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Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo

Heather B Adkins1, Caterina Bianco, Susan G Schiffer

  • 1Biogen Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, USA.

The Journal of Clinical Investigation
|August 20, 2003
PubMed

Insights

Cripto protein overexpression in tumors is linked to cancer growth. Blocking Cripto

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Cripto, an Epidermal Growth Factor-Cripto, FRL-1, Cryptic (EGF-CFC) family protein, is overexpressed in numerous human solid tumors.
  • While Cripto's role in embryogenesis involves complexing with Alk4 to mediate Transforming Growth Factor-beta (TGF-beta) ligand Nodal signaling, its precise mechanism in promoting cell transformation and tumorigenesis remains largely undefined.
  • Understanding Cripto's interactions with other TGF-beta ligands is crucial for elucidating its oncogenic potential.

Purpose of the Study:

  • To investigate the interaction between Cripto and the TGF-beta ligand Activin B.
  • To determine if Cripto overexpression affects Activin B-mediated growth inhibition in breast cancer cells.
  • To evaluate the therapeutic potential of targeting Cripto signaling using antibodies.

Main Methods:

  • Investigated the direct binding of Cripto to Activin B.
  • Assessed the effect of Cripto overexpression on Activin B-induced growth suppression in cancer cells.
  • Utilized an anti-CFC domain antibody (A8.G3.5) to block Cripto-ligand interactions and signaling.
  • Evaluated the efficacy of A8.G3.5 in inhibiting tumor growth in testicular and colon cancer xenograft models.

Main Results:

  • Demonstrated for the first time that Cripto directly binds to Activin B.
  • Showed that Cripto overexpression antagonizes Activin B's growth-inhibitory effects on breast cancer cells.
  • The anti-CFC antibody A8.G3.5 disrupted both Cripto-Nodal and Cripto-Activin B signaling by blocking Cripto's association with Alk4 or Activin B.
  • A8.G3.5 significantly inhibited tumor cell growth by up to 70% in colon and testicular cancer xenografts, where both Nodal and Activin B were expressed.

Conclusions:

  • Cripto's interaction with Activin B provides a novel mechanism for antagonizing growth inhibition, potentially promoting tumorigenesis by disrupting growth homeostasis.
  • Functional blockade of Cripto signaling, particularly through antibodies targeting its CFC domain, effectively inhibits tumor growth.
  • Antibodies targeting the Cripto CFC domain represent a promising therapeutic strategy for various solid tumors overexpressing Cripto.

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