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Cripto: a novel target for antibody-based cancer immunotherapy.
Pei Xiang Xing1, Xiu Feng Hu, Geoffrey A Pietersz
1Cancer Immunotherapy Laboratory, Austin Research Institute, Heidelberg, Victoria, Australia. px.xing@ari.unimelb.edu.au
Cancer Research
|June 3, 2004
Summary
Monoclonal antibodies targeting Cripto, a protein found in many cancers, effectively inhibit tumor growth and induce cancer cell death. These anti-Cripto antibodies show therapeutic potential for various human cancers.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Cripto, a member of the epidermal growth factor-Cripto-FRL-Criptic (EGF-CFC) family, is a potential target for cancer immunotherapy.
- Monoclonal antibodies (mAbs) were developed against a specific peptide motif of Cripto.
Purpose of the Study:
- To investigate the therapeutic potential of anti-Cripto monoclonal antibodies in various human cancers.
- To evaluate the efficacy of these mAbs in inhibiting cancer cell growth and tumor development both in vitro and in vivo.
Main Methods:
- Production of rat monoclonal antibodies against a Cripto 17-mer peptide (EGF-like motif).
- Testing mAb reactivity against a panel of human cancer cell lines and normal tissues.
- Assessing the in vitro effects of mAbs on cancer cell growth, alone and in combination with cytotoxic drugs.
- Evaluating the in vivo efficacy of mAbs in preventing tumor development and inhibiting established tumors in mouse xenograft models.
- Investigating the molecular mechanisms underlying the inhibitory effects of anti-Cripto mAbs.
Main Results:
- The developed mAbs demonstrated specific reactivity with breast, colon, lung, stomach, and pancreas cancers, with minimal reaction in normal tissues.
- Anti-Cripto mAbs significantly inhibited cancer cell growth in vitro, with enhanced effects when combined with chemotherapy drugs like 5-fluorouracil, epirubicin, and cisplatin.
- In vivo studies showed that anti-Cripto mAbs prevented tumor formation and reduced the growth of established colon cancer xenografts in Scid mice.
- The growth inhibition mechanisms involved inducing cancer cell apoptosis, activating c-Jun-NH(2)-terminal kinase and p38 kinase pathways, and blocking Akt phosphorylation.
Conclusions:
- Cripto represents a unique and promising therapeutic target for human cancers.
- Monoclonal antibodies targeting Cripto exhibit significant anti-cancer activity, suggesting their potential as a valuable therapeutic strategy.