title: Combating non-Hodgkin lymphoma by targeting both CD20 and HLA-DR through CD20-243 CrossMab.
abstract: Although rituximab has revolutionized the treatment of hematological malignancies, the acquired resistance is one of the prime obstacles for cancer treatment, and development of novel CD20-targeting antibodies with potent anti-tumor activities and specificities is urgently needed. Emerging evidence has indicated that lysosomes can be considered as an "Achilles heel" for cancer cells, and might serve as an effective way to kill resistant cancer cells. HLA-DR antibody L243 has been recently reported to elicit potent lysosome-mediated cell death in lymphoma and leukemia cells, suggesting that HLA-DR could be used as a potential target against lymphoma. In this study, we generated a bispecific immunoglobulin G-like antibody targeting both CD20 and HLA-DR (CD20-243 CrossMab) through CrossMab technology. We found that the CrossMab could induce remarkably high levels of complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity and anti-proliferative activity. Notably, although HLA-DR is expressed on normal and malignant cells, the CrossMab exhibited highly anti-tumor specificity, showing efficient eradication of hematological malignancies both in vitro and in vivo. Our data indicated that combined targeting of CD20 and HLA-DR could be an effective approach against malignancies, suggesting that CD20-243 CrossMab would be a promising therapeutic agent against lymphoma.
authors.affiliation: International Joint Cancer Institute; Second Military Medical University; Shanghai, PR China; PLA General Hospital Cancer Center; PLA School of Medicine; Beijing, PR China; The State Key Laboratory of Antibody Medicine & Targeting Therapy and Shanghai Key Laboratory of Cell Engineering & Antibody; Shanghai, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: PLA General Hospital Cancer Center; PLA School of Medicine; Beijing, PR China.
authors.forename: Feiyue
authors.initials: F
authors.lastname: Xie
authors.forename: Xin
authors.initials: X
authors.lastname: Tong
authors.affiliation: International Joint Cancer Institute; Second Military Medical University; Shanghai, PR China.
authors.forename: Huafei
authors.initials: H
authors.lastname: Li
authors.affiliation: International Joint Cancer Institute; Second Military Medical University; Shanghai, PR China.
authors.forename: Yaling
authors.initials: Y
authors.lastname: Chen
authors.affiliation: International Joint Cancer Institute; Second Military Medical University; Shanghai, PR China.
authors.forename: Weizhu
authors.initials: W
authors.lastname: Qian
authors.affiliation: School of Pharmaceutical; Liaocheng University; Liaocheng, PR China.
authors.forename: Shuyan
authors.initials: S
authors.lastname: Duan
authors.affiliation: School of Pharmaceutical; Liaocheng University; Liaocheng, PR China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zheng
authors.affiliation: School of Pharmaceutical; Liaocheng University; Liaocheng, PR China.
authors.forename: Ziye
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: International Joint Cancer Institute; Second Military Medical University; Shanghai, PR China.
authors.forename: Bohua
authors.initials: B
authors.lastname: Li
authors.affiliation: International Joint Cancer Institute; Second Military Medical University; Shanghai, PR China; The State Key Laboratory of Antibody Medicine & Targeting Therapy and Shanghai Key Laboratory of Cell Engineering & Antibody; Shanghai, PR China.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Zhang
authors.affiliation: International Joint Cancer Institute; Second Military Medical University; Shanghai, PR China; PLA General Hospital Cancer Center; PLA School of Medicine; Beijing, PR China; The State Key Laboratory of Antibody Medicine & Targeting Therapy and Shanghai Key Laboratory of Cell Engineering & Antibody; Shanghai, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.affiliation: International Joint Cancer Institute; Second Military Medical University; Shanghai, PR China; PLA General Hospital Cancer Center; PLA School of Medicine; Beijing, PR China; The State Key Laboratory of Antibody Medicine & Targeting Therapy and Shanghai Key Laboratory of Cell Engineering & Antibody; Shanghai, PR China; School of Pharmaceutical; Liaocheng University; Liaocheng, PR China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Dai
authors.affiliation: International Joint Cancer Institute; Second Military Medical University; Shanghai, PR China; PLA General Hospital Cancer Center; PLA School of Medicine; Beijing, PR China; The State Key Laboratory of Antibody Medicine & Targeting Therapy and Shanghai Key Laboratory of Cell Engineering & Antibody; Shanghai, PR China; School of Pharmaceutical; Liaocheng University; Liaocheng, PR China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: International Joint Cancer Institute; Second Military Medical University; Shanghai, PR China; PLA General Hospital Cancer Center; PLA School of Medicine; Beijing, PR China; The State Key Laboratory of Antibody Medicine & Targeting Therapy and Shanghai Key Laboratory of Cell Engineering & Antibody; Shanghai, PR China; School of Pharmaceutical; Liaocheng University; Liaocheng, PR China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Hou
authors.affiliation: International Joint Cancer Institute; Second Military Medical University; Shanghai, PR China; PLA General Hospital Cancer Center; PLA School of Medicine; Beijing, PR China; The State Key Laboratory of Antibody Medicine & Targeting Therapy and Shanghai Key Laboratory of Cell Engineering & Antibody; Shanghai, PR China; School of Pharmaceutical; Liaocheng University; Liaocheng, PR China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity; D018951:Antigens, CD20 / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D006684:HLA-DR Antigens / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000627:therapeutic use; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology* / Q000628:therapy; D008247:Lysosomes / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D000069283:Rituximab; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D006684:HLA-DR Antigens; D007074:Immunoglobulin G; D000069283:Rituximab
keywords: CD20 antibody; CrossMab; HLA-DR; lysosome-mediated cell death; resistant cancer cell; rituximab