Facilitation of endoglin‐targeting cancer therapy by development/utilization of a novel genetically engineered mouse model expressing humanized endoglin (CD105)

• Published in: International journal of cancer Vol. 136; no. 2; pp. 452 - 461
• Main Authors: Toi, Hirofumi, Tsujie, Masanori, Haruta, Yuro, Fujita, Kanako, Duzen, Jill, Seon, Ben K.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 15.01.2015
• Subjects: Angiogenesis; Animals; Antibodies, Monoclonal - therapeutic use; antiendoglin monoclonal antibodies; Antigens, CD - genetics; Antigens, CD - immunology; Apoptosis; Blotting, Southern; Blotting, Western; Breast Neoplasms - blood supply; Breast Neoplasms - pathology; Breast Neoplasms - therapy; Cancer; Cancer therapies; Cell Proliferation; Clinical trials; Colonic Neoplasms - blood supply; Colonic Neoplasms - pathology; Colonic Neoplasms - therapy; Disease Models, Animal; Endoglin; Female; genetically engineered mouse model; humanized endoglin; Humans; Medical research; Metastasis; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Molecular Targeted Therapy; Neoplasm Metastasis; Neovascularization, Pathologic - prevention & control; Receptors, Cell Surface - antagonists & inhibitors; Receptors, Cell Surface - genetics; Receptors, Cell Surface - immunology; Rodents; synergy; Tumor Cells, Cultured; Tumors; vascular targeting cancer therapy; synergy; genetically engineered mouse model; humanized endoglin; antiendoglin monoclonal antibodies; vascular targeting cancer therapy
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28994

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. What's new? Endoglin (ENG) is a TGF‐β coreceptor that is essential for vascular development and angiogenesis. A chimeric anti‐human ENG (hENG) monoclonal antibody has shown promising safety and clinical efficacy in clinical trials of patients with various advanced solid tumors. Here, the authors developed a novel genetically engineered mouse model expressing a functional humanized ENG to optimize ongoing and future hENG antibody‐based cancer therapy in patients. The homozygous genetically engineered mice developed normally and were healthy. Growth of established breast and colon tumors as well as metastasis and microvessel density in the mice were effectively suppressed by systemic administration of hENG mAbs.