A humanized anti-osteopontin antibody inhibits breast cancer growth and metastasis in vivo
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Osteopontin (OPN) has been implicated as an important mediator of breast cancer progression and metastasis and has been investigated for use as a potential therapeutic target in the treatment of breast cancer. However, the in vivo antitumor effect of anti-OPN antibodies on breast cancer has not been reported. In this study, a mouse anti-human OPN antibody (1A12) was humanized by complementarity-determining region grafting method based on computer-assisted molecular modeling. A humanized version of 1A12, denoted as hu1A12, was shown to possess affinity comparable to that of its parental antibody. The ability of hu1A12 to inhibit cell migration, adhesion, invasion and colony formation was assessed in a highly metastatic human breast cancer cell line MDA-MB-435S. The results indicated that hu1A12 was effective in inhibiting the cell adhesion, migration, invasion and colony formation of MDA-MB-435S cells in vitro. hu1A12 also showed significant efficacy in suppressing primary tumor growth and spontaneous metastasis in a mouse lung metastasis model of human breast cancer. The specific epitope recognized by hu1A12 was identified to be 212NAPSD216, adjacent to the calcium binding domain of OPN. Our data strongly support that OPN is a potential target for the antibody-based therapies of breast cancer. The humanized anti-OPN antibody hu1A12 may be a promising therapeutic agent for the treatment of human breast cancer.
KeywordsBreast cancer Humanized antibody Immunogenicity Metastasis Osteopontin
We thank Ms. Yang Yang and Ms. Jing Xu for their technical assistance as well as antibody production facility of National Engineering Research Center for Antibody Medicine for providing the purified control antibodies. This work was supported by National Natural Science Foundation of China, Ministry of Science & Technology of China (973 & 863 program projects), National Key Project for Infectious Disease, National Key New Drug Creation and Manufacturing Program and Shanghai Commission of Science & Technology. This study is also supported by Shanghai Leading Academic Discipline Project.
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