Preclinical Characterization of SGN-70, a Humanized Antibody Directed against CD70

• Published in: Clinical cancer research 2008-12, Vol.14 (23), p.7763-7772
• Main Authors: MCEARCHERN, Julie A, SMITH, Leia M, GREWAL, Iqbal S, LAW, Che-Leung, MCDONAGH, Charlotte F, KLUSSMAN, Kerry, GORDON, Kristine A, MORRIS-TILDEN, Carol A, DUNIHO, Steven, RYAN, Maureen, BOURSALIAN, Tamar E, CARTER, Paul J
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antibody Affinity; Antineoplastic agents; Antineoplastic Agents - immunology; Antineoplastic Agents - pharmacology; Biological and medical sciences; cancer therapy; Carcinoma, Renal Cell - immunology; Carcinoma, Renal Cell - metabolism; CD27 Ligand - immunology; CD27 Ligand - metabolism; CD70; Humans; Immunohistochemistry; Kidney Neoplasms - immunology; Kidney Neoplasms - metabolism; Lymphoma - immunology; Lymphoma - metabolism; Medical sciences; Mice; Mice, SCID; monoclonal antibody; Pharmacology. Drug treatments; Tissue Array Analysis; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-0493

Purpose: 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. Experimental Design: 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 Fcγ receptor binding compared with SGN-70. Results : Immunohistochemical analysis identified CD70 expression on ∼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 .