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US 2026/0144818 A1Published application
Armed chimeric receptors and methods of use thereof
AssigneeSenti Biosciences, Inc.
InventorsAlba Gonzalez-Junca, Nicholas Frankel
Life of this patent
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Abstract
Described herein are immunoresponsive cells engineered to express cytokines and chimeric receptors. Also described herein are nucleic acids, cells, and methods directed to the same.
Claims17
A multicistronic expression system comprising:
- (a) an exogenous polynucleotide sequence encoding a first cytokine;
- (b) an exogenous polynucleotide sequence encoding a second cytokine;
- and
- (c) an exogenous polynucleotide sequence encoding an activating chimeric antigen receptor (aCAR), optionally wherein the aCAR comprises:
- (i) a first antigen-binding domain, (ii) one or more intracellular signaling domains that stimulate an immune response, and (iii) one or more polypeptides selected from the group consisting of:
- a signal peptide, a transmembrane domain, a hinge domain, a spacer region, one or more peptide linkers, and combinations thereof;
- and
- (d) an exogenous polynucleotide sequence encoding an inhibitory CAR (iCAR),
- wherein each exogenous polynucleotide sequence comprises a 5′ end and a 3′ end.
6 more elements
A multicistronic expression system comprising:
- (a) an exogenous polynucleotide sequence encoding a first cytokine;
- (b) an exogenous polynucleotide sequence encoding a second cytokine;
- and
- (c) an exogenous polynucleotide sequence encoding an activating chimeric antigen receptor (aCAR),
- wherein each exogenous polynucleotide sequence comprises a 5′ end and a 3′ end, and
- wherein the aCAR comprises:
- (i) a first antigen-binding domain that binds to a target selected from:
- CEA, CEACAM1, CEACAM5, and CEACAM6, optionally wherein the first antigen-binding domain of the aCAR binds CEACAM5, optionally wherein the first antigen binding domain of the aCAR comprises the amino acid sequence set forth in SEQ ID NO:
- 381;
- (ii) one or more intracellular signaling domains that stimulate an immune response;
- and
- (iii) one or more polypeptides selected from the group consisting of:
- a signal peptide, a transmembrane domain, a hinge domain, a spacer region, one or more peptide linkers, and combinations thereof.
10 more elements
The multicistronic expression system of any one of the preceding claims, wherein:
- (i) the one or more intracellular signaling domains of the aCAR are selected from the group consisting of:
- CD3-zeta, FcR gamma, FcR beta, CD3 gamma, CD3 delta, CD3 epsilon, CD5, CD22, CD79a, CD79b, CD278, FcεRI, DAP10, DAP12, CD66d, CD97, CD2, ICOS, CD27, CD154, CD8, OX40, 4-1BB, CD28, ZAP40, CD30, GITR, HVEM, DAP10, DAP12, MyD88, 2B4, CD40, PD-1, LFA-1, CD7, LIGHT, NKG2C, B7-H3, an MHC class I molecule, a TNF receptor protein, an Immunoglobulin-like protein, a cytokine receptor, an integrin, a SLAM protein, an activating NK cell receptor, BTLA, a Toll ligand receptor, CDS, ICAM-1, (CD11a/CD18), BAFFR, KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLAl, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, ITGB7, NKG2D, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, and combinations thereof, and/or
- (ii) the aCAR comprises a hinge domain selected from the group consisting of a human Ig (immunoglobulin) hinge, an IgG4 hinge, an IgG2 hinge, a CD8a hinge, or an IgD hinge, a KIR2DS2 hinge, an LNGFR hinge, a LIR1 hinge, a PDGFR-beta extracellular linker, and combinations thereof, and/or
- (iii) the aCAR comprises a transmembrane domain selected from the group consisting of:
- PDGFR-beta, CD8, CD28, CD3zeta-chain, CD4, 4-1BB, OX40, ICOS, CTLA-4, PD-1, LAG-3, 2B4, LNGFR, NKG2D, EpoR, TNFR2, B7-1, LIR1, and BTLA, and/or
- (iv) the aCAR comprises a signal peptide selected from the group consisting of:
- IgE, IL12, IL2, optimized IL2, trypsiongen-2, Gaussia luciferase, CD5, human IgKVII, murine IgKVII, VSV-G, prolactin, serum albumin preprotein, azurocidin preprotein, osteonectin, CD33, IL6, IL8, CCL2, TIMP2, VEGFB, osteoprotegerin, serpin E1, GROalpha, CXCL12, IL21, CD8, NKG2D, TNFR2, GMCSF, and GM-CSFRa.
4 more elements
The multicistronic expression system of any one of the preceding claims, wherein:
- (i) the exogenous polynucleotide encoding the first cytokine, the exogenous polynucleotide encoding the second cytokine, the exogenous polynucleotide encoding the aCAR, and the exogenous polynucleotide encoding the iCAR are comprised within a single expression vector, or
- (ii) the exogenous polynucleotide encoding the first cytokine, the exogenous polynucleotide encoding the second cytokine, and the exogenous polynucleotide encoding the aCAR are comprised within a first expression vector, and the exogenous polynucleotide encoding the iCAR is comprised within a second expression vector.
The multicistronic expression system of any one of the preceding claims, further comprising ribosome skipping sites between each exogenous polynucleotide.
The multicistronic expression system of any one of the preceding claims, wherein:
- (i) the first cytokine is IL15, optionally wherein the IL15 comprises the amino acid sequence set forth in SEQ ID NO:
- 285, or optionally wherein the IL15 is controlled-release IL15 (crIL15), and/or
- (ii) the second cytokine is IL21, optionally wherein the IL21 comprises the amino acid sequence set forth in SEQ ID NO:
- 360, or optionally wherein the IL21 is controlled-release IL21 (crIL21), and/or
- (iii) the first or second cytokine comprises an amino acid sequence set forth in any one of SEQ ID NOs:
- 355-359, 361, and 391, and/or
- (iv) the first or second cytokine is encoded by a nucleic acid sequence set forth in any one of SEQ ID NOs:
- 367-372, and 392.
5 more elements
A multicistronic expression system comprising:
- (a) an exogenous polynucleotide sequence encoding a first cytokine;
- (b) an exogenous polynucleotide sequence encoding a second cytokine;
- and
- (c) an exogenous polynucleotide sequence encoding a chimeric antigen receptor (CAR),
- wherein each exogenous polynucleotide sequence comprises a 5′ end and a 3′ end.
2 more elements
Dependencies are inferred from the claim text.