IP Library › Granted Patent US 12,188,005
Granted Patent B2
US 12,188,005 · App. 16/985,797 · Granted Jan 7, 2025

NK cells with an increased antibody-dependent cellular toxicity (ADCC) against tumors

Inventors: Richard W. Childs (Bethesda, MD); Mattias C. V. Carlsten (Bethesda, MD)
Assignee: The United States of America, as represented by the Secretary, Department of Health and Human Services
C07K16/2896A61K39/39558A61K39/4613A61K39/464402A61K39/464421A61K45/06A61P35/00C07K14/70535C07K14/7158C07K16/2887C12N5/0646A61K2039/505A61K2039/545A61K2039/57A61K2039/572A61K2239/48C07K2317/21C07K2317/24C07K2317/54C07K2317/55C07K2317/732C12N2501/21C12N2501/2302C12N2501/599C12N2510/00
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Quick Facts
Patent No.
US 12,188,005
App. No.
16/985,797
Granted
Jan 7, 2025
Kind
B2
Abstract

Disclosed herein are modified NK cells, compositions comprising modified NK cells, and methods for treating a tumor or hyperproliferative disease in a subject. In some embodiments, the modified NK cells include NK cells including a heterologous nucleic acid molecule encoding a CD16 protein comprising a valine at amino acid position 158 (CD16-V158), a heterologous nucleic acid molecule encoding a CCR7 protein, or both. In some embodiments, methods include treating a subject with a tumor by administering a composition comprising an anti-cancer monoclonal antibody and administering a composition comprising the modified NK cells to the subject. Also disclosed are methods of making modified NK cells by obtaining a population of NK cells from a subject and transfecting the population of NK cells with a heterologous nucleic acid molecule encoding CD16-V158, a heterologous nucleic acid molecule encoding a CCR7 protein, or both.

Claims (37)

1. A method of treating a subject with multiple myeloma, comprising:

obtaining a population of natural killer (NK) cells from the subject or a donor;

transfecting the population of NK cells with:

a heterologous nucleic acid molecule encoding a CD16 protein comprising a valine at amino acid position 158 of the mature CD16 protein; and

a heterologous nucleic acid molecule encoding a CCR7 protein,

thereby producing a population of modified NK cells;

blocking CD38 surface antigen of the population of modified NK cells by treating with a Fab or F(ab)2 fragment of an anti-CD38 monoclonal antibody to produce a population of CD38-blocked modified NK cells;

administering a composition comprising a monoclonal antibody to the subject, wherein the monoclonal antibody binds to cancer cells expressing CD38; and

administering a composition comprising the CD38-blocked modified NK cells to the subject.

2. The method of claim 1 , wherein the population of NK cells is expanded in vitro prior to transfection with the heterologous nucleic acid molecule.

3. The method of claim 1 , wherein:

the nucleic acid molecule encoding the CD16 protein comprising a valine at amino acid position 158 of the mature CD16 protein encodes a protein comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 6, wherein the valine at amino acid position 158 of the mature CD16 protein corresponds to amino acid 212 of SEQ ID NO: 4 or amino acid 176 of SEQ ID NO: 6; and/or

the nucleic acid molecule encoding the CD16 protein comprising a valine at amino acid position 158 of the mature CD16 protein comprises the nucleic acid sequence of SEQ ID NO: 3 or SEQ ID NO: 5.

4. The method of claim 1 , wherein:

the nucleic acid molecule encoding the CCR7 protein encodes a protein comprising the amino acid sequence of SEQ ID NO: 9; and/or

the nucleic acid molecule encoding the CCR7 protein comprises the nucleic acid sequence of SEQ ID NO: 8 or SEQ ID NO: 10.

5. The method of claim 1 , wherein the monoclonal antibody is daratumumab.

6. The method of claim 1 , wherein the composition comprising the CD38-blocked modified NK cells is administered to the subject after administering the composition comprising the monoclonal antibody to the subject.

7. The method of claim 6 , wherein the composition comprising the CD38-blocked modified NK cells is administered to the subject about 1-8 hours after the composition comprising the monoclonal antibody is administered to the subject.

8. A method of treating a subject with lymphoma, comprising:

obtaining a population of natural killer (NK) cells from the subject or a donor;

transfecting the population of NK cells with:

a heterologous nucleic acid molecule encoding a CD16 protein comprising a valine at amino acid position 158 of the mature CD16 protein; and

a heterologous nucleic acid molecule encoding a CCR7 protein,

thereby producing a population of modified NK cells;

administering a composition comprising a monoclonal antibody to the subject, wherein the monoclonal antibody binds to cancer cells expressing CD20; and

administering a composition comprising the modified NK cells to the subject.

9. The method of claim 8 , wherein the population of NK cells is expanded in vitro prior to transfection with the heterologous nucleic acid molecule.

10. The method of claim 8 , wherein:

the nucleic acid molecule encoding the CD16 protein comprising a valine at amino acid position 158 of the mature CD16 protein encodes a protein comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 6, wherein the valine at amino acid position 158 of the mature CD16 protein corresponds to amino acid 212 of SEQ ID NO: 4 or amino acid 176 of SEQ ID NO: 6; and/or

the nucleic acid molecule encoding the CD16 protein comprising a valine at amino acid position 158 of the mature CD16 protein comprises the nucleic acid sequence of SEQ ID NO: 3 or SEQ ID NO: 5.

11. The method of claim 8 , wherein:

the nucleic acid molecule encoding the CCR7 protein encodes a protein comprising the amino acid sequence of SEQ ID NO: 9; and/or

the nucleic acid molecule encoding the CCR7 protein comprises the nucleic acid sequence of SEQ ID NO: 8 or SEQ ID NO: 10.

12. The method of claim 8 , wherein the monoclonal antibody is rituximab, ofatumumab, veltuzumab, ibritumomab tiuxetan, obinutuzumab, ublituomab, tositumomab, or ocaratuzumab.

13. The method of claim 8 , wherein the composition comprising the modified NK cells is administered to the subject after administering the composition comprising the monoclonal antibody to the subject.

14. The method of claim 13 , wherein the composition comprising the modified NK cells is administered to the subject about 1-8 hours after the composition comprising the monoclonal antibody is administered to the subject.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 5, 2020
From: CHILDS, RICHARD W.; CARLSTEN, MATTIAS C.V.
To: THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES
Reel/Frame 053410/0626 →
Continuity (3)
Division 15525921
Provisional Application 62079975 · Nov 14, 2014
Related Publication 20200360436A1 · Nov 19, 2020
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