The anti-Fn14 antibody BIIB036 inhibits tumor growth in xenografts and patient derived primary tumor models and enhances efficacy of chemotherapeutic agents in multiple xenograft models.
Agonistic antibodies targeting Fn14, the receptor for TWEAK, have demonstrated anti-tumor activity in xenograft models. Herein, we further explore the therapeutic potential of the humanized anti-Fn14 agonistic antibody, BIIB036, as a single agent and in combination with standard of care cancer therapeutics. Pharmacokinetic studies of BIIB036 in tumor-bearing mice revealed a half-life of approximately three days suggesting twice a week dosing would be necessary to maintain efficacy. However, in multiple xenograft models, BIIB036 treatment resulted in extended tumor growth inhibition up to 40-50 d following cessation of dosing, suggesting that frequent administration of BIIB036 may not be necessary to maintain prolonged anti-tumor activity. Subsequent xenograft studies revealed that maximal efficacy was achieved with BIIB036 dosing once every two weeks, by either intraperitoneal or subcutaneous administration. Xenograft tumors that were initially treated with BIBI036 and then re-grew up to 1000 mm³ following cessation of the first cycle of treatment remained sensitive to a second cycle of treatment. BIIB036 was also evaluated in patient derived primary colon tumor models, where efficacy compared favorably with a standard of care agent. Lastly, BIIB036 enhanced the efficacy of several standard of care chemotherapeutics, including paclitaxel in MDA-MBA-231 breast tumor xenografts, paclitaxel or carboplatin in HOP62 non-small cell lung xenografts, and 5-FU in NCI-N87 gastric xenografts, with no overlapping toxicities. These studies thus establish BIIB036 as a promising therapeutic agent with durable anti-tumor activity in human xenografts as well as patient derived primary tumor models, and enhanced activity and tolerability in combination with standard of care chemotherapeutics. Taken together, the data presented herein suggest that BIIB036 warrants evaluation in the clinic.
Biogen Idec, Cambridge, MA, USA. jennifer.michaelson@biogenidec.com
Jennifer S
JS
Michaelson
Rebecca
R
Kelly
Lu
L
Yang
Xiamei
X
Zhang
Kathleen
K
Wortham
Ingrid B J K
IB
Joseph
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000074050:TWEAK Receptor; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C576382:BIIB036; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; D016190:Carboplatin; D017239:Paclitaxel; D005472:Fluorouracil