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Published on: July 12, 2018
Preclinical characterization of SGN-70, a humanized antibody directed against CD70
Julie A McEarchern1, Leia M Smith, Charlotte F McDonagh
1Seattle Genetics, Inc., Bothell, Washington 98021, USA. Jmcearchern@seagen.com
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 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.
Insights
A new humanized antibody, SGN-70, targets CD70+ cancers. This antibody demonstrated significant antitumor activity in preclinical models by utilizing Fc-dependent functions to eliminate cancer cells.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- CD70 is a tumor necrosis factor family member expressed on various hematologic malignancies and carcinomas.
- Restricted expression of CD70 on normal cells makes it an attractive target for antibody-based cancer therapies.
Purpose of the Study:
- To develop and evaluate the antitumor activities of SGN-70, a novel humanized anti-CD70 monoclonal antibody (mAb).
Main Methods:
- Immunohistochemical staining assessed CD70 expression in Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, and renal cell carcinoma.
- In vitro assays tested SGN-70's binding and cytotoxic activities.
- In vivo studies evaluated SGN-70's efficacy in mice with lymphoma and multiple myeloma xenografts.
Main Results:
- CD70 expression was confirmed on a significant proportion of multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma, and renal cell carcinoma tumors.
- SGN-70 induced lysis of CD70+ tumor cells through Fc-dependent mechanisms like ADCC, phagocytosis, and complement fixation.
- In vivo, SGN-70 treatment reduced tumor burden and improved survival in tumor-bearing mice.
Conclusions:
- SGN-70 is a promising humanized IgG1 mAb for treating CD70+ cancers.
- The antibody exhibits potent Fc-dependent effector functions and demonstrates significant in vivo antitumor activity.
