Methods for improving anti-CD37 immunoconjugate therapy
Methods for identifying and treating patients having cancer who are likely to respond to treatment with an anti-CD37 immunoconjugate (e.g., IMGN529) are provided.
1. A method for treating a B cell cancer in a patient comprising administering an anti-CD37 immunoconjugate to the patient, wherein an increased expression level has been detected in a cancer sample obtained from the patient for at least one gene selected from the group consisting of: SLC6A16, CD79A, CHI3L2, FAM117B, LPAR5, NFATC1, PTPN22, RBM38, and SGPP1;
wherein the anti-CD37 immunoconjugate has the formula (A)-(L)-(M), wherein:
(A) is an antibody or antigen-binding fragment thereof that specifically binds to CD37 and comprises heavy and light chain variable region CDR sequences of SEQ ID NOs: 4-6 and SEQ ID NOs: 7-9, respectively;
(L) is a linker; and
(M) is a maytansinoid; and
wherein the linker (L) links (A) to (M).
2. The method of claim 1 , wherein an increased expression level of CD 37 has also been detected in a cancer sample from the patient.
3. The method of claim 1 , wherein an increased expression level of at least 2 genes selected from the group consisting of: SLC6A16, CD79A, CHI3L2, FAM117B, LPAR5, NFATC1, PTPN22, RBM38, and SGPP1, has been detected in a cancer sample obtained from the patient.
4. The method of claim 1 , wherein the immunoconjugate comprises an antibody or antigen-binding fragment thereof having the variable heavy chain sequence of SEQ ID NO: 12 and the variable light chain sequence of SEQ ID NO: 15 or having the variable heavy chain sequence of SEQ ID NO: 22 and the variable light chain sequence of SEQ ID NO: 15.
5. The method of claim 1 , wherein the maytansinoid is DM1 or DM4.
6. The method of claim 1 , wherein the linker in the immunoconjugate is SMCC.
7. The method of claim 1 , wherein the immunoconjugate comprises an antibody or antigen-binding fragment thereof having the variable heavy chain sequence of SEQ ID NO: 12 and the variable light chain sequence of SEQ ID NO: 15, the cytotoxic agent DM1, and the linker SMCC.
8. The method of claim 1 , wherein the immunoconjugate comprises an antibody or antigen-binding fragment thereof having the full-length heavy chain amino acid sequence of SEQ ID NO: 18 and the full-length light chain amino acid sequence of SEQ ID NO: 21, the cytotoxic agent DM1, and the linker SMCC.
9. The method of claim 1 , further comprising detecting the expression level in the cancer sample obtained from the patient prior to administering the immunoconjugate.
10. The method of claim 1 , wherein the detection method is cytofluorometry, flow cytometry, protein microarray, immunoassay, mass spectrometry, fluorescence activated cell sorting (FACS), ELISA, SDS-PAGE, dot blot, nucleotide microarray, quantitative PCR, semi-quantitative PCR, RNase protection assay, in situ hybridization, or RNA-Seq.
11. The method of claim 1 , wherein the increased expression has been detected by comparing the expression level of the at least one gene to the expression level of at least one reference gene selected from the group consisting of: ACTB, GAPDH, GUSB, HPRT1, and 18S rRNA.
12. The method of claim 11 , wherein the increased expression is an increase that is at least 1.5-fold greater than the change in expression level of the reference gene.
13. The method of claim 1 , wherein the increased expression level is increased mRNA.
14. The method of claim 1 , wherein the increased expression level is increased protein.
15. The method of claim 1 , wherein the cancer sample is tissue, blood, plasma, bone marrow, or lymph.
16. The method of claim 1 further comprising administering a corticosteroid to the patient.
17. The method of claim 16 , wherein the corticosteroid is administered prior to the administration of the immunoconjugate, or the corticosteroid is administered during the administration of the immunoconjugate.
18. The method of claim 17 , wherein the corticosteroid is administered from about 30 to about 60 minutes prior to administration of the immunoconjugate.
19. The method of claim 1 further comprising administering a growth factor to the patient.
20. The method of claim 1 , wherein the B cell cancer is a lymphoma.
21. The method of claim 1 , wherein the B cell cancer is a diffuse large B-cell lymphoma (DLBCL.
22. The method of claim 1 , wherein the B cell cancer is an activated B cell like diffuse large B-cell lymphoma (ABC-DLBCL).
23. The method of claim 1 , wherein the B cell cancer is a germinal center B cell like diffuse B-cell lymphoma (GCB-DLBCL).
24. The method of claim 7 , wherein the B cell cancer is a diffuse large B-cell lymphoma (DLBCL).
25. The method of claim 7 , wherein the B cell cancer is an activated B cell like diffuse large B-cell lymphoma (ABC-DLBCL).
26. The method of claim 7 , wherein the B cell cancer is a germinal center B cell like diffuse B-cell lymphoma (GCB-DLBCL).