Preclinical characterization of SGN-70, a humanized antibody directed against CD70.
OBJECTIVE
CD70 (CD27L) is a member of the tumor necrosis factor family aberrantly expressed on a number of hematologic malignancies and some carcinomas. CD70 expression on malignant cells coupled with its highly restricted expression on normal cells makes CD70 an attractive target for monoclonal antibody (mAb)-based therapies. We developed a humanized anti-CD70 antibody, SGN-70, and herein describe the antitumor activities of this mAb.


METHODS
CD70 expression on primary tumors was evaluated by immunohistochemical staining of Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, and renal cell carcinoma tissue microarrays. The CD70-binding and cytotoxic activities of SGN-70 were tested in vitro using a number of cell-based assays. The in vivo antitumor properties of SGN-70 were tested in severe combined immunodeficient mice bearing disseminated lymphoma and multiple myeloma xenografts. Mechanism-of-action studies were conducted using SGN-70v, a variant mAb with equivalent target-binding activity but impaired Fcgamma receptor binding compared with SGN-70.


RESULTS
Immunohistochemical analysis identified CD70 expression on approximately 40% of multiple myeloma isolates and confirmed CD70 expression on a high percentage of Hodgkin lymphoma Reed-Sternberg cells, non-Hodgkin lymphoma, and renal cell carcinoma tumors. SGN-70 lysed CD70+ tumor cells via Fc-dependent functions, including antibody-dependent cellular cytotoxicity and phagocytosis and complement fixation. In vivo, SGN-70 treatment significantly decreased tumor burden and prolonged survival of tumor-bearing mice.


CONCLUSIONS
SGN-70 is a novel humanized IgG1 mAb undergoing clinical development for the treatment of CD70+ cancers. SGN-70 possesses Fc-dependent antibody effector functions and mediates antitumor activity in vivo.
McEarchern
Julie A
JA
Seattle Genetics, Inc., Bothell, Washington 98021, USA. Jmcearchern@seagen.com
Smith
Leia M
LM
McDonagh
Charlotte F
CF
Klussman
Kerry
K
Gordon
Kristine A
KA
Morris-Tilden
Carol A
CA
Duniho
Steven
S
Ryan
Maureen
M
Boursalian
Tamar E
TE
Carter
Paul J
PJ
Grewal
Iqbal S
IS
Law
Che-Leung
CL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D000915:Antibody Affinity; D000970:Antineoplastic Agents / Q000276:immunology* / Q000494:pharmacology; D053282:CD27 Ligand / Q000276:immunology* / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000276:immunology / Q000378:metabolism; D008223:Lymphoma / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D053282:CD27 Ligand; C505771:CD70 protein, human