title: Facilitation of endoglin-targeting cancer therapy by development/utilization of a novel genetically engineered mouse model expressing humanized endoglin (CD105).
abstract: Endoglin (ENG) is a TGF-β coreceptor and essential for vascular development and angiogenesis. A chimeric antihuman ENG (hENG) monoclonal antibody (mAb) c-SN6j (also known as TRC105) shows promising safety and clinical efficacy features in multiple clinical trials of patients with various advanced solid tumors. Here we developed a novel genetically engineered mouse model to optimize the ENG-targeting clinical trials. We designed a new targeting vector that contains exons 4-8 of hENG gene to generate novel genetically engineered mice (GEMs) expressing functional human/mouse chimeric (humanized) ENG with desired epitopes. Genotyping of the generated mice confirmed that we generated the desired GEMs. Immunohistochemical analysis demonstrated that humanized ENG protein of the GEMs expresses epitopes defined by 7 of our 8 anti-hENG mAbs tested. Surprisingly the homozygous GEMs develop normally and are healthy. Established breast and colon tumors as well as metastasis and tumor microvessels in the GEMs were effectively suppressed by systemic administration of anti-hENG mAbs. Additionally, test result indicates that synergistic potentiation of antitumor efficacy can be induced by simultaneous targeting of two distinct epitopes by anti-hENG mAbs. Sorafenib and capecitabine also showed antitumor efficacy in the GEMs. The presented novel GEMs are the first GEMs that express the targetable humanized ENG. Test results indicate utility of the GEMs for the clinically relevant studies. Additionally, we generated GEMs expressing a different humanized ENG containing exons 5-6 of hENG gene, and the homozygous GEMs develop normally and are healthy.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY; Department of Surgery, Megumino Hospital, Eniwa, Hokkaido, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Toi
authors.forename: Masanori
authors.initials: M
authors.lastname: Tsujie
authors.forename: Yuro
authors.initials: Y
authors.lastname: Haruta
authors.forename: Kanako
authors.initials: K
authors.lastname: Fujita
authors.forename: Jill
authors.initials: J
authors.lastname: Duzen
authors.forename: Ben K
authors.initials: BK
authors.lastname: Seon
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D017209:Apoptosis; D015139:Blotting, Southern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D000071063:Endoglin; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface
keywords: antiendoglin monoclonal antibodies; genetically engineered mouse model; humanized endoglin; synergy; vascular targeting cancer therapy