Granted Patent
B2
US 12,534,536 · App. 17/008,506 · Granted Jan 27, 2026
Natural killer cells expressing a chimeric antigen receptor that binds CD38
Assignee:
ONK THERAPEUTICS LIMITED
C07K16/2896A61K38/177A61K40/15A61K40/31A61K40/36A61K40/4222A61P35/00C12N5/0646A61K2035/124A61K2039/505A61K2239/38A61K2239/46A61K2239/48C07K2317/56C07K2317/565C07K2319/70
View Patent ↗
Loading inventors, assignments & file history…
Abstract
Disclosed herein are engineered natural killer cells that have been modified to express chimeric antigen receptors (CARs). The cells optionally contain other modifications that improve tumor specific cytotoxicity and homing to tumor sites. Also contemplated are methods for using the engineered natural killer cells to treat patients with cancer.
Claims (10)
1 . An isolated mammalian natural killer (NK) cell that expresses a chimeric antigen receptor (CAR) that binds CD38, wherein the CAR comprises:
i) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 23 or 28; and
ii) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 1 or 7.
2 . The isolated mammalian NK cell of claim 1 , wherein the CAR comprises a co-stimulatory domain comprising the amino acid sequence of SEQ ID NO: 41, SEQ ID NO: 42, or SEQ ID NO: 43.
3 . The isolated mammalian NK cell of claim 1 , further expressing a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) variant that has increased affinity for a TRAIL receptor as compared to wildtype TRAIL.
4 . The isolated mammalian NK cell of claim 3 , wherein the TRAIL variant has an increased affinity for DR4 and/or DR5 as compared to wildtype TRAIL.
5 . The isolated mammalian NK cell of claim 3 , wherein the TRAIL variant has at least a 25% increase in affinity for DR4 and/or DR5 as compared to wildtype TRAIL.
6 . The isolated mammalian NK cell of claim 3 , wherein the TRAIL variant comprises an amino acid substitution selected from the group consisting of D269H, S159R, E195R, G131R, N199R, and any combination thereof.
7 . The isolated mammalian NK cell of claim 3 , wherein a sequence encoding the CAR and/or a sequence encoding the TRAIL variant is integrated into the genome of the NK cell.
8 . The isolated mammalian NK cell of claim 3 , wherein a sequence encoding the CAR is integrated into the genome of the NK cell.
Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Nov 14, 2025
From: NATIONAL UNIVERSITY OF IRELAND, GALWAY
To: ONKIMMUNE LIMITED
Reel/Frame 072906/0657 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Nov 14, 2025
From: O'DWYER, MICHAEL EAMON PETER
To: NATIONAL UNIVERSITY OF IRELAND, GALWAY
Reel/Frame 072906/0661 →
CHANGE OF NAME
Recorded Nov 14, 2025
From: ONKIMMUNE LIMITED
To: ONK THERAPEUTICS LIMITED
Reel/Frame 072906/0684 →
Continuity (3)
Provisional Application
62432302
· Dec 9, 2016
References Cited (72)
US 8207304B2
· Nash
· 2012
[cited by examiner]
US 20180344768A1
· O'Dwyer et al.
· 2018
[cited by applicant]
US 20190321402A1
· O'Dwyer et al.
· 2019
[cited by applicant]
WO WO2004074320A2
· 2004
[cited by examiner]
WO WO2006099875A1
· 2006
[cited by applicant]
WO WO2009077857A2
· 2009
[cited by applicant]
WO WO2011154453A1
· 2011
[cited by examiner]
WO WO2016109668A1
· 2016
[cited by applicant]
Tettamanti (British J. Haematology, 2013, vol. 161, p. 389-401).
[cited by examiner]
Glienke (Frontiers in Pharm., Feb. 12, 2015, vol. 6, Article 21, p. 1-7).
[cited by examiner]
Chu (Leukemia, 2014, vol. 28, No. 4, p. 917-927).
[cited by examiner]
Chu (Cancer Immunol. Res., Apr. 2015, vol. 3, No. 4, p. 333-344).
[cited by examiner]
Rezvani (Mol. Therapy, Aug. 2017, vol. 25, No. 8, p. 1769-1781).
[cited by examiner]
Mehta (Frontiers in Immunol., Feb. 2018, vol. 9, Article 283, p. 1-12).
[cited by examiner]
Hu (ACTA Pharmacologica Sinica, 2018, vol. 39, p. 167-176).
[cited by examiner]
Van de Donk (Blood, Feb. 11, 2016, vol. 127, No. 6, p. 681-695.
[cited by examiner]
Drent (Haematologica, Feb. 8, 2016, vol. 101, No. 5, p. 616-625).
[cited by examiner]
Lokhorst (Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N. Engl. J. Med. 2015, 373, 1207-1219).
[cited by examiner]
Deckert (SAR650984, a novel humanized CD38-targeting antibody, demonstrates potent antitumor activity in models of multiple myeloma and other CD38+ hematologic malignancies. Clin. Cancer Res.2014, 20, 4574-4583).
[cited by examiner]
Krejcik (“Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma”. Blood, 2016, vol. 128, p. 384-394).
[cited by examiner]
Drent (“A Rational Strategy for Reducing On-Target Off-Tumor Effects of CD38-Chimeric Antigen Receptors by Affinity Optimization”. Mol. Ther., 2017, vol. 25, p. 1946-1958).
[cited by examiner]
Malavasi (Blood, “CD38 and antibody therapy: What can basic science add?”, 2016, vol. 128, 36).
[cited by examiner]
Harrer (Human Gene Therapy, 2018, vol. 29, No. 5, p. 547-558).
[cited by examiner]
Liu (Leukemia, 2018, vol. 32, p. 520-531).
[cited by examiner]
Hudecek (Clin. Cancer Res., 2013, vol. 19, p. 3153-3164).
[cited by examiner]
Caruso (Cancer Res., 2015, vol. 75, p. 3505-3518).
[cited by examiner]
Liu (Cancer Res., 2015, vol. 75, p. 3596-3607).
[cited by examiner]
Bostrom, J., et al., “Variants of the Antibody Herceptin That Interact with HER2 and VEGF at the Antigen Binding Site,”
[cited by applicant]
Caruso, H., et al., “Tuning Sensitivity of CAR to EGFR Density Limits Recognition of Normal Tissue While Maintaining Potent Antitumor Activity,”
[cited by applicant]
Casneuf, T., et al., “Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma,”
[cited by applicant]
Chu, J., et al., “CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma,”
[cited by applicant]
Chu, Y., et al., “Targeting CD20+ Aggressive B-cell Non-Hodgkin Lymphoma by Anti-CD20 CAR mRNA-Modified Expanded Natural Killer Cells In Vitro and in NSG Mice,”
[cited by applicant]
Deckert, J., et al., “SAR650984, a novel humanized CD38-targeting antibody, demonstrates potent antitumor activity in models of multiple myeloma and other CD38
[cited by applicant]
Drent, E., et al., “Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma,”
[cited by applicant]
Drent, E., et al., “A Rational Strategy for Reducing On-Target Off-Tumor Effects of CD38-Chimeric Antigen Receptors by Affinity Optimization,”
[cited by applicant]
Feng, X., et al., “The proteasome inhibitor bortezomib disrupts tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and natural killer (NK) cell killing of TRAIL receptor-positive multiple myeloma…
[cited by applicant]
Glienke, W., et al., “Advantages and applications of CAR-expressing natural killer cells,”
[cited by applicant]
Groth, A., et al., “New Gene-Immunotherapy Combining TRAIL-Lymphocytes and EpCAMxCD3 Bispecific Antibody for Tumor Targeting,”
[cited by applicant]
Harrer, D.C., et al., “Chimeric Antigen Receptors in Different Cell Types: New Vehicles Join the Race,”
[cited by applicant]
Heo, T-H., et al., “Potential therapeutic implications of IL-6/IL-6R/gp130-targeting agents in breast cancer,”
[cited by applicant]
Hu, Y., et al., “Chimeric antigen receptor (CAR)-transduced natural killer cells in tumor immunotherapy,”
[cited by applicant]
Hudecek, M., et al., “Receptor Affinity and Extracellular Domain Modifications Affect Tumor Recognition by ROR1-Specific Chimeric Antigen Receptor T Cells,”
[cited by applicant]
Kim, J.H., et al., “High Cleavage Efficiency of a 2A Peptide Derived from Porcine Teschovirus-1 in Human Cell Lines, Zebrafish and Mice,”
[cited by applicant]
Klingemann, H., “Are natural killer cells superior CAR drivers?”
[cited by applicant]
Klingemann, H., et al., “Natural Killer Cells for Immunotherapy—Advantages of the NK-92 Cell Line over Blood NK Cells,”
[cited by applicant]
Kobayashi, E., et al., “A chimeric antigen receptor for TRAIL-receptor 1 induces apoptosis in various types of tumor cells,”
[cited by applicant]
Krejcik, J., et al., “Daratumumab depletes CD38
[cited by applicant]
Lamdan, H., et al., “Affinity maturation and fine functional mapping of an antibody fragment against a novel neutralizing epitope on human vascular endothelial growth factor,”
[cited by applicant]
Liu, X., et al., “Affinity-Tuned ErbB2 or EGFR Chimeric Antigen Receptor T Cells Exhibit an Increased Therapeutic Index against Tumors in Mice,”
[cited by applicant]
Liu, E., et al., “Cord blood NK cells engineered to express IL-15 and a CD 19-targeted CAR show long-term persistence and potent anti-tumor activity,”
[cited by applicant]
Lokhorst, H., et al., “Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma,”
[cited by applicant]
Malavasi, F., et al., “CD38 and antibody therapy: What can basic science add?”
[cited by applicant]
Mehta, R.S., et al., “Chimeric Antigen Receptor Expressing Natural Killer Cells for the Immunotherapy of Cancer,”
[cited by applicant]
Raposo, B., et al., “Epitope-Specific antibody response is controlled by immunoglobulin Vh polymorphisms,”
[cited by applicant]
Rezvani, K., et al., “Engineering Natural Killer Cells for Cancer Immunotherapy,”
[cited by applicant]
Senn, B.M., et al., “Combinatorial immunoglobulin light chain variability creates sufficient B cell diversity to mount protective antibody responses against pathogen infections,”
[cited by applicant]
Stikvoort, A., et al., “CD38 Specific Chimeric Antigen Receptor KHYG-1 Natural Killer Cells: A Potential ‘Off the Shelf’ Therapy for Multiple Myeloma,” ASH Annual Meeting Poster Abstract and Poster, Session 653, Dec. 2,…
[cited by applicant]
Tettamanti, S., et al., “Targeting of acute myeloid leukaemia by cytokine-induced killer cells redirected with a novel CD123-specific chimeric antigen receptor,”
[cited by applicant]
Truneh, A., et al., “Temperature-sensitive Differential Affinity of TRAIL for Its Receptors,”
[cited by applicant]
Van De Donk, N.W.C.J., et al., “Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma,”
[cited by applicant]
Vink, T., et al., “A simple, robust and highly efficient transient expression system for producing antibodies,”
[cited by applicant]
Wang, Y., et al. “Fratricide of NK Cells in Daratumumab Therapy for Multiple Myeloma Overcome by Ex Vivo Expanded Autologous NK Cells,”
[cited by applicant]
Yang, S., et al., “Development of Retargeted CD38-Specific NK-92 Cell Line for Potential Anti-Myeloma Immunotherapy,”
[cited by applicant]
Yoshinaga, K., et al., “Ig L-Chain Shuffling for Affinity Maturation of Phage Library-derived Human Anti-human MCP-1 Antibody Blocking its Chemotactic Activity,”
[cited by applicant]
Zhao, Z., et al., “Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells,”
[cited by applicant]
Dahlberg, C.I.M., et al., “Natural Killer Cell-Based Therapies Targeting Cancer: Possible Strategies to Gain and Sustain Anti-Tumor Activity,” Front. Immunol. 6:605, Frontiers Media S.A., Switzerland (Nov. 2015).
[cited by applicant]
Daratumumab Compound Summary, National Library of Medicine, PubChem Reference Collection SID 481101587, accessed at http://pubchem.ncbi.nlm.nih.gov/compound/Daratumumab on Aug. 14, 2024 (11 pages).
[cited by applicant]