, NKG2D, and NKR-P1A.

12 . The chimeric receptor of claim 11 , wherein the modulatory SD is derived from:
a) KLRG1 and comprises the amino acid sequence of SEQ ID NO: 32 or a variant thereof having at least about 80% sequence identity to SEQ ID NO: 32; b) DC-SIGN and comprises the amino acid sequence of SEQ ID NO: 43 or a variant thereof having at least about 80% sequence identity to SEQ ID NO: 43; c) NKG2D and comprises the amino acid sequence of SEQ ID NO: 22 or a variant thereof having at least about 80% sequence identity to SEQ ID NO: 22; or d) NKR-P1A and comprises the amino acid sequence of SEQ ID NO: 33 or a variant thereof having at least about 80% sequence identity to SEQ ID NO: 33.

13 . The chimeric receptor of claim 11 or 12 , wherein the extracellular antigen-binding domain comprises an extracellular domain derived from a stimulatory immune checkpoint molecule or a binding moiety capable of binding to a ligand of the stimulatory immune checkpoint molecule.

14 . A recombinant nucleic acid comprising a nucleotide sequence encoding a chimeric receptor according to any one of claims 1 to 13 .

15 . The recombinant nucleic acid of claim 14 , wherein the nucleotide sequence is incorporated into an expression cassette or an expression vector.

16 . The recombinant nucleic acid of claim 15 , wherein the expression vector is a viral vector.

17 . The recombinant nucleic acid of claim 16 , wherein the viral vector is a lentiviral vector, an adenovirus vector, an adeno-associated virus vector, or a retroviral vector.

18 . A composition comprising a recombinant nucleic acid according to any one of claims 14 to 17 , wherein the composition is formulated for introducing the recombinant nucleic acid into a cell.

19 . The composition of claim 18 , wherein the composition is formulated as a lipid nanoparticle (LNP), liposome, or viral particle.

20 . A recombinant immune cell comprising:
a) a chimeric receptor according to any one of claims 1 to 13 ; or b) a recombinant nucleic acid according any one of claims 14 to 17 .

21 . The recombinant immune cell of claim 20 , wherein the recombinant immune cell is a recombinant T cell.

22 . The recombinant T cell of claim 21 , wherein the recombinant T cell is a recombinant CD4 + T cell or a recombinant CD8 + T cell.

23 . The recombinant immune cell of any one of claims 20 to 22 , wherein the recombinant immune cell comprises a chimeric receptor according to any one of claims 2 to 10 and has one or more of the following properties:
a) enhanced proliferation in response to stimulation with the target antigen as compared to a corresponding cell that comprises a corresponding receptor where the intracellular SD is derived from CD28 or 4-1BB;
b) enhanced expression of activation marker CD69 in response to stimulation with the target antigen as compared to a corresponding cell that comprises a corresponding receptor where the intracellular SD is derived from CD28 or 4-1BB;
c) enhanced expression of IFNγ, TNFα, IL-2, and/or IL-4 in response to stimulation with the target antigen as compared to a corresponding cell that comprises a corresponding receptor where the intracellular SD is derived from CD28 or 4-1BB;
d) enhanced resistance to exhaustion in response to stimulation with the target antigen as compared to a corresponding cell that comprises a corresponding receptor where the intracellular SD is derived from CD28 or 4-1BB; and
e) enhanced killing of target cells expressing the target antigen as compared to a corresponding cell that comprises a corresponding receptor where the intracellular SD is derived from CD28 or 4-1BB.

24 . The recombinant immune cell of any one of claims 20 to 22 , wherein the recombinant immune cell comprises a chimeric receptor according to any one of claims 11 to 13 and has one or more of the following properties:
a) reduced proliferation in response to stimulation with the target antigen as compared to a corresponding cell that comprises a corresponding receptor where the intracellular SD is derived from an inhib

Assignees

• Univ California

Inventors

• Roybal Kole T
• Goodman Daniel B
• Azimi Camillia
• Marson Alexander
• Bluestone Jeffrey A

Classifications

• A61K40/4215

  Receptors for tumor necrosis factors [TNF], e.g. lymphotoxin receptor [LTR], CD30 · CPC title

• A61K40/4211

  CD19 or B4 · CPC title

• A61K40/4202

  Receptors, cell surface antigens or cell surface determinants · CPC title

• A61K40/31

  Chimeric antigen receptors [CAR] · CPC title

• A61K40/11

  T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells · CPC title