Anti-CD38 antibodies for treatment of acute lymphoblastic leukemia
The present invention relates to combination therapies with anti-CD38 antibodies.
1. A method of treating a subject having acute lymphoblastic leukemia (ALL), comprising administering to the subject in need thereof an anti-CD38 antibody comprising heavy chain complementarity determining regions (HCDR) 1 (HCDR1), 2 (HCDR2) and 3 (HCDR3) sequences of SEQ ID NOs: 6, 7 and 8, respectively, and light chain complementarity determining regions (LCDR) 1 (LCDR1), 2 (LCDR2) and 3 (LCDR3) sequences of SEQ ID NOs: 9, 10 and 11, respectively, in combination with vincristine, wherein the subject is resistant or has acquired resistance to treatment with a BCR-ABL kinase inhibitor.
2. The method of claim 1 , wherein the anti-CD38 antibody comprises a heavy chain variable region (VH) of SEQ ID NO: 4 and a light chain variable region (VL) of SEQ ID NO: 5.
3. The method of claim 1 , wherein the anti-CD38 antibody induces in vitro killing of the ALL cells that express CD38 by antibody-dependent cell-mediated cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), apoptosis, or in vitro modulation of CD38 enzymatic activity.
4. The method of claim 3 , wherein the anti-CD38 antibody is of IgG1, IgG2, IgG3 or IgG4 isotype.
5. The method of claim 4 , wherein the anti-CD38 antibody has a biantennary glycan structure with fucose content of about 50%, 40%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 14%, 13%, 12%, 11% 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or 0%.
6. The method of claim 4 , wherein the anti-CD38 antibody comprises a substitution in the antibody Fc at amino acid positions 256, 290, 298, 312, 356, 330, 333, 334, 360, 378 or 430, wherein residue numbering is according to the EU index.
7. The method of claim 4 , wherein the anti-CD38 antibody comprises a heavy chain of SEQ ID NO: 12 and a light chain of SEQ ID NO: 13.
8. The method of claim 1 , wherein the ALL is B-cell lineage ALL, T-cell lineage ALL, adult ALL or pediatric ALL.
9. The method of claim 8 , wherein the ALL is refractory or relapsed ALL.
10. The method of claim 8 , wherein the anti-CD38 antibody is administered as a remission induction or as postinduction therapy.
11. The method of claim 8 , wherein the subject has a white blood cell count of at least about 1×10 9 /L.
12. The method of claim 8 , wherein the ALL cells have a Philadelphia chromosome.
13. The method of claim 1 , wherein the BCR-ABL kinase inhibitor is imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, saracatinib, tozasertib danusertib or ibrutinib.
14. The method of claim 1 , wherein the anti-CD38 antibody and vincristine are administered simultaneously, sequentially or separately.
15. The method of claim 1 or 8 , wherein the subject is further treated or has been treated with radiotherapy.
16. The method of claim 1 or 8 , wherein the subject has received hematopoietic stem cell transplantation.