Cripto was also the subject of a joint BGEN/IMGN/NCI abstract
Inhibition of human tumor xenografts by anti-Cripto antibodies.
Doreen J. LePage, Heather Adkins, Cindy Bottiglio, Glenna Heaney, Paul Rayhorn, Anne Zichittella, Olivia Orozco, Konrad Miatkowski, Ling Ling Chen, Steve Fawell, Matthew Jarpe, Cheryl Dionne, Robert J. Lutz, David Salomon, Michele Sanicola, Biogen, Inc., Cambridge, MA; ImmunoGen, Cambridge, MA; National Cancer Institute, Bethesda, MD.
Cripto is required for signaling during embryogenesis by the TGF-beta ligand, Nodal, through the Activin type I receptor, Alk4. Transgenic MMTV-Cripto animals develop mammary tumors, and Cripto overexpression is noted in many solid tumors including 70-80% of breast, colon and lung. This finding highlights Cripto as an important oncogene, yet how it promotes cell transformation is unclear. We report the first characterization of blocking Cripto monoclonal antibodies which inhibit Cripto signaling in vitro and tumor growth in vivo. Utilizing Cripto mutants, we identified antibodies to epitopes important for signaling in transformed cells and interactions with Alk4. Two blocking antibodies, Cripto antibodies A27.F6.1 and A8.G3.5, inhibited tumor growth in a human cancer NCCIT xenograft model by 30 and 70% respectively, while a non-blocking Cripto antibody did not. We further show that Cripto can bind directly to Activin B and that Cripto blocks Activin B induced growth inhibition of human breast cancer cells. This blocking effect is reversed by a Cripto antibody that inhibits Cripto-Alk4 interactions. Therefore, we propose that Cripto promotes tumorigenesis by blocking Activin B growth inhibitory signals through forming non-productive complexes with Alk4. In addition to testing the therapeutic utility of blocking Cripto function, we also tested the ability of anti-Cripto antibodies to deliver a lethal payload with a Cripto antibody-drug conjugate. Cripto is a good candidate for this strategy, given the high level of expression of Cripto
noted in human tumor samples relative to normal adjacent tissue. We report here that an anti-Cripto antibody conjugated to the maytansinoid drug, DM1, causes the regression of preformed tumors in two human xenograft tumor models. |
