title: An antibody-cytotoxic conjugate, BIIB015, is a new targeted therapy for Cripto positive tumours.
abstract: BIIB015 is an immunoconjugate created for the treatment of solid tumours and is currently in Phase I of clinical evaluation. BIIB015 consists of a humanised monoclonal antibody against the Cripto protein carrying a payload, via a hindered disulphide linker, of the maytansinoid derivative, DM4. Cripto is a GPI-linked protein required for signal transduction of the TGF-beta ligand, Nodal. Cripto has been previously described as an oncogene and fits the classic pattern of an embryonic gene that is re-expressed in a transformed tumour cell. Cripto expression is highly prevalent on a number of solid tumours, including greater than 75% of breast, lung, and colorectal tumours. Our report documents for the first time that targeting the cell surface Cripto protein with an anti-Cripto antibody-cytotoxic conjugate is an effective means of inhibiting or regressing growth of Cripto positive tumours. BIIB015 which utilises a 'cleavable' linker containing a disulphide bond exhibits superior activity when compared to huB3F6 mAb conjugates with different linker systems, including one with a 'non-cleavable' linker. BIIB015 displays specificity for Cripto in both in vitro and in vivo experiments. In human xenograft models originating from lung (Calu-6), colon (CT-3), testicular (NCCIT) and breast (MDA-MB-231) tumour samples, BIIB015 shows robust activity with results ranging from >50% tumour inhibition to complete tumour regression. The efficacy seen in the MDA-MB-231 model, a triple negative (-HER2, -ER, and -PR) tumour, is particularly exciting since there is currently no approved therapy for this indication. In addition, BIIB015 can be combined with standard of care chemotherapeutics for enhanced efficacy.
authors: Biogen Idec, Inc, Discovery Oncology, 14 Cambridge Center, Cambridge, MA 02142, USA.
authors: Rebecca K
authors: RK
authors: Kelly
authors: Dian L
authors: DL
authors: Olson
authors: Yaping
authors: Y
authors: Sun
authors: Dingyi
authors: D
authors: Wen
authors: Kathleen A
authors: KA
authors: Wortham
authors: Giovanna
authors: G
authors: Antognetti
authors: Anne E
authors: AE
authors: Cheung
authors: Olivia E
authors: OE
authors: Orozco
authors: Lu
authors: L
authors: Yang
authors: Veronique
authors: V
authors: Bailly
authors: Michele
authors: M
authors: Sanicola
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D007150:Immunohistochemistry / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008956:Models, Chemical; D009363:Neoplasm Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D058851:GPI-Linked Proteins; D018796:Immunoconjugates; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; C070636:TDGF1 protein, human; C568070:huB3F6-SPDB-DM4 immunoconjugate