title: A Novel Fusion Antibody Exhibits Antiangiogenic Activity and Stimulates NK Cell-mediated Immune Surveillance Through Fused NKG2D Ligand.
abstract: A single-chain variable fragment (scFv) targeting vascular endothelial growth factor receptor 2 was previously generated from a phage display library in our laboratory. However, it has shortened half-life and lacks Fc fragment for effector cell recognition. To address these challenges, a ligand of NK-cell receptor NKG2D was fused to the scFv and created a fusion protein scFv-major histocompatibility complex class I-related chain A (MICA), which is expected to recognize tumor cells through the scFv moiety and stimulate NK cells through the MICA. The fusion protein demonstrated specific binding to both vascular endothelial growth factor receptor 2 and NKG2D in protein-based and cell-based assays. In addition, it demonstrated antiangiogenic activities including restraining the proliferation, migration, transwell invasion, and tube formation of human umbilical vein endothelial cells. Furthermore, the fusion protein exhibited significant cytotoxicity on K562, MDA-MB-435, and B16F10 cells and triggered NK92 cell-mediated cytotoxicity on MDA-MB-435 cells by stimulating the release of significant cytokines. The fusion protein targeting strategy, therefore, provides a means to engage lymphocyte effector cells against tumor specific antigen overexpressing tumor cells.
authors.affiliation: *State Key Laboratory of Natural Medicines, School of Life Science & Technology, China Pharmaceutical University, Nanjing †ImmuneOnco BiopharmCo., Ltd, Shanghai, P.R. China.
authors.forename: Desmond O
authors.initials: DO
authors.lastname: Acheampong
authors.forename: Mingying
authors.initials: M
authors.lastname: Tang
authors.forename: Youfu
authors.initials: Y
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.forename: Wei
authors.initials: W
authors.lastname: Xie
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Chen
authors.forename: Wenzhi
authors.initials: W
authors.lastname: Tian
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D017951:Antigen Presentation; D002465:Cell Movement; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007157:Immunologic Surveillance; D007167:Immunotherapy / Q000379:methods*; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000628:therapy*; D038081:Organogenesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D057127:Single-Chain Antibodies / Q000494:pharmacology*
chemical_list: D020533:Angiogenesis Inhibitors; D015395:Histocompatibility Antigens Class I; D055655:NK Cell Lectin-Like Receptor Subfamily K; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; C508053:ERBB2 protein, human