title: Apomab, a fully human agonistic antibody to DR5, exhibits potent antitumor activity against primary and metastatic breast cancer.
abstract: Apomab, a fully human agonistic DR5 monoclonal antibody, triggers apoptosis through activation of the extrinsic apoptotic signaling pathway. In this study, we assessed the cytotoxic effect of Apomab in vitro and evaluated its antitumor activity in murine models of breast cancer development and progression. MDA-MB-231-TXSA breast cancer cells were transplanted into the mammary fat pad or directly into the tibial marrow cavity of nude mice. Apomab was administered early, postcancer cell transplantation, or after tumors progressed to an advanced stage. Tumor burden was monitored progressively using bioluminescence imaging, and the development of breast cancer-induced osteolysis was measured using microcomputed tomography. In vitro, Apomab treatment induced apoptosis in a panel of breast cancer cell lines but was without effect on normal human primary osteoblasts, fibroblasts, or mammary epithelial cells. In vivo, Apomab exerted remarkable tumor suppressive activity leading to complete regression of well-advanced mammary tumors. All animals transplanted with breast cancer cells directly into their tibiae developed large osteolytic lesions that eroded the cortical bone. In contrast, treatment with Apomab following an early treatment protocol inhibited both intraosseous and extraosseous tumor growth and prevented breast cancer-induced osteolysis. In the delayed treatment protocol, Apomab treatment resulted in the complete regression of advanced tibial tumors with progressive restoration of both trabecular and cortical bone leading to full resolution of osteolytic lesions. Apomab represents a potent immunotherapeutic agent with strong activity against the development and progression of breast cancer and should be evaluated in patients with primary and metastatic disease.
authors.affiliation: Discipline of Orthopaedics and Trauma Level 4, Bice Building, Royal Adelaide Hospital, North Terrace, Adelaide 5000, South Australia, Australia.
authors.forename: Irene
authors.initials: I
authors.lastname: Zinonos
authors.forename: Agatha
authors.initials: A
authors.lastname: Labrinidis
authors.forename: Michelle
authors.initials: M
authors.lastname: Lee
authors.forename: Vasilios
authors.initials: V
authors.lastname: Liapis
authors.forename: Shelley
authors.initials: S
authors.lastname: Hay
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ponomarev
authors.forename: Peter
authors.initials: P
authors.lastname: Diamond
authors.forename: Andrew C W
authors.initials: AC
authors.lastname: Zannettino
authors.forename: David M
authors.initials: DM
authors.lastname: Findlay
authors.forename: Andreas
authors.initials: A
authors.lastname: Evdokiou
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D010014:Osteolysis / Q000473:pathology; D053218:Receptors, Death Domain / Q000819:agonists*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D053218:Receptors, Death Domain; C530969:apomab