An antibody-cytotoxic conjugate, BIIB015, is a new targeted therapy for Cripto positive tumours

Eur J Cancer. 2011 Jul;47(11):1736-46. doi: 10.1016/j.ejca.2011.02.023. Epub 2011 Mar 31.


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.

MeSH terms

  • Animals
  • Antibodies / chemistry*
  • Antibodies, Monoclonal / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Survival
  • Female
  • GPI-Linked Proteins / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunoconjugates / pharmacology*
  • Immunohistochemistry / methods
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Male
  • Mice
  • Mice, SCID
  • Models, Chemical
  • Neoplasm Proteins / metabolism
  • Neoplasm Transplantation
  • Neoplasms / metabolism*


  • Antibodies
  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • GPI-Linked Proteins
  • Immunoconjugates
  • Intercellular Signaling Peptides and Proteins
  • Neoplasm Proteins
  • TDGF1 protein, human
  • huB3F6-SPDB-DM4 immunoconjugate