CD38-modulating antibody

Abstract

The present disclosure provides antibodies that bind to human CD38. Specifically, the antibodies and their antigen-binding portions are defined by specific functional properties. The antibodies exhibit characteristics suitable for manufacturing and can be provided as fully human antibodies (e.g., fully human monoclonal antibodies or antigen-binding fragments) that may be useful in medical methods and compositions, particularly for the treatment of cancer. [Selection diagram] Figure 20

Claims

1. An anti-CD38 human IGg1 antibody or antigen-binding fragment thereof, exhibits antibody-dependent cell-mediated cytotoxicity (ADCC) activity against CD38+ target cells; exhibits no complement-dependent cytotoxicity (CDC) activity against CD38+ target cells or exhibits reduced CDC activity compared to daratumumab under the same conditions; Induce immune effector cell activation, The antibody or antigen-binding fragment thereof specifically binds to an epitope of human CD38, the epitope comprising at least amino acids 65-79 of SEQ ID NO:

47. An anti-CD38 antibody or an antigen-binding fragment thereof.

2. i) the antibody or antigen-binding fragment thereof does not exhibit CDC or exhibits CDC in a a. with an EC50 at least 0.5-fold higher or at least 1-fold higher than daratumumab, or b. exhibits a maximal % lysis measured in Raji cells and / or Daudi cells in the presence of 10% complement that is less than half the maximal % lysis exhibited by daratumumab; ii) the antibody or antigen-binding fragment thereof induces CDC with an EC50 value of greater than 0.05 μg / mL on Daudi cells and / or Raji cells in the presence of 10% complement; iii) the reduction in CDC activity is such that the EC50 of the antibody or antigen-binding fragment thereof is at least 0.5-fold or at least 1-fold higher than the EC50 of daratumumab under the same conditions; iv) reduced CDC activity compared to daratumumab is such that the maximum % cytolysis is less than or equal to half of the maximum % cytolysis exhibited by daratumumab under the same conditions; v) the antibody or antigen-binding fragment thereof exhibits antibody-dependent cellular phagocytosis (ADCP) against CD38-expressing cells; vii) the antibody or antigen-binding fragment thereof increases T cell proliferation in CD4+ cells and / or CD8+ cells by at least 20% compared to untreated cells; viii) the antibody or antigen-binding fragment thereof induces secretion of a cytokine selected from the group consisting of IL-2, TNF-α, IFN-γ, IL-10, and / or GM-CSF in CD4+ cells and / or CD8+ cells in an amount that exceeds the secretion induced by daratumumab under the same conditions; ix) the antibody or antigen-binding fragment thereof induces NK cell activation; xi) the antibody has an inhibitory effect on CD38 cyclase activity; xii) the antibody binds to the extracellular domain of human CD38; and / or xiii) the antibody is defucosylated; The anti-CD38 antibody or antigen-binding fragment thereof described in claim 1.

3. The anti-CD38 antibody or antigen-binding fragment thereof of claim 1 or 2, wherein the antibody or antigen-binding fragment thereof induces T cell activation.

4. i) the NFAT signaling of the antibody or antigen-binding fragment thereof is at least 20% greater than the NFAT signaling of daratumumab when T cell activation is determined by measuring NFAT signaling in luciferase reporter Jurkat cells; and / or ii) T cell activation is characterized by increased T cell proliferation and / or increased cytokine secretion, said cytokines being selected from the group consisting of IL-2, TNF-α, IFN-γ, IL-10, and GM-CSF; The anti-CD38 antibody or antigen-binding fragment thereof described in claim 3.

5. The anti-CD38 antibody or antigen-binding fragment thereof according to any one of claims 1 to 4, wherein when the antibody or antigen-binding fragment thereof induces NK cell activation, the NK cell activation is characterized by an increase in NK cell proliferation, an increase in intracellular IFNg, and / or an increase in the expression level of CD107a.

6. When the antibody has an inhibitory effect on CD38 cyclase activity, i) the inhibitory effect on said CD38 cyclase activity is at least 10% lower compared to the CD38 cyclase activity in the presence of a non-IgG binding control antibody as measured by conversion of NGD+ to cGDPR in Jurkat cells; and / or ii) the anti-CD38 antibody or antigen-binding fragment thereof reduces CD38 cyclase activity to 25% or more of CD38 cyclase activity in the presence of a non-IgG binding control antibody as measured by conversion of NGD+ to cGDPR in Jurkat cells; The anti-CD38 antibody or antigen-binding fragment thereof described in claim 4.

7. the antibody or antigen-binding fragment thereof i) a monoclonal antibody, a Fab fragment, an F(ab')2 fragment, a single chain variable fragment (scFv), an scFv-Fc fragment, or a single chain antibody (scAb); and / or ii) contained in a bispecific antibody, a multispecific antibody, or an immunoconjugate further comprising a therapeutic or diagnostic agent; An anti-CD38 antibody or antigen-binding fragment thereof according to any one of claims 1 to 6.

8. A nucleic acid molecule encoding the antibody or antigen-binding fragment thereof according to any one of claims 1 to 7.

9. A nucleic acid vector comprising the nucleic acid molecule of claim 8.

10. A host cell comprising the nucleic acid vector of claim 9.

11. A method for producing an antibody or antigen-binding fragment thereof according to any one of claims 1 to 7, comprising culturing a host cell according to claim 10.

12. A composition comprising an antibody or antigen-binding fragment thereof according to any one of claims 1 to 7.

13. The composition of claim 12, further comprising a pharma- ceutically acceptable carrier or excipient.

14. 14. The composition of claim 12 or claim 13 for the treatment of cancer.

15. A composition for treating cancer, comprising the antibody or antigen-binding fragment thereof according to any one of claims 1 to 7.

16. The composition of claim 15 further comprising a second pharmaceutical agent.

17. The composition of claim 15 or 16, wherein the cancer is a solid tumor or a hematological cancer.

Images