期刊
MOLECULAR THERAPY-ONCOLYTICS
卷 27, 期 -, 页码 256-269出版社
CELL PRESS
DOI: 10.1016/j.omto.2022.11.001
关键词
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资金
- Ministry of Science and Technology of the People's Republic of China (973 Program) [2012CB837600]
- Beijing Municipal Science and Technology Commission
- Beijing Key Laboratory of Pathogen Invasion and Immune Defense [Z171100002217064]
The study successfully developed pH-dependent anti-EGFR antibodies with cross-species reactivity, demonstrating their tumor-selective binding to EGFR under acidic conditions and potential to overcome limitations of antibody binding to normal tissues.
The clinical use of anti-EGFR antibody-based cancer therapy has been limited by antibody-EGFR binding in normal tis-sues, so developing pH-dependent anti-EGFR antibodies that selectively bind with EGFR in tumors-by taking advan-tage of the acidity of tumor microenvironment relative to normal tissues-may overcome these limitations. Here, we generated pH-dependent anti-EGFR antibodies with cross -species reactivity for human and mouse EGFR, and we demon-strate that pH-dependent antibodies exhibit tumor-selective binding by binding strongly to EGFR under acidic conditions (pH 6.5) but binding weakly under neutral (pH 7.4) condi-tions. Based on screening a non-immune human antibody library and antibody affinity maturation, we initially generated antibodies with cross-species reactivity for human and mouse EGFR. A structure model was subsequently constructed and interrogated for hotspots affecting pH -dependent binding, which supported development of a cross-reactive pH-dependent anti-EGFR antibody, G532. Compared with its non-pH-dependent antibody variant, G532 exhibits improved tumor selectivity, tumor penetration, and antitumor activity. Thus, beyond showing that pH -dependent anti-EGFR antibodies can overcome multiple limitations with antibody-based cancer therapies targeting EGFR, our study illustrates a structure-guided antibody -antigen binding pH-dependency engineering strategy to enhance antibody tumor selectivity and tumor penetration, which can inform the future development of antibody-based cancer therapies targeting other ubiquitously expressed molecules.
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