# US 12,215,347 B2 · Chimeric antigen receptors with enhanced signaling and activities and uses thereof > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,215,347 B2 - Document ID: US12215347B2 - Status: Granted - Kind: B2 - Application number: 17/381,693 - Filed: 2021-07-21 - Published: 2022-01-27 - Granted: 2025-02-04 - Earliest claimed: 2020-07-21 - Assignees: Allogene Therapeutics, Inc. - Applicants: Allogene Therapeutics, Inc. - Inventors: Michael Thomas Bethune; Yi Zhang; Thomas John Van Blarcom; Siler Panowski; Barbra Johnson Sasu - Web page: https://patentgrep.com/patent/US12215347B2 ## CPC - C12N 5/0636: {T lymphocytes} - A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells - A61K 40/31: Chimeric antigen receptors [CAR] - A61K 40/4202: {Receptors, cell surface antigens or cell surface determinants} - A61P 35/00: Antineoplastic agents - C07K 14/7051: {T-cell receptor (TcR)-CD3 complex} - C07K 16/28: against receptors, cell surface antigens or cell surface determinants - C12N 15/86: Viral vectors - A61K 2239/22: Intracellular domain - C07K 2317/622: Single chain antibody (scFv) - C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation - C07K 2319/03: containing a transmembrane segment - C07K 2319/33: fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies - C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) ## Abstract Provided herein are recombinant antigen receptors, for example chimeric antigen receptors (CARs), that comprise modified cytoplasmic domains that provide improved signalling and thereby provide improved performance and safety. Also provided are polynucleotides encoding the recombinant antigen receptors, vectors comprising the polynucleotides, and engineered immune cells comprising the vectors and/or polynucleotides. The invention further provides methods for engineering immune cells to express the recombinant antigen receptors. Improved recombinant antigen receptor signalling is also provided by co-expressing a first recombinant antigen receptor and a second recombinant antigen receptor or co-expressing a recombinant antigen receptor and a protein involved in transducing the signal from the activated recombinant antigen receptor. Also provided are methods of treating a variety of conditions, including, but not limited to, blood cancers and cancers characterized by solid tumors, by administering the engineered cells to patients suffering from such a condition. ## Claims ### Claim 1 A recombinant antigen receptor comprising an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain that comprises a co-stimulatory domain and an ITAM-containing domain, wherein the ITAM-containing domain comprises from N-terminus to C-terminus (a) CD3z1 ITAM, CD3d ITAM, CD3z2 ITAM, CD3e ITAM, CD3z3 ITAM, CD3g ITAM, (b) CD3z1 (YAEL (SEQ ID NO: 152)) ITAM, CD3z2 (YAEL (SEQ ID NO: 152)) ITAM, CD3z3 (YAGL (SEQ ID NO: 153)) ITAM, or (c) CD3z1 (YAEL (SEQ ID NO: 152)) ITAM, CD3d (YAPL (SEQ ID NO: 154)) ITAM, CD3z2 (YAEL (SEQ ID NO: 152)) ITAM, CD3e (YAPI (SEQ ID NO: 155)) ITAM, CD3z3 (YAGL (SEQ ID NO: 153)) ITAM, CD3g (YAPL (SEQ ID NO: 154)) ITAM. ### Claim 2 (depends on 1) The recombinant antigen receptor of claim 1, wherein the recombinant antigen receptor is a chimeric antigen receptor (CAR). ### Claim 3 (depends on 1) The recombinant antigen receptor of claim 1, wherein the antigen binding domain comprises a heavy chain variable domain (VH) and a light chain variable domain (VL). ### Claim 4 (depends on 1) The recombinant antigen receptor of claim 1, wherein the co-stimulatory domain comprises 4-1BB co-stimulatory domain. ### Claim 5 (depends on 1) The recombinant antigen receptor of claim 1, wherein the intracellular domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 30, 35 and 37. ### Claim 6 (depends on 5) The recombinant antigen receptor of claim 5, wherein the intracellular domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 30 and 37. ### Claim 7 (depends on 5) The recombinant antigen receptor of claim 5, wherein the intracellular domain comprises an amino acid sequence of SEQ ID NO:35. ### Claim 8 (depends on 1) A polynucleotide comprising a DNA sequence encoding the recombinant antigen receptor of claim 1. ### Claim 9 (depends on 8) A vector comprising the polynucleotide of claim 8. ### Claim 10 (depends on 1) An engineered immune cell comprising the recombinant antigen receptor according to claim 1. ### Claim 11 (depends on 10) A pharmaceutical composition comprising the engineered immune cell of claim 10. ### Claim 12 A recombinant antigen receptor comprising an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the intracellular domain comprises a 4-1BB co-stimulatory domain, a CD3z ITAM-containing domain, and further comprises an additional Lck recruiting motif (LRM), wherein the additional LRM is a CD8 LRM, and wherein the CD8 LRM comprises, consists of or consists essentially of the amino acid sequence of SEQ ID NO: 56.