IP Library › Granted Patent US 12,378,300
Granted Patent B2
US 12,378,300 · App. 16/934,606 · Granted Aug 5, 2025

Elimination of CD19-positive lymphoid malignancies by CD19-car expressing NK cells

Inventors: Hans G. Klingemann (San Diego, CA); Laurent H. Boissel (San Diego, CA); Patrick Soon-Shiong (San Diego, CA)
Assignee: ImmunityBio, Inc.
C07K14/70535A61K9/0019A61K40/15A61K40/31A61K40/4211A61P35/00A61P35/04C07K14/5443C07K14/55C07K14/7051C07K16/2803C12N5/0646A61K38/00A61K2039/54A61K2239/31A61K2239/48C07K2317/622C07K2317/732C07K2317/76C07K2319/02C07K2319/30C07K2319/33
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Quick Facts
Patent No.
US 12,378,300
App. No.
16/934,606
Granted
Aug 5, 2025
Kind
B2
Abstract

Provided herein are compositions of NK-92® cells that express a CD19 CAR, CD16 and IL2, and the method of using these cells to and treat cancer in a patient.

Claims (19)

1. A recombinant nucleic acid comprising a sequence that encodes an anti-cluster of differentiation 19 (CD19) chimeric antigen receptor (CAR), wherein the anti-CD19 CAR comprises an antigen binding domain comprising a CD19-specific single chain variable fragment (scfv), wherein the C-terminus of the scfv is fused via a peptide linker to the N-terminus of a hinge domain, wherein an intracellular signaling domain comprises the hinge domain at its N-terminus, a transmembrane domain, and an Fc∈RIγ cytoplasmic signaling domain at its C-terminus, and wherein the intracellular signaling domain has the amino acid sequence of amino acids 274-407 of SEQ ID NO: 12.

2. The recombinant nucleic acid of claim 1 further comprising a nucleic acid sequence that encodes a fragment crystallizable receptor RIII (FcγRIIIA).

3. The recombinant nucleic acid of claim 2 wherein the FcγRIIIA receptor has the amino acid sequence of SEQ ID NO: 1.

4. The recombinant nucleic acid of claim 2 wherein the FcγRIIIA receptor has the amino acid sequence of SEQ ID NO:2.

5. The recombinant nucleic acid of claim 1 further comprising a nucleic acid sequence that encodes a cytokine.

6. The recombinant nucleic acid of claim 5 wherein the cytokine is interleukin 2 (IL-2) or interleukin 15 (IL-15).

7. The recombinant nucleic acid of claim 6 wherein the cytokine has the amino acid sequence of SEQ ID NO:6 (IL2).

8. The recombinant nucleic acid of claim 2 further comprising a nucleic acid sequence that encodes a cytokine.

9. The recombinant nucleic acid of claim 8 wherein the FcγRIIIA receptor has the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO:2, and wherein the cytokine has the amino acid sequence of SEQ ID NO:6 or SEQ ID NO:7.

10. The recombinant nucleic acid of claim 8 wherein the nucleic acid sequence that encodes the anti-CD19 CAR, the nucleic acid sequence that encodes the FcγRIIIA receptor, and the nucleic acid sequence that encodes the cytokine are arranged in a tricistronic construct.

11. The recombinant nucleic acid of claim 10 further comprising a nucleic acid sequence that encodes a P2A peptide, wherein the nucleic acid sequence that encodes a P2A peptide is between the nucleic acid sequence that encodes the anti-CD19 CAR and the nucleic acid sequence that encodes the Fc receptor, and further comprising a nucleic acid sequence comprising an internal ribosome entry site (IRES), wherein the sequence comprising an IRES is between the nucleic acid sequence that encodes the Fc receptor and the nucleic acid sequence that encodes the cytokine.

12. The recombinant nucleic acid of claim 10 wherein the tricistronic construct encodes a protein sequence having the amino acid sequence of SEQ ID NO: 14.

13. A recombinant vector comprising the recombinant nucleic acid of claim 1 .

14. The recombinant vector of claim 13 having the nucleic acid sequence of SEQ ID NO: 13 or a portion thereof, wherein the portion comprises the recombinant nucleic acid of claim 1 .

15. The recombinant nucleic acid of claim 6 , wherein the IL-2 or IL-15 further comprises an endoplasmic reticulum retention sequence.

16. The recombinant nucleic acid of claim 15 , wherein the cytokine has the amino acid sequence of SEQ ID NO:7 (er-IL2).

17. A recombinant NK cell comprising the nucleic acid of claim 1 .

18. The recombinant NK cell of claim 17 , wherein the NK cell is an NK-92 cell.

19. The recombinant nucleic acid of claim 1 , wherein the peptide linker is comprised of at least 2 alanine residues.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 7, 2025
From: BOISSEL, LAURENT H.; KLINGEMANN, HANS G.; SOON-SHIONG, PATRICK
To: NANTKWEST, INC.
Reel/Frame 071056/0891 →
SECURITY INTEREST Recorded Jan 2, 2024
From: IMMUNITYBIO, INC.; NANTCELL, INC.; RECEPTOME, INC.; VBC HOLDINGS LLC; ALTOR BIOSCIENCE, LLC; ETUBICS CORPORATION; IGDRASOL, INC.
To: INFINITY SA LLC, AS PURCHASER AGENT
Reel/Frame 066179/0074 →
CHANGE OF NAME Recorded Aug 18, 2021
From: NANTKWEST, INC.
To: IMMUNITYBIO, INC.
Reel/Frame 057221/0005 →
Continuity (3)
Division 16529251 · Aug 1, 2019
Provisional Application 62753719 · Oct 31, 2018
Related Publication 20200376033A1 · Dec 3, 2020
References Cited (80)
US 7618817B2 · Campell · 2009 [cited by applicant]
US 8034332B2 · Klingemann · 2011 [cited by applicant]
US 8313943B2 · Campell · 2012 [cited by applicant]
US 9150636B2 · Campell · 2015 [cited by applicant]
US 9181322B2 · Campell · 2015 [cited by applicant]
US 10138462B2 · Klingemann · 2018 [cited by applicant]
US 10456420B2 · Lee et al. · 2019 [cited by applicant]
US 10738279B2 · Lee · 2020 [cited by applicant]
US 11077143B2 · Klingemann et al. · 2021 [cited by applicant]
US 11655452B2 · Ma et al. · 2023 [cited by applicant]
US 20020068044A1 · Klingemann · 2002 [cited by applicant]
US 20180100016A1 · Song · 2018 [cited by applicant]
US 20180163176A1 · Lee · 2018 [cited by applicant]
US 20180187149A1 · Ma et al. · 2018 [cited by applicant]
US 20180193383A1 · Lee et al. · 2018 [cited by applicant]
US 20200129553A1 · Klingemann et al. · 2020 [cited by applicant]
CN 105384820A · 2016 [cited by applicant]
CN 107427578A · 2017 [cited by applicant]
CN 107709552A · 2018 [cited by applicant]
CN 108300698A · 2018 [cited by applicant]
JP 2018510881A · 2018 [cited by applicant]
KR 1020180008862A · 2018 [cited by applicant]
WO 9849268A1 · 1998 [cited by applicant]
WO 2016160602A2 · 2016 [cited by applicant]
WO 2016201304A1 · 2016 [cited by applicant]
WO 2018064594A2 · 2018 [cited by applicant]
WO 2018098306A1 · 2018 [cited by applicant]
WO 2018129346A1 · 2018 [cited by applicant]
WO 2018165291A1 · 2018 [cited by applicant]
WO 2019152513A1 · 2019 [cited by applicant]
WO 2019226708A4 · 2019 [cited by applicant]
WO 2020028654A1 · 2020 [cited by applicant]
WO 2020028656A1 · 2020 [cited by applicant]
WO 2020091869A1 · 2020 [cited by applicant]
Yu et al., Synthetic fusion protein design and applications Biotech. Adv., vol. 33, 155-164. [cited by examiner]
Chen et al., Fusion protein linkers: Property, design and functionality , Advanced Drug Delivery Reviews 65 (2013) 1357-1369. [cited by examiner]
Notice of Allowability for U.S. Appl. No. 17/341,098, filed Mar. 8, 2023; pp. 1-5. [cited by examiner]
Decision of Refusal received for Japanese Patent Application Serial No. 2020-556293 dated Jul. 22, 2022, 4 pages. (Including English Translation). [cited by applicant]
Notice of Final Rejection received for Korean Patent Application Serial No. 10-2020-7028888 dated Jul. 14, 2023, 8 pages. (Including English Translation). [cited by applicant]
Notice of Allowance received for Canadian Patent Application Serial No. 3,092,709 dated Jul. 4, 2023, 1 page. [cited by applicant]
Examination Report received for Australian Patent Application Serial No. 2019371340 dated Nov. 23, 2021, 3 pages. [cited by applicant]
Examination Report No. 2 received for Australian Patent Application Serial No. 2019371340 dated Jan. 14, 2022, 5 pages. [cited by applicant]
Notice of Acceptance received for Australian Patent Application Serial No. 2019371340 dated Feb. 18, 2022, 3 pages. [cited by applicant]
Extended European Search Report received for EP Patent Application Serial No. 19879733.4 dated Oct. 29, 2021, 8 pages. [cited by applicant]
International Search Report and Written Opinion received for PCT Application Serial No. PCT/US2019/044691, dated Nov. 15, 2019, 14 pages. [cited by applicant]
Liu et al., “Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent anti-tumor activity”, Leukemia, Feb. 2018, vol. 32, No. 2, pp. 520-531. [cited by applicant]
Herberman et al., “Natural Killer Cells: Their Roles in Defenses Against Disease”, Science, 1981, vol. 214, pp. 24-30. [cited by applicant]
Gong et al., “Characterization of a Human Cell Line (NK-92) With Phenotypical and Functional Characteristics of Activated Natural Killer Cells”, Leukemia, 1994, vol. 8, No. 4, pp. 652-658. [cited by applicant]
Wang et al., “CD19: A Biomarkerfor B Cell Development, Lymphoma Diagnosis and Therapy”, Experimental Hematology & Oncology, 2012, vol. 1, No. 36, pp. 1-7. [cited by applicant]
Haynes et al., “Redirecting Mouse CTL Against Colon Carcinoma: Superior Signaling Efficacy of Single-Chain Variable Domain Chimeras Containing TCR-zeta vs Fc epsilon RI-gamma”, The Journal of Immunology, 2001, vol. 166,… [cited by applicant]
Cartellieri et al., “Chimeric Antigen Receptor-Engineered T Cells for Immunotherapy of Cancer”, Journal of Biomedicine and Biotechnology, 2010, vol. 2010, pp. 1-14. [cited by applicant]
Konstantinidis et al., “Targeting IL-2 to the End oplasmic Reticulum Confines Auto crine Growth Stimulation to NK-92 Cells”, Experimental Hematology, 2005, vol. 33, pp. 159-164. [cited by applicant]
Sarcia-Sanchez et al., “Cytosine Deaminase Adenoviral Vector and 5-fluorocytosine Selectively Reduce Breast Cancer Cells 1 Million-Fold When They Contaminate Hemalopoielic Cells: A Potential Purging Method for Aulologou… [cited by applicant]
Stasi et al., “Inducible Apoptosis as a Safety Switch for Adoptive Cell Therapy”, The New England journal of Medicine, 2011, vol. 365, No. 18, pp. 1673-1683. [cited by applicant]
Morgan Richard A, “Live and Let Die: A New Suicide Gene Therapy Moves to the Clinic”, Molecular Therapy, Jan. 2012, vol. 20, No. 1, pp. 11-13. [cited by applicant]
Klingemann et al., “Interleukin-6 does not support interleukin-2 induced generation of human lymphokine-activated killer cells”, Cancer Immunology, Immunotherapy, 1991, vol. 33, pp. 395-397. [cited by applicant]
Oelsner et al., “Continuously Expanding CAR NK-92 Cells Display Selective Cytotoxicity Against B-cell Leukemia and Lymphoma”, Cytotherapy, 2016, vol. 19, No. 2, pp. 1-15. [cited by applicant]
Touati et al., “A Suicide Gene Therapy Combining the Improvement of Cyclophosphamide Tumor Cytotoxicity and the Development of an Anti-Tumor Immune Response”, Current Gene Therapy, 2014, vol. 14, pp. 236-246. [cited by applicant]
Boissel et al., “Transfection with mRNA for CD19 specific chimeric antigen receptor restores NK cell mediated killing of CLL cells”, Leukemia Research, 2009, vol. 33, pp. 1255-1259. [cited by applicant]
Boissel et al., “Comparison of mRNA and lentiviral based transfection of natural killer cells with chimeric antigen receptors recognizing lymphoid antigens”, Leukemia & Lymphoma, May 2012, vol. 53, No. 5, pp. 958-965. [cited by applicant]
Boissel et al., “Relargeting NK-92 cells by means of CD19- and CD20-specific chimeric antigen receptors compares favorably with antibody-dependent cellular cytotoxicity”, Oncolmmunology, 2013, vol. 2, No. 10, 9 pages. [cited by applicant]
Romanski et al., “CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cellmalignancies”, J Cell Mal Med, 2016, vol. 20, No. 7, pp. 1287-1294. [cited by applicant]
Suck et al., “NK-92: an ‘off-the-shelf therapeutic’ for adoptive natural killer cell-based cancer immunotherapy”, Cancer Immunol Immunother, 2015, vol. 65, No. 4, 8 pages. [cited by applicant]
Non-Final Rejection received for U.S. Appl. No. 16/529,251 dated Mar. 23, 2020, 16 pages. [cited by applicant]
Notice of Allowance received for U.S. Appl. No. 16/529,251 dated Jul. 1, 2020, 12 pages. [cited by applicant]
Notice of Allowance received for U.S. Appl. No. 16/529,251 dated Jul. 6, 2020, 30 pages. [cited by applicant]
First Examination Report received for Israel Patent Application Serial No. 277413 dated Jan. 15, 2022, 12 pages. (Including English Translation). [cited by applicant]
Office Action received for Canadian Patent Application Serial No. 3092709 dated Sep. 16, 2021, 11 pages. [cited by applicant]
International Preliminary Report on Patentability Chapter I received for PCT Application Serial No. PCT/US2019/044691, dated May 14, 2021, 9 pages. [cited by applicant]
Notice of Allowance received for Canadian Patent Application Serial No. 3,092,709 dated Sep. 27, 2022, 1 page. [cited by applicant]
Office Action received for Israel Patent Application Serial No. 277413 dated Nov. 24, 2022, 9 pages. (Including English Translation). [cited by applicant]
Request for the Submission of an Opinion received for the Korean Patent Application Serial No. 10-2020-7028888 dated Jan. 27, 2023, 9 pages. (Including English Translation). [cited by applicant]
Reconsideration Examination Report received for the Japanese Patent Application Serial No. 2020-556293 dated Feb. 21, 2023, 9 pages. (Including English Translation). [cited by applicant]
Re-Transference to the Board of Appeal Trial received for the Japanese Patent Application Serial No. 2020-556293 dated Feb. 24, 2023, 2 pages. (Including English Translation). [cited by applicant]
First Office Action issued for CN Application No. 201980023744.6 dated Aug. 26, 2023, 17 pages (including English Translation). [cited by applicant]
First Office Action issued for JP Application No. 2022-181212 dated Oct. 24, 2023, 06 pages (including English. [cited by applicant]
Second Notice of Final Rejection issued for KR Application No. 10-2020-7028888 dated Oct. 31, 2023, 06 pages (including English Translation). [cited by applicant]
First Office Action issued for KR Application No. 10-2023-7035191 dated Nov. 27, 2023, 08 pages (including English Translation). [cited by applicant]
Notice of Reasons for Refusal received for Japanese Patent Application Serial No. 2020-556293 dated Dec. 24, 2021, 6 pages. (Including English Translation). [cited by applicant]
Second Office Action issued for CN Application No. 201980023744.6 dated Jun. 28, 2024, 20 pages (including English Translation). [cited by applicant]