Granted Patent
B2
US 12,584,138 · App. 17/446,024 · Granted Mar 24, 2026
Quadricistronic system comprising a homing receptor and chimeric antigen receptor for stable genetic modification of cellular immunotherapies
Inventors:
Hans G. Klingemann (Culver City, CA); Laurent H. Boissel (Culver City, CA); Nathan T. Schomer (Culver City, CA)
Assignee:
ImmunityBio, Inc.
C12N15/625A61K9/0029A61K40/15A61K40/31A61K40/4211A61K40/4219A61P35/02C07K14/5443C07K14/55C07K14/7051C07K14/70553C07K14/70564C07K14/70596C07K14/82C12N5/0646C12N15/85A61K2239/31A61K2239/38A61K2239/48
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Abstract
Provided herein are modified NK-92® cells comprising one or more nucleic acids encoding i) a homing receptor, ii) Antigen Binding Protein (ABP) or Chimeric Antigen Recpetor (CAR) that specifically binds to a target antigen, iii) an Fc Receptor such as CD16 or CD16-158V, and/or iv) a cytokine, wherein the nucleic acid sequence is operably linked to a promoter. Further provided herein are modified NK-92® cells comprising one or more nucleic acids encoding i) IL-12 and/or TGF-beta trap, ii) an Antigen Binding Protein (ABP) or Chimeric Antigen Recpetor (CAR) that specifically binds to a target antigen, iii) an Fc Receptor such as CD16 or CD16-158V, and/or iv) a cytokine, wherein the nucleic acid sequence is operably linked to a promoter. Also provided are compositions and kits comprising the modified NK-92® cells, as well as methods of treating cancer using the modified cells.
Claims (22)
1 . A recombinantly modified natural killer (NK)-92 cell stably transfected with a nucleic acid:
wherein the NK-92 cell has American Type Culture Collection (ATCC) Deposit No. CRL-2407;
wherein the nucleic acid encodes an anti-programmed cell death 1 ligand 1 (PD-L1) chimeric antigen receptor (CAR) having the amino acid sequence of SEQ ID NO:69, an Fc receptor, a CCR7 homing receptor, and a cytokine; and
wherein the recombinant cell expresses the anti PD-L1 CAR and the Fc receptor on a cell surface of the recombinant cell;
wherein the Fc receptor is CD16;
wherein the cytokine is IL-12; and
wherein surface expression of the CCR7 enables the recombinant NK-92 cell to migrate towards CCL21 and/or CCL19.
2 . The recombinant NK-92 cell of claim 1 wherein the Fc receptor has the amino acid sequence of SEQ ID NO:12.
3 . The recombinant NK-92 cell of claim 2 wherein the amino acid sequence of SEQ ID NO: 12 has a F158V mutation.
4 . The recombinant NK-92 cell of claim 1 wherein the cytokine is a single chain IL-12 having the amino acid sequence of SEQ ID NO:61.
5 . The recombinant NK-92 cell of claim 1 wherein the cytokine is a heterodimeric IL-12 with a p35 component having the amino acid sequence of SEQ ID NO: 58 and a p40 component having the amino acid sequence of SEQ ID NO:60.
6 . A recombinantly modified NK92 cell stably transfected with a recombinant nucleic acid and expressing from the recombinant nucleic acid an anti-programmed cell death 1 ligand 1 (PD-L1) chimeric antigen receptor (CAR) having the amino acid sequence of SEQ ID NO:69, an Fc receptor, a CCR7 homing receptor, and a cytokine, wherein the anti PD-L1 CAR and the Fc receptor are expressed on a cell surface of the recombinantly modified NK92, and wherein the NK-92 cell has ATCC Deposit No. CRL-2407;
wherein the Fc receptor is CD16;
wherein the cytokine is IL-12; and
wherein surface expression of the CCR7 enables the recombinant NK-92 cell to migrate towards CCL21 and/or CCL19.
7 . The recombinant NK-92 cell of claim 6 , wherein the Fc receptor has the amino acid sequence of SEQ ID NO: 12, optionally having a F158V mutation.
8 . The recombinant NK-92 cell of claim 6 , wherein the cytokine is a single chain IL-12 having the amino acid sequence of SEQ ID NO:61.
9 . The recombinant NK-92 cell of claim 6 , wherein the cytokine is a heterodimeric IL-12 with a p35 component having the amino acid sequence of SEQ ID NO:58 and a p40 component having the amino acid sequence of SEQ ID NO:60.
10 . A method of treating a cancer in a subject, comprising administering to the subject a therapeutically effective amount of a composition to the subject, the composition comprising a plurality of recombinant modified NK-92 cells according to claim 1 , and where the cancer has cancer cells expressing PD-L1.
11 . The method of claim 10 , wherein from 1×10 3 to 1×10 10 , per m 2 of the recombinant NK-92 cells are administered to the subject.
12 . The method of claim 10 , wherein the recombinant NK-92 cells are administered parenterally, intravenously, peritumorally, intratumorally, or by infusion.
13 . The method of claim 10 , wherein the subject receives a further therapy selected from the group consisting of radiotherapy, surgery, hormone therapy, and immunotherapy.
Assignments (2)
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 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Oct 12, 2021
From: KLINGEMANN, HANS G.; BOISSEL, LAURENT H.; SCHOMER, NATHAN T.
To: IMMUNITYBIO, INC.
Reel/Frame 057762/0733 →
Continuity (7)
Provisional Application
62713323
· Aug 1, 2018
Provisional Application
62713278
· Aug 1, 2018
Provisional Application
62713310
· Aug 1, 2018
Provisional Application
62713264
· Aug 1, 2018
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