| Autor: |
Cardillo TM; Immunomedics, Inc., Morris Plains, New Jersey. dmg.gscancer@att.net tcardillo@immunomedics.com., Govindan SV; Immunomedics, Inc., Morris Plains, New Jersey., Zalath MB; Immunomedics, Inc., Morris Plains, New Jersey., Rossi DL; Immunomedics, Inc., Morris Plains, New Jersey., Wang Y; Immunomedics, Inc., Morris Plains, New Jersey., Chang CH; Immunomedics, Inc., Morris Plains, New Jersey., Goldenberg DM; Immunomedics, Inc., Morris Plains, New Jersey. dmg.gscancer@att.net tcardillo@immunomedics.com. |
| Jazyk: |
angličtina |
| Zdroj: |
Molecular cancer therapeutics [Mol Cancer Ther] 2018 Jan; Vol. 17 (1), pp. 150-160. Date of Electronic Publication: 2017 Nov 13. |
| DOI: |
10.1158/1535-7163.MCT-17-0354 |
| Abstrakt: |
HLA-DR is a member of the MHC class II antigen family expressed on hematologic and solid tumors. Antibodies directed against HLA-DR have demonstrated some clinical success, but toxicities limited development. IMMU-140 is an anti-HLA-DR antibody-drug conjugate composed of the active metabolite of irinotecan, SN-38, conjugated to a humanized anti-HLA-DR IgG 4 antibody (IMMU-114); the IgG 4 naked antibody is devoid of immune functions. Our aim was to determine if SN-38, the metabolite of a drug not commonly used in hematopoietic cancers, would be effective and safe when targeted to HLA-DR-expressing tumors. IMMU-140 had dual-therapeutic mechanisms, as evidenced by its retention of nonoverlapping anti-HLA-DR nonclassical apoptotic signaling and classical apoptosis mediated by its SN-38 payload. In seven human disease models [acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), acute myeloid leukemia (AML), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL), and melanoma], IMMU-140 provided significant therapeutic efficacy compared with controls, in vitro , in 3D spheroid models, and in vivo Except for MM and HL, IMMU-140 imparted significantly improved antitumor effects compared with parental IMMU-114. Even in intractable AML and ALL, where IMMU-114 only had modest antitumor effects, IMMU-140 therapy mediated >80% improvement in survival. Therapy was well tolerated, as demonstrated by no marked loss in body weight. Combined with doxorubicin, IMMU-140 produced significantly greater antitumor effects in HL than with monotherapy and without any added toxicity. The dual-therapeutic action of IMMU-140 resulted in promising therapeutic activity in a range of hematopoietic tumors and melanoma, and therefore warrants clinical development. Mol Cancer Ther; 17(1); 150-60. ©2017 AACR .
(©2017 American Association for Cancer Research.) |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
