SGN-70, a Humanized Anti-CD70 Antibody, Targets CD70-Expressing Hematologic Tumors.

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 restricted to activated lymphocytes but is aberrantly expressed in hematologic malignancies and solid tumors including non-Hodgkin’s lymphoma (NHL), Hodgkin’s disease, multiple myeloma (MM), Waldenstrom’s macroglobulinemia, renal cell carcinoma, glioblastoma, and nasopharyngeal carcinoma. To target CD70-expressing hematologic malignancies, we have engineered a humanized IgG1 anti-CD70 antibody that mediates lysis of tumor targets via ADCC and CDC and facilitates antibody dependent cellular phagocytosis in vitro. In vivo, administration of SGN-70 prolonged survival of SCID mice bearing CD70+ disseminated human NHL or MM xenografts. Intravenous injection of the CD70+ MM cell line MM.1S resulted in disease as measured by onset of paralysis, presence of CD138+ MM cells in the bone marrow, and increasing levels of circulating human Ig lambda light chain. SGN-70 treatment of MM.1S-bearing mice significantly delayed onset of paralysis and reduced the monoclonal protein levels detected in serum approximately 4-fold compared to untreated or non-binding antibody control-treated mice. Whereas myeloma cells comprised 32±6.4 % of mononuclear cells in the long bone marrow of control mice, SGN-70 treatment reduced the myeloma cell fraction to 4.9±1.9% of mononuclear cells recovered. SGN-70 treatment also significantly extended the survival of mice bearing disseminated Raji tumors (NHL) compared to control mice. Survival benefit was absent when mice received an Fc-modified antibody deficient in effector functions, confirming that the activity of SGN-70 in these models was dependent upon Fc-FcγR interaction with host immune cells. Together, these data demonstrate that SGN-70 possesses effector cell-mediated antitumor activity and provides rationale for clinical study of SGN-70 in CD70+ hematologic malignancies.