期刊
ONCOIMMUNOLOGY
卷 4, 期 3, 页码 -出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/2162402X.2014.994391
关键词
calreticulin exposure; CrossMab; HER2-overexpressing breast cancer; pertuzumab; trastuzumab; T cell immunity
资金
- National Natural Science Foundation of China [81402552, 81301956]
- Innovation Program of Shanghai Municipal Education Commission [2015z90030001]
- Natural Science Foundation of Beijing, China [7154238]
- Roche's Scientific Corporation Program
- Project of PLA Eleventh-Five Year Research Program of China
- Research Fund of Ministry of Public Health
- Young Scholar Program of Second Military Medical University [2014QN01]
Although trastuzumab has succeeded in breast cancer treatment, acquired resistance is one of the prime obstacles for breast cancer therapies. There is an urgent need to develop novel HER2 antibodies against trastuzumab resistance. Here, we first rational designed avidity-imporved trastuzumab and pertuzumab variants, and explored the correlation between the binding avidity improvement and their antitumor activities. After characterization of a pertuzumab variant L56TY with potent antitumor activities, a bispecific immunoglobulin G-like CrossMab (Tras-Permut CrossMab) was generated from trastuzumab and binding avidity-improved pertuzumab variant L56TY. Although, the antitumor efficacy of trastuzumab was not enhanced by improving its binding avidity, binding avidity improvement could significantly increase the anti-proliferative and antibody-dependent cellular cytotoxicity (ADCC) activities of pertuzumab. Further studies showed that Tras-Permut CrossMab exhibited exceptional high efficiency to inhibit the progression of trastuzumab-resistant breast cancer. Notably, we found that calreticulin (CRT) exposure induced by Tras-Permut CrossMab was essential for induction of tumor-specific T cell immunity against tumor recurrence. These data indicated that simultaneous blockade of HER2 protein by Tras-Permut CrossMab could trigger CRT exposure and subsequently induce potent tumor-specific T cell immunity, suggesting it could be a promising therapeutic strategy against trastuzumab resistance.
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