TY - JOUR
T1 - Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors
AU - De Weers, Michel
AU - Tai, Yu Tzu
AU - Van Der Veer, Michael S.
AU - Bakker, Joost M.
AU - Vink, Tom
AU - Jacobs, Daniëlle C H
AU - Oomen, Lukas A.
AU - Peipp, Matthias
AU - Valerius, Thomas
AU - Slootstra, Jerry W.
AU - Mutis, Tuna
AU - Bleeker, Wim K.
AU - Anderson, Kenneth C.
AU - Lokhorst, Henk M.
AU - Van De Winkel, Jan G J
AU - Parren, Paul W H I
PY - 2011/2/1
Y1 - 2011/2/1
N2 - CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.
AB - CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.
UR - http://www.scopus.com/inward/record.url?scp=79251570884&partnerID=8YFLogxK
U2 - https://doi.org/10.4049/jimmunol.1003032
DO - https://doi.org/10.4049/jimmunol.1003032
M3 - Article
C2 - 21187443
SN - 0022-1767
VL - 186
SP - 1840
EP - 1848
JO - Journal of Immunology
JF - Journal of Immunology
IS - 3
ER -