Granted Patent
B2
US 12,344,843 · App. 16/943,335 · Granted Jul 1, 2025
Altering gene expression in cart cells and uses thereof
Inventors:
Yangbing Zhao (Lumberton, NJ); Jiangtao Ren (Philadelphia, PA); Xiaojun Liu (Wallingford, PA); Carl H. June (Merion Station, PA)
C12N15/1138A61K35/17A61K35/26A61K39/001102A61K40/11A61K40/22A61K40/31A61K40/32A61K40/36A61K40/416A61K40/418A61K40/4211A61K40/4269A61K40/4274A61P35/00A61P37/06C12N5/0636C12N15/85A61K2039/5156A61K2039/5158A61K40/50C12N2310/10C12N2310/20C12N2501/48C12N2501/515C12N2501/599C12N2501/998C12N2510/00
View Patent ↗
Loading inventors, assignments & file history…
Abstract
The present invention relates to compositions and methods for generating a modified T cell with a nucleic acid capable of downregulating endogenous gene expression selected from the group consisting of TCR α chain, TCR β chain, beta-2 microglobulin, a HLA molecule, CTLA-4, PD1, and FAS and further comprising a nucleic acid encoding a modified T cell receptor (TCR) comprising affinity for a surface antigen on a target cell or an electroporated nucleic acid encoding a chimeric antigen receptor (CAR). Also included are methods and pharmaceutical compositions comprising the modified T cell for adoptive therapy and treating a condition, such as an autoimmune disease.
Claims (27)
1. A CRISPR-modified T cell comprising:
(i) a CRISPR-mediated insertion or deletion in an endogenous TCR a chain (TRAC) and an endogenous TCR β chain (TRBC) gene locus causing downregulated gene expression of the endogenous TRAC gene and the endogenous TRBC gene;
(ii) a CRISPR-mediated insertion or deletion in an endogenous beta 2-microglobulin (B2M) gene locus causing downregulated gene expression of the endogenous B2M gene; and
(iii) a nucleic acid encoding a chimeric antigen receptor (CAR) having an affinity for a tumor associated-antigen (TAA) on a target cell, wherein the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular domain;
wherein the CRISPR system that mediates the insertion or deletion in the endogenous TRAC gene, the endogenous TRBC gene, or the endogenous B2M gene comprises a CRISPR-associated (Cas) nuclease and:
(a) a first guide RNA comprising a nucleic acid sequence capable of targeting the sequence of SEQ ID NO: 15 in the coding sequence of the TRAC gene;
(b) a second guide RNA comprising a nucleic acid sequence capable of targeting the sequence of SEQ ID NO: 16 in the coding sequence of the TRBC gene; and
(c) a third guide RNA comprising a nucleic acid sequence capable of targeting the sequence of SEQ ID NO: 42 in the coding sequence of the B2M gene.
2. The CRISPR-modified T cell of claim 1 , further comprising:
(iv) a CRISPR-mediated insertion or deletion in a gene locus causing downregulated gene expression of a HLA molecule, wherein the HLA molecule is not a class I HLA molecule.
3. The CRISPR-modified T cell of claim 1 , wherein the antigen binding domain of the CAR:
(a) comprises an antibody selected from the group consisting of a monoclonal antibody, a polyclonal antibody, a synthetic antibody, a human antibody, a humanized antibody, a single domain antibody, a single chain variable fragment, and an antigen-binding fragments thereof; and/or
(b) specifically binds an antigen on a target cell.
4. The CRISPR-modified T cell of claim 3 , wherein the antigen comprises:
(a) CD19; and/or
(b) prostate-specific membrane antigen (PSMA) and/or prostate stem cell antigen (PSCA).
5. The CRISPR-modified T cell of claim 1 , wherein:
(a) the CAR further comprises a hinge region; and/or
(b) the transmembrane domain is selected from the group consisting of the alpha, beta, or zeta chain of a T cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, and CD154.
6. The CRISPR-modified T cell of claim 1 , wherein the intracellular domain comprises:
(a) a costimulatory signaling domain and an intracellular signaling domain; and/or
(b) one or more of a costimulatory domain of a protein selected from the group consisting of CD3, CD83, CD86, CD27, CD28, 4-1BB (CD137), CD127, 4-1BBL, CD134, PD-1, PD-1L, CD7, LIGHT, DAP10, DAP12, CD2, ICAM-1, LFA-1, lymphocyte-specific protein tyrosine kinase (LCK), TNFR2, CD30, CD40, ICOS (CD278), NKG2C, B7-H3, or a variant thereof; and/or
(c) an intracellular domain selected from the group consisting of cytoplasmic signaling domains of TCR, CD3 zeta chain (CD32), common FcRy, FcγRIIa, FcεRIβ, FcR gamma, CD3 gamma, CD3 delta, CD3 epsilon, CD22, CD79a, CD79b, and CD66d, or a variant thereof.
7. A pharmaceutical composition comprising the modified T cell of claim 1 and a pharmaceutically acceptable carrier.
8. The CRISPR-modified T cell of claim 1 , wherein the modified T cell comprises:
(a) a TRAC gene comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO: 18-26; and/or
(b) a TRBC gene comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO: 28-34, and 36-41.
Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded May 1, 2025
From: ZHAO, YANGBING; REN, JIANGTAO; LIU, XIAOJUN; JUNE, CARL H.
To: THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA
Reel/Frame 070998/0512 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Sep 15, 2023
From: ZHAO, YANGBING; REN, JIANGTAO; LIU, XIAOJUN; JUNE, CARL H.
To: THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA
Reel/Frame 064920/0860 →
Continuity (3)
Continuation
15516240
Provisional Application
62073651
· Oct 31, 2014
References Cited (220)
US 4444887A
· Hoffmann
· 1984
[cited by applicant]
US 4694778A
· Learn et al.
· 1987
[cited by applicant]
US 4716111A
· Osband et al.
· 1987
[cited by applicant]
US 4816567A
· Cabilly et al.
· 1989
[cited by applicant]
US 5199942A
· Gillis et al.
· 1993
[cited by applicant]
US 5225539A
· Winter
· 1993
[cited by applicant]
US 5229275A
· Goroff et al.
· 1993
[cited by applicant]
US 5350674A
· Boenisch et al.
· 1994
[cited by applicant]
US 5413923A
· Kucherlapati et al.
· 1995
[cited by applicant]
US 5530101A
· Queen et al.
· 1996
[cited by applicant]
US 5545806A
· Lonberg et al.
· 1996
[cited by applicant]
US 5565332A
· Hoogenboom et al.
· 1996
[cited by applicant]
US 5567610A
· Borrebaeck et al.
· 1996
[cited by applicant]
US 5569825A
· Lonberg et al.
· 1996
[cited by applicant]
US 5573905A
· Lerner et al.
· 1996
[cited by applicant]
US 5585089A
· Queen et al.
· 1996
[cited by applicant]
US 5585362A
· Wilson et al.
· 1996
[cited by applicant]
US 5625126A
· Lonberg et al.
· 1997
[cited by applicant]
US 5626561A
· Butler et al.
· 1997
[cited by applicant]
US 5633425A
· Lonberg et al.
· 1997
[cited by applicant]
US 5661016A
· Lonberg et al.
· 1997
[cited by applicant]
US 5766886A
· Studnicka et al.
· 1998
[cited by applicant]
US 5787900A
· Butler et al.
· 1998
[cited by applicant]
US 5814318A
· Lonberg et al.
· 1998
[cited by applicant]
US 5843069A
· Butler et al.
· 1998
[cited by applicant]
US 5902745A
· Butler et al.
· 1999
[cited by applicant]
US 5913998A
· Butler et al.
· 1999
[cited by applicant]
US 5939598A
· Kucherlapati et al.
· 1999
[cited by applicant]
US 5980889A
· Butler et al.
· 1999
[cited by applicant]
US 5993434A
· Dev et al.
· 1999
[cited by applicant]
US 6080840A
· Slanetz et al.
· 2000
[cited by applicant]
US 6120766A
· Hale et al.
· 2000
[cited by applicant]
US 6143291A
· June et al.
· 2000
[cited by applicant]
US 6181964B1
· Hofmann et al.
· 2001
[cited by applicant]
US 6233482B1
· Hofmann et al.
· 2001
[cited by applicant]
US 6241701B1
· Hofmann et al.
· 2001
[cited by applicant]
US 6331415B1
· Cabilly et al.
· 2001
[cited by applicant]
US 6407213B1
· Carter et al.
· 2002
[cited by applicant]
US 6516223B2
· Hofmann et al.
· 2003
[cited by applicant]
US 6548640B1
· Winter
· 2003
[cited by applicant]
US 6567694B2
· Hayakawa
· 2003
[cited by applicant]
US 6678556B1
· Nolan et al.
· 2004
[cited by applicant]
US 7171264B1
· Hofmann et al.
· 2007
[cited by applicant]
US 7173116B2
· Fewell et al.
· 2007
[cited by applicant]
US 8623642B2
· Wang
· 2014
[cited by applicant]
US 8697359B1
· Zhang
· 2014
[cited by applicant]
US 8906682B2
· Kalos et al.
· 2014
[cited by applicant]
US 8911993B2
· Kalos et al.
· 2014
[cited by applicant]
US 8916381B1
· Kalos et al.
· 2014
[cited by applicant]
US 8975071B1
· Kalos et al.
· 2015
[cited by applicant]
US 9101584B2
· Kalos et al.
· 2015
[cited by applicant]
US 9102760B2
· Kalos et al.
· 2015
[cited by applicant]
US 9102761B2
· Kalos et al.
· 2015
[cited by applicant]
US 20040014645A1
· Draghia-Akli et al.
· 2004
[cited by applicant]
US 20050042664A1
· Wu et al.
· 2005
[cited by applicant]
US 20050048617A1
· Wu et al.
· 2005
[cited by applicant]
US 20050070841A1
· Mathiesen et al.
· 2005
[cited by applicant]
US 20070036773A1
· Cooper et al.
· 2007
[cited by applicant]
US 20070128708A1
· Gamelin et al.
· 2007
[cited by applicant]
US 20090304657A1
· Morgan et al.
· 2009
[cited by applicant]
US 20100145026A1
· De Romeuf et al.
· 2010
[cited by applicant]
US 20130217117A1
· Thomson et al.
· 2013
[cited by applicant]
US 20130266551A1
· Campana et al.
· 2013
[cited by applicant]
US 20140134195A1
· Russell
· 2014
[cited by examiner]
US 20150037304A1
· Gregory et al.
· 2015
[cited by applicant]
US 20160348073A1
· Meissner
· 2016
[cited by examiner]
US 20170016025A1
· Poirot
· 2017
[cited by examiner]
US 20170175128A1
· Welstead et al.
· 2017
[cited by applicant]
US 20170274014A1
· Brogdon et al.
· 2017
[cited by applicant]
CN 101854949A
· 2010
[cited by applicant]
CN 106103475
· 2016
[cited by applicant]
EP 239400A2
· 1987
[cited by applicant]
EP 519596A1
· 1992
[cited by applicant]
EP 592106A1
· 1994
[cited by applicant]
WO 9109967A1
· 1991
[cited by applicant]
WO 9110741A1
· 1991
[cited by applicant]
WO 9317105A1
· 1993
[cited by applicant]
WO 9633735A1
· 1996
[cited by applicant]
WO 9634096A1
· 1996
[cited by applicant]
WO 9816654A1
· 1998
[cited by applicant]
WO 9824893A2
· 1998
[cited by applicant]
WO 9846645A2
· 1998
[cited by applicant]
WO 9850433A2
· 1998
[cited by applicant]
WO 2005113595A2
· 2005
[cited by applicant]
WO 2006031221A1
· 2006
[cited by applicant]
WO 2007131092A2
· 2007
[cited by applicant]
WO 2007150054A2
· 2007
[cited by applicant]
WO 2008037943A1
· 2008
[cited by applicant]
WO 2008039818A2
· 2008
[cited by applicant]
WO 2008121420A1
· 2008
[cited by applicant]
WO 2011059836A2
· 2011
[cited by applicant]
WO 2012019002
· 2012
[cited by applicant]
WO 2012038055A1
· 2012
[cited by applicant]
WO 2013074916A1
· 2013
[cited by applicant]
WO 2013126712A1
· 2013
[cited by applicant]
WO 2013158292
· 2013
[cited by applicant]
WO 2013166051A1
· 2013
[cited by applicant]
WO 2013176915A1
· 2013
[cited by applicant]
WO 2013176916A1
· 2013
[cited by applicant]
WO 2013177247A1
· 2013
[cited by applicant]
WO 2014011988A2
· 2014
[cited by applicant]
WO 2014039523A1
· 2014
[cited by applicant]
WO 2014059173A2
· 2014
[cited by applicant]
WO 2014153470A2
· 2014
[cited by applicant]
WO 2014160030A2
· 2014
[cited by applicant]
WO 2014165177A1
· 2014
[cited by applicant]
WO 2014184741A1
· 2014
[cited by applicant]
WO 2014184744A1
· 2014
[cited by applicant]
WO 2014186585A2
· 2014
[cited by applicant]
WO 2014191128A1
· 2014
[cited by applicant]
WO 2015136001A1
· 2015
[cited by applicant]
WO 2015155341A1
· 2015
[cited by applicant]
WO 2015161276A2
· 2015
[cited by applicant]
WO 2016054086A1
· 2016
[cited by applicant]
WO 2016069282A1
· 2016
[cited by applicant]
Louis , et al., “Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma”, Blood 2011 118: 6050-6056.
[cited by applicant]
Marks , et al., “By-passing Immunization Human Antibodies from V-gene Libraries Displayed on Phage”, J. Mol. Biol. 222, 1991, 581-597.
[cited by applicant]
Maus , et al., “Adoptive Immunotherapy for Cancer or Viruses.”, 2014, Annu Rev Immunol 32:189-225.
[cited by applicant]
McCafferty , et al., “Phage antibodies: filamentous phage displaying antibody variable domains”, Nature 348, 1990, 552-554.
[cited by applicant]
Mitchell , et al., “Selective Modification of Antigen-Specific T Cells by RNA Electroporation.”, Hum Gene Ther. May 2008 ; 19(5): 511-521.
[cited by applicant]
Morea , et al., “Antibody modeling: implications for engineering and design”, Methods, 20(3):267-79 (2000).
[cited by applicant]
Nacheva , et al., “Preventing nondesired RNA-primed RNA extension catalyzed by T7 RNA polymerase”, Eur. J. Biochem. 270, 2003, 1485-1465.
[cited by applicant]
Nakagawa , et al., “Development of next-generation adoptive immunotherapy using cytotoxic T-lymphocyte (CTL) expressing chimeric antigen-rectpor (CAR)”, Drug Delivery System, 2013, vol. 28, pp. 35-44 (partial translatio…
[cited by applicant]
Nishikawa , et al., “Nonviral vectors in the new millennium: delivery barriers in gene transfer”, Hum. Gene Ther. 12 (8), 2001, 861-870 (abstract only).
[cited by applicant]
Padlan , et al., “A possible procedure for reducing the immunogenicity of antibody variable domains while preserving their ligand-binding properties”, Molecular Immunology 28(4/5), 1991, 489-498.
[cited by applicant]
Pedersen , et al., “Comparison of surface accessible residues in human and murine immunoglobulin Fv domains. Implication for humanization of murine antibodies.”, J. Mol. Biol., 235(3):959-73 (1994).
[cited by applicant]
Porter , et al., “Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia”, 2011 N. Engl. J. Med. 365 (8):725-33 (Aug. 25, 2011).
[cited by applicant]
Presta , “Antibody engineering”, Current Opinion in Biotechnology 3, 1992, 394-398.
[cited by applicant]
Presta , et al., “Humanization of an antibody directed against IgE”, J. Immunol., 151:2623-32 (1993).
[cited by applicant]
Rethi , et al., “Priming of T cells to Fas-mediated proliferative signals by interleukin-7”, Blood, 2008 112: 1195-1204.
[cited by applicant]
Riechmann , et al., “Reshaping human antibodies for therapy”, Nature, 332:323-327 (1988).
[cited by applicant]
Robbins , et al., “Single and Dual Amino Acid Substitutions in TCR CDRs Can Enhance Antigen-Specific T Cell Functions”, J Immunol 2008; 180:6116-6131.
[cited by applicant]
Roder , et al., “The EBV-hybridoma technique”, Methods Enzymol., 121:140-167 (1986).
[cited by applicant]
Roguska , et al., “A comparison of two murine monoclonal antibodies humanized by CDR-grafting and variable domain resurfacing”, Protein Eng., 9(10):895-904 (1996).
[cited by applicant]
Roguska , et al., “Humanization of murine monoclonal antibodies through variable domain resurfacing”, Proc. Natl. Acad. Sci. 91, 1994, 969-973.
[cited by applicant]
Rosenberg , et al., “Use of Tumor-Infiltrating Lymphocytes and Interleukin-2 in the Immunotherapy of Patients with Metastatic Melanoma”, New Eng. J. of Med. 319:1676-1680, 1988.
[cited by applicant]
Sandhu , “A rapid procedure for the humanization of monoclonal antibodies.”, Gene, 150(2):409-10(1994).
[cited by applicant]
Schenborn , et al., “A novel transcription property of SP6 and T7 RNA polymerases: dependence on template structure”, Nuc. Acids Res. 13, 1985, 6223-6236.
[cited by applicant]
Sims , et al., “A humanized CD18 antibody can block function without cell destruction”, J. Immunol., 151:2296-2308 (1993).
[cited by applicant]
Skerra , et al., “Assembly of a Functional Immunoglobulin Fv Fragment in
[cited by applicant]
Smits , et al., “RNA-based gene transfer for adult stem cells and T cells”, Leukemia (2004) 18, 1898-1902.
[cited by applicant]
Stepinski , et al., “Synthesis and properties of mRNAs containing the novel “anti-reverse” cap analogs 7-methyl(3′-0-methyl) GpppG and 7-methyl(3′-deoxy)GpppG”, RNA, 7:1468-95 (2001).
[cited by applicant]
Studnicka , et al., “Human-engineered monoclonal antibodies retain full specific binding activity by preserving non-CDR complementarity-modulating residues”, Protein Engineering, 7(6):805-814 (1994).
[cited by applicant]
Tan , et al., “‘Superhumanized’ antibodies: reduction of immunogenic potential by complementarity-determining region grafting with human germline sequences: application to an anti-CD28”, J. Immunol., 169:1119-25 (2002).
[cited by applicant]
Vaughan, Tristan J., et al., “Human antibodies by design”, Vaughan, et al., “Human antibodies by design”, Nature Biotechnology, vol. 16, No. 6, pp. 535-539, 1998, 1998, 535-539.
[cited by applicant]
Verhoeyen , et al., “Reshaping human antibodies: grafting an antilysozyme activity”, Science, 239:1534-1536 (1988).
[cited by applicant]
Ward , et al., “Binding activities of a repertoire of single immunoglobulin variable domains secreted from
[cited by applicant]
Wu , et al., “Humanization of a murine monoclonal antibody by simultaneous optimization of framework and CDR residues.”, J. Mol. Biol., 294:151-162 (1999).
[cited by applicant]
Yotnda , et al., “Efficient infection of primitive hematopoietic stem cells by modified adenovirus”, 2001, Gene Therapy, 8:930-937.
[cited by applicant]
Zhao , et al., “High-Efficiency Transfection of Primary Human and Mouse T Lymphocytes Using RNA Electroporation”, Molecular Therapy, vol. 13, No. 1, Jan. 2006.
[cited by applicant]
Zhao , et al., “Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor”, Cancer Res 70(22):9053-9061, 2010.
[cited by applicant]
Bargou , et al., “Tumor Regression in Cancer Patients by Very Low Doses of a T Cell-Engaging Antibody”, Science 321, 974-77 (2008).
[cited by applicant]
Barrett , et al., “Regimen-Specific Effects of RNA-Modified Chimeric Antigen Receptor T Cells in Mice with Advanced Leukemia”, Human Gene Therapy 24:717-727 (Aug. 2013).
[cited by applicant]
Barrett , et al., “Treatment of Advanced Leukemia in Mice with mRNA Engineered T Cells”, Human Gene Therapy 22, Dec. 2011, 1575-1586.
[cited by applicant]
Bierer , et al., “Cyclosporin A and FK506: molecular mechanisms of immunosuppression and probes for transplantation biology.”, Current Opinion in Immunology 1993, 5:763-773.
[cited by applicant]
Bird , et al., “Single-Chain Antigen-Binding Proteins”, 1988, Science 242(4877):423-426.
[cited by applicant]
Bruggermann , et al., “Designer Mice: The Production of Human Antibody Repertoires in Transgenic Animals.”, Year in Immunol., 7:33-40 (1993).
[cited by applicant]
Caldas , et al., “Design and synthesis of germline-based hemi-humanized single-chain Fv agains the CD18 surface antigen.”, Protein Engineering vol. 13 No. 5 pp. 353-360, 2000.
[cited by applicant]
Carpenito , et al., “Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains.”, 2009, PNAS 106(9):3360-3365.
[cited by applicant]
Carter , et al., “Humanization of an anti-p185HER2 antibody for human cancer therapy.”, 1992, Proc Natl Acad Sci USA 89:4285-4289.
[cited by applicant]
Chang , et al., “A general method for facilitating heterodimeric pairing between two proteins: Application to expression of alpha and beta T-Cell receptor extracellular segments.”, 1994, Proc Natl Acad Sci USA 91:11408-…
[cited by applicant]
Chen , et al., “Structural and kinetic basis for heightened immunogenicity of T cell vaccines”, 2005, The Journal of Experimental Medicine 201(8):1243-1255.
[cited by applicant]
Chothia , et al., “Canonical structures for the hypervariable regions of immunoglobulins.”, J Mol Biol. Aug. 20, 1987;196(4):901-17. (Abstract).
[cited by applicant]
Clackson , et al., “Making antibody fragments using phage display libraries.”, 1991, Nature 352:624-628.
[cited by applicant]
Cougot , et al., “‘Cap-tabolism’.”, Trends Biochem Sci. Aug. 2004;29(8):436-44. (Abstract).
[cited by applicant]
Couto , et al., “Anti-BA46 Monoclonal Antibody Mc3: Humanization Using a Novel Positional Consensus and in Vivo and in Vibro Characterization.”, 1995, Cancer Research 55:1717-1722.
[cited by applicant]
Couto , et al., “Designing Human Consensus Antibodies with Minimal Positional Templates.”, 1995, Cancer Research 55:(Suppl) 5973S-5977S.
[cited by applicant]
Davodeau , et al., “Secretion of Disculfide-linked Human T-cell Receptor gamma-delta Heterodimers.”, 1993, J. Biol Chem 268(21):15455-15460.
[cited by applicant]
Duchosal , et al., “Immunization of hu-PBL-SCID mice and the rescue of human monoclonal Fab fragments through combinatorial libraries.”, 1992, Nature 355:258-262.
[cited by applicant]
Elango , et al., “Optimized transfection of mRNA transcribed from a d(A/T) 100 tail-containing vector.”, Biochem Biophys Res Commun. May 13, 2005;330(3):958-66. (Abstract).
[cited by applicant]
Garboczi , et al., “Assembly, specific binding, and crystallization of a human TCR-alphabeta wit an antigenic Tax peptide from human T lymphotropic virus type 1 and the class I MHX molwxulw HLA-A2.”, 1996, The Journal o…
[cited by applicant]
Garboczi , et al., “Structure of the complex between human T-cell receptor, viral peptide and HLA-A2.”, 1996, Nature 384:134-141 (Abstract).
[cited by applicant]
Golden , et al., “High-level production of a secreted heterodimeric alpha-beta murine T-cell receptor in
[cited by applicant]
Griffiths , et al., “Human anti-self antibodies with high specificity from phage display libraries.”, The EMBO Journal vol. 12, No. 2, pp. 725-734, 1993.
[cited by applicant]
Henderson , et al., “Comparison of the effects of FK-506, cyclosporin A and rapamycin on IL-2 production.”, 1991, Immunology 73:316-321.
[cited by applicant]
Hoogenboom , et al., “By-passing immunisation. Human antibodies from synthetic repertoires of germline VH gene segments arranged in vitro.”, J Mol Biol Sep. 2, 19920;227(2):381-8. (Abstract).
[cited by applicant]
Huston , et al., “Protein engineering of antibody binding sites: Recovery of sepcific activity in an anti-digoxin single-chain Fv analogue produced in
[cited by applicant]
Jakobovits , et al., “Analysis of homozygous mutant chimeric mice: Deletion of the immunoglobulin heavy-chain joining region blocks B-cell development and antibody production”, Proc. Natl. Acad. Sci. 90, 1993, 2551-2555.
[cited by applicant]
Jakobovits , et al., “Germ-line transmission and expression of a human-derived yeast artificial chromosome.”, 1993, Nature 362:255-258.
[cited by applicant]
Johnson , et al., “Human antibody engnieering.”, 1993, Current Opinion in Structural Biology 3:564-571.
[cited by applicant]
Jones , et al., “Replacing the complementarity-determining regions in a human antibody with those from a mouse”, Nature, 321:522-525 (1986).
[cited by applicant]
Klinger , et al., “Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion to T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab”, Blood, 2012 119: 6226-62…
[cited by applicant]
Kochenderfer , et al., “Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells”, Blood, 116(9), 2010, 3875-3886.
[cited by applicant]
Kuball , et al., “Increasing functional avidity of TCR-redirected T cells by removing defined N-glycosylation sites in the TCR constant domain.”, 2009, J Exp Med 206(2):463-475.
[cited by applicant]
Li , et al., “Inhibition of HIV-1 infection of primary CD4 T-cells by gene editing of CCR5 using adenovirus-delivered CRISPR/Cas9”, Li, et al., 2015, J Virol 96:2381-2393.
[cited by applicant]
Liao , et al., “Activation of lyphocytes by anti-CD3 single-chain antibody dimers expressed on the plasma membrane of tumor cells.”, 2000, Gene Therapy 7(1):339-347.
[cited by applicant]
Liu , et al., “Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes”, Cell 66:807-815, 1991.
[cited by applicant]
Lonberg , et al., “Human antibodies from transgenic mice.”, Int. Rev. Immunol., 13:65-93 (1995).
[cited by applicant]
Zhao et al. “Primary Human Lymphocytes Transduced with NY-ESO-1 Antigen-Specific TCR Genes Recognize and Kill Diverse Human Tumor Cell Lines”, The Journal of Immunology; vol. 174, No. 7, pp. 4415-4423, Apr. 1, 2005 (Yea…
[cited by applicant]
Stadtmauer et al. (CRISPR-engineered T cells in patients with refractory cancer; Science, vol. 367, eaba7365, pp. 1-12, published online Feb. 28, 2020, and supplementary materials (Year: 2020).
[cited by applicant]
Sakuma, et al., “Multiplex genome engineering in human cells using all-in-one CRISPR/Cas9 vector system.” Scientific Reports, Jun. 23, 2014, vol. 4, 5400 (pp. 1-6), ISSN 0004325722.
[cited by applicant]
Niu, et al., “Generation of Gene-Modified Cynomolgus Monkey via Cas9/RNA-Mediated Gene Targeting in One-Cell Embryos.” Cell, Feb. 13, 2014, vol. 156, pp. 836-843, ISSN 0004325723.
[cited by applicant]
Wang, et al., “One-Step Generation of Mice Carrying Mutations in Multiple Genes by CRISPR/Cas-Mediated Genome Engineering.” Cell, 2013, vol. 153, pp. 910-918, ISSN 0004325724.
[cited by applicant]
Kershaw et al, Gene-engineered T cells for cancer therapy, Nature, 2013, pp. 525-541.
[cited by applicant]
Saff, et al., “Activation-Induced Cell Death Limits Exector Function of CD4 Tumor-Speci{c T Cells”, J Immunol (2004) 172 (11): 6598-6606.
[cited by applicant]
Themeli, et al., “Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy”, Nat Biotechnol. Oct. 2013 ; 31(10): 928-933.
[cited by applicant]
Torikai, et al., “A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR”, Blood, 119(24):5697-5705, 201…
[cited by applicant]
Dotti, G., et al., “Human cytotoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis”, Blood 105 (12):4677-4684, 2005.
[cited by applicant]
Torikai, H., et al., “Toward eliminating HLA class I expression to generate universal cells from allogeneic donors”, Blood. 2013, 122(8):1341-1349.
[cited by applicant]
Zhou, P., et al., “In vivo Discovery of Immunotherapy Targets in the Tumor Microenvironment”, Nature. Feb. 6, 2014, 506(7486):52-57.
[cited by applicant]
Mandal, P.K., et al., “Efficient ablation of genes in human hematopoietic stem and effector cells using CRISPR/Cas9”, Cell Stem Cell, Nov. 6, 2014;15(5):643-652.
[cited by applicant]