title: Tailored immunoconjugate therapy depending on a quantity of tumor stroma.
abstract: The purpose of this study was to clarify the appropriate combination of targeting antibody and conjugate-design of anti-tumor immunoconjugate depending on a quantity of tumor stroma. Most human solid tumors including pancreatic cancer (PC) forming hypovascular and stroma-rich tumor hinders the penetration of monoclonal antibodies (mAbs) into the cells, and that leads to failure of the conventional cell-targeting immunoconjugate strategy. To overcome this drawback, SN-38 as topoisomerase 1 inhibitor was conjugated to a mAb to collagen 4, a plentiful component of the tumor stroma via ester-bond. The immunoconjugate, which was able to release SN-38 in physiological condition outside the cells, was effective to stroma-rich PC-tumor. On the other hand, anti-CD 20 mAb-PEG-SN-38 via carbamate-bond as conventional immunoconjugate, enabled SN-38 to be released by a carboxylesterase inside of the tumor cell following the internalization, showed strong anti-tumor activity against malignant lymphoma as hypervascular and stroma-poor tumor. The conjugate-design, in parallel with the choice of targeting antibodies, should be selected to maximize the therapeutic effect in each individual tumor having a distinct stromal structure.
authors.affiliation: Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yasunaga
authors.forename: Shino
authors.initials: S
authors.lastname: Manabe
authors.forename: David
authors.initials: D
authors.lastname: Tarin
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsumura
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D003094:Collagen / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology / Q000494:pharmacology*; D000077146:Irinotecan; D008223:Lymphoma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D003094:Collagen; D002166:Camptothecin