title: Engineered anti-CD70 antibody with multiple effector functions exhibits in vitro and in vivo antitumor activities.
abstract: Antigens expressed on malignant cells in the absence of significant expression on normal tissues are highly desirable targets for therapeutic antibodies. CD70 is a TNF superfamily member whose normal expression is highly restricted but is aberrantly expressed in hematologic malignancies including non-Hodgkin lymphoma (NHL), Hodgkin disease, and multiple myeloma. In addition, solid tumors such as renal cell carcinoma, nasopharyngeal carcinoma, thymic carcinoma, meduloblastoma, and glioblastoma express high levels of this antigen. To functionally target CD70-expressing cancers, a murine anti-CD70 monoclonal antibody was engineered to contain human IgG1 constant domains. The engineered antibody retained the binding specificity of the murine parent monoclonal antibody and was shown to induce Fc-mediated effector functions including antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis in vitro. Further, administration of this antibody significantly prolonged survival of severe combined immunodeficient (SCID) mice bearing CD70+ disseminated human NHL xenografts. Survival of these mice was dependent upon the activity of resident effector cells including neutrophils, macrophages, and natural killer (NK) cells. These data suggest that an anti-CD70 antibody, when engineered to contain human IgG1 constant domains, possesses effector cell-mediated antitumor activity and has potential utility for anticancer therapy.
authors.affiliation: Seattle Genetics, Inc, Bothell, WA 98021, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: McEarchern
authors.forename: Ezogelin
authors.initials: E
authors.lastname: Oflazoglu
authors.forename: Leigh
authors.initials: L
authors.lastname: Francisco
authors.forename: Charlotte F
authors.initials: CF
authors.lastname: McDonagh
authors.forename: Kristine A
authors.initials: KA
authors.lastname: Gordon
authors.forename: Ivan
authors.initials: I
authors.lastname: Stone
authors.forename: Kerry
authors.initials: K
authors.lastname: Klussman
authors.forename: Eileen
authors.initials: E
authors.lastname: Turcott
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Paul
authors.initials: P
authors.lastname: Carter
authors.forename: Iqbal S
authors.initials: IS
authors.lastname: Grewal
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wahl
authors.forename: Che-Leung
authors.initials: CL
authors.lastname: Law
mesh_terms: D000818:Animals; D000906:Antibodies / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D000918:Antibody Specificity; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents; D053282:CD27 Ligand / Q000276:immunology*; D045744:Cell Line, Tumor; D003165:Complement System Proteins; D006801:Humans; D007107:Immune System / Q000166:cytology; D007074:Immunoglobulin G; D008228:Lymphoma, Non-Hodgkin / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D010587:Phagocytosis; D015202:Protein Engineering / Q000379:methods*; D015996:Survival Rate; D014183:Transplantation, Heterologous
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D053282:CD27 Ligand; D007074:Immunoglobulin G; D003165:Complement System Proteins