Blocking CD38 using anti-CD38 F(ab′)2 to protect NK cells
Provided herein are methods of inhibiting growth or proliferation of cells expressing CD38 by contacting the CD38-expressing cells with 1) NK cells bound to an anti-CD38 F(ab′) 2 fragment and 2) an anti-CD38 antibody, in either order or simultaneously. Also provided herein are methods of treating or inhibiting a hyperproliferative disorder or an autoimmune disorder in a subject by administering to the subject 1) NK cells bound to an anti-CD38 F(ab′) 2 fragment and 2) an anti-CD38 antibody, in either order or simultaneously.
1. A method of inhibiting growth or proliferation of CD38-expressing cells, comprising:
contacting a population of natural killer (NK) cells with a F(ab′) 2 fragment of a first anti-CD38 antibody, thereby producing a population of NK cells bound to the F(ab′) 2 fragment of the first anti-CD38 antibody; and
contacting a population of CD38-expressing cells with a second anti-CD38 antibody and the population of NK cells bound to the F(ab′) 2 fragment of the first anti-CD38 antibody, thereby inhibiting growth or proliferation of the CD38-expressing cells.
2. The method of claim 1 , wherein the F(ab′) 2 fragment of the first anti-CD38 antibody comprises the F(ab′) 2 fragment of a human anti-CD38 antibody or a humanized anti-CD38 antibody and/or wherein the second anti-CD38 antibody comprises a human anti-CD38 antibody, a humanized anti-CD38 antibody, or a fragment thereof.
3. The method of claim 2 , wherein the first anti-CD38 antibody and/or the second anti-CD38 antibody comprise daratumumab or SAR650984.
4. The method of claim 1 , wherein the first anti-CD38 antibody and the second anti-CD38 antibody are the same.
5. The method of claim 1 , wherein the population of NK cells comprises CD16 positive and/or CD56 positive NK cells.
6. The method of claim 1 , wherein contacting the population of NK cells with the F(ab′) 2 fragment of the first anti-CD38 antibody occurs in vitro or ex vivo and/or contacting the population of CD38-expressing cells with the second anti-CD38 antibody and the population of NK cells bound to the ab′) 2 fragment of the first anti-CD38 antibody occurs in vivo, in vitro, or ex vivo.
7. The method of claim 6 , further comprising expanding the population of NK cells in vitro or ex vivo prior to contacting the population of NK cells with the F(ab′) 2 fragment of the first anti-CD38 antibody.
8. The method of claim 6 , wherein contacting the population of CD38-expressing cells with the second anti-CD38 antibody and the population of NK cells bound to the F(ab′) 2 fragment of the first anti-CD38 antibody comprises administering the second anti-CD38 antibody and the population of NK cells bound to the F(ab′) 2 fragment of the first anti-CD38 antibody to a subject with a disorder comprising CD38-expressing cells.
9. The method of claim 8 , wherein administering the population of NK cells bound to the F(ab′) 2 fragment of the first anti-CD38 antibody to the subject occurs before, after, or substantially simultaneously with administering the second anti-CD38 antibody to the subject.
10. The method of claim 1 , wherein the CD38-expressing cells comprise CD38-expressing cancer cells or CD38-expressing T-cells, B-cells, NK cells, or plasma cells.
11. The method of claim 10 , wherein the CD38-expressing cancer cells comprise solid tumor cells or hematological malignancy cells.
12. The method of claim 11 , wherein the hematological malignancy cells comprise multiple myeloma cells, acute lymphocytic leukemia cells, acute myeloid leukemia cells, chronic lymphocytic leukemia cells, chronic myeloid leukemia cells, Hodgkin's lymphoma cells, non-Hodgkin's lymphoma cells, T-LGL leukemia cells, NK cell leukemia cells, or hairy cell leukemia cells.
13. A method of treating or inhibiting a hyperproliferative disorder or an autoimmune disorder in a subject, comprising:
administering to the subject an effective amount of a population of natural killer (NK) cells bound to a F(ab′) 2 fragment of a first anti-CD38 antibody; and
administering to the subject an effective amount of a second anti-CD38 antibody, wherein the second anti-CD38 antibody is administered to the subject before, after, or substantially simultaneously with administering the population of natural killer (NK) cells bound to a F(ab′) 2 fragment of a first anti-CD38 antibody, thereby treating or inhibiting the hyperproliferative disorder.
14. The method of claim 13 , wherein the F(ab′) 2 fragment of the first anti-CD38 antibody comprises the F(ab′) 2 fragment of a human anti-CD38 antibody or a humanized anti-CD38 antibody and/or wherein the second anti-CD38 antibody comprises a human anti-CD38 antibody, a humanized anti-CD38 antibody, or a fragment thereof.
15. The method of claim 14 , wherein the first anti-CD38 antibody and/or the second anti-CD38 antibody comprise daratumumab or SAR650984.
16. The method of claim 13 , wherein the first anti-CD38 antibody and the second anti-CD38 antibody are the same.
17. The method of claim 13 , wherein the population of NK cells comprises CD16 positive and/or CD56 positive NK cells.
18. The method of claim 13 , wherein the population of NK cells bound to the F(ab′) 2 fragment of the first anti-CD38 antibody is produced in vitro or ex vivo by contacting a population of natural killer (NK) cells with the F(ab′) 2 fragment of the first anti-CD38 antibody.
19. The method of claim 18 , further comprising expanding the population of NK cells in vitro or ex vivo prior to contacting the population of NK cells with the F(ab′) 2 fragment of the first anti-CD38 antibody.
20. The method of claim 13 , wherein the population of NK cells comprises autologous NK cells or allogeneic NK cells.
21. The method of claim 13 , wherein the hyperproliferative disorder comprises a solid tumor or a hematological malignancy.
22. The method of claim 21 , wherein the hematological malignancy comprises multiple myeloma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma.
23. The method of claim 21 , wherein the cells of the solid tumor or the hematological malignancy express CD38.
24. A method of treating or inhibiting a hyperproliferative disorder in a subject comprising:
contacting a population of NK cells isolated from the subject with a F(ab′) 2 fragment of a first anti-CD38 antibody to produce a population of NK cells bound to the F(ab′) 2 fragment of the first anti-CD38 antibody;
administering to the subject a therapeutically effective amount of a second anti-CD38 antibody or fragment thereof; and
administering to the subject the population of NK cells bound to the F(ab′) 2 fragment of the first anti-CD38 antibody, thereby treating or inhibiting the hyperproliferative disorder.
25. A pharmaceutical composition comprising a population of natural killer (NK) cells bound to a F(ab′) 2 fragment of an anti-CD38 antibody and a pharmaceutically acceptable carrier.
26. The pharmaceutical composition of claim 25 , wherein the F(ab′) 2 fragment of the anti-CD38 antibody comprises a F(ab′) 2 fragment of a human anti-CD38 antibody or a humanized anti-CD38 antibody.
27. The pharmaceutical composition of claim 25 , wherein the anti-CD38 antibody comprises daratumumab or SAR650984.