Preclinical Characterization of SGN-70, a Humanized Antibody Directedagainst CD70 Julie A. McEarchern, Leia M. Smith, Charlotte F. McDonagh, Kerry Klussman, KristineA. Gordon, Carol A. Morris-Tilden, Steven Duniho, Maureen Ryan, Tamar E. Boursalian, PaulJ. Carter, Iqbal S. Grewal, and Che-Leung Law Abstract 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 cellscoupledwithitshighlyrestrictedexpressiononnormalcellsmakesCD70anattractivetarget 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 immunohisto- chemical 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 conductedusing SGN-70v, avariantmAbwithequivalent target-bindingactivitybutimpairedFcg receptorbindingcompared with SGN-70. Results : Immunohistochemical analysis identified CD70 expression on f40% 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 cytotoxic- ity 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 IgG1mAb undergoing clinical development for the treatment of CD70 + cancers. SGN-70 possesses Fc-dependent antibody effector functions and mediates antitumor activity in vivo. The advent of antibody engineering technologies has largely overcome the critical barrier of antibody immunogenicity and enabled the development and subsequent Food and Drug Administration approval of therapeutic antibodies for cancer and other diseases (1). To reduce tumor burden in patients, therapeutic antibodies use one or more mechanisms that include growth factor neutralization (bevacizumab) and receptor antag- onism (trastuzumab, cetuximab); sensitization of tumor cells toward chemotherapy and radiation therapy (rituximab, trastu- zumab, cetuximab); and recruitment of the innate immune system to mediate antibody-dependent cellular cytotoxicity (ADCC), complement fixation, and phagocytosis of tumor cells (rituximab, alemtuzumab, trastuzumab, cetuximab; ref. 1). To achieve optimal targeting specificity and limit potential side effects, cell surface receptors that show restricted or no expression in normal tissues, including all vital organs, limited ability to be shed from cell surface, and increased or aberrant expression upon cellular transformation are attractive targets for antibody-based therapeutics (2). The tumor necrosis factor family member CD70 (3) possesses all of these characteristics. Interaction between CD70 and its receptor CD27 contributes to robust immune responses, partly through costimulation of T and B lymphocyte maturation into effector as well as memory cells (4, 5). In normal tissues, CD70 expression is restricted to cells of hematopoietic origin, and it is only transiently induced upon activation of T and B lymphocytes (6, 7), natural killer cells (8, 9), and maturation of dendritic cells (10, 11). As a result, histologic analysis of normal tissues reveals rare CD70-expressing cells only in lymphoid tissues like the thymus, spleen, peripheral lymph nodes, and gut-associated lymphoid tissues (12, 13). CD70 has been detected on transformed cells of both hema- topoietic and epithelial origin, including the Reed-Sternberg cells Cancer Therapy: Preclinical Authors’Affiliation: Seattle Genetics, Inc., Bothell,Washington Received 2/22/08; revised 6/30/08; accepted 7/27/08. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). C.F. McDonaghand P.J. Carterare currentlyemployedby Merrimack Pharmaceuticals, Inc.,andVLSTCorporation,respectively. Requestsforreprints: JulieMcEarchern,SeattleGenetics,Inc.,2182330thDrive Southeast, Bothell,WA 98021. Phone: 425-527-4638; Fax: 425-527-4609; E-mail: Jmcearchern@seagen.com. F 2008 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-08-0493 www.aacrjournals.org ClinCancerRes2008;14(23)December1,2008 7763 Research. on July 19, 2017. © 2008 American Association for Cancer clincancerres.aacrjournals.org Downloaded from