Cripto: a novel target for antibody-based cancer immunotherapy.
Cripto, a member of the epidermal growth factor-Cripto-FRL-Criptic (EGF-CFC) family, has been described recently as a potential target for immunotherapy (Adkins et al., J Clin Invest 2003;112:575-87). We have produced rat monoclonal antibodies (mAbs) to a Cripto 17-mer peptide, corresponding to the "EGF-like" motif of Cripto. The mAbs react with most cancers of the breast, colon, lung, stomach, and pancreas but do not react or react weakly with normal tissues. The mAbs inhibit cancer cell growth in vitro, and this effect was greater with cytotoxic drugs such as 5-fluorouracil, epirubicin, and cisplatin. The anti-Cripto mAbs prevent tumor development in vivo and inhibit the growth of established tumors of LS174T colon xenografts in Scid mice. The growth inhibitory effects with these mAbs may be greater than those described elsewhere, possibly because of IgM giving more effective cross-linking or binding to a different epitope (EGF-like region versus CFC region). The mechanism of inhibitory effects of the Cripto mAbs includes both cancer cell apoptosis, activation of c-Jun-NH(2)-terminal kinase and p38 kinase signaling pathways and blocking of Akt phosphorylation. Thus, Cripto is a unique target, and mAbs to Cripto could be of therapeutic value for human cancers.
Xing
Pei Xiang
PX
Cancer Immunotherapy Laboratory, Austin Research Institute, Heidelberg, Victoria, Australia. px.xing@ari.unimelb.edu.au
Hu
Xiu Feng
XF
Pietersz
Geoffrey A
GA
Hosick
Howard L
HL
McKenzie
Ian F C
IF
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology* / Q000628:therapy*; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors* / Q000276:immunology*; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D010446:Peptide Fragments; C070636:TDGF1 protein, human; C489450:Tdgf1 protein, mouse; D004815:Epidermal Growth Factor