6LUN

NN2101 Antibody Fab fragment

Summary for 6LUN

• Entry DOI: 10.2210/pdb6lun/pdb
• Descriptor: NN2101 (3 entities in total)
• Functional Keywords: antibody, structural protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 4
• Total formula weight: 94677.59

Authors

Kim, H.N.,Seo, M.D.,Park, S.K. (deposition date: 2020-01-30, release date: 2021-02-03, Last modification date: 2024-11-06)

Primary citation

Kim, J.O.,Kim, H.N.,Kim, K.H.,Baek, E.J.,Park, J.Y.,Ha, K.,Heo, D.R.,Seo, M.D.,Park, S.G.
Development and characterization of a fully human antibody targeting SCF/c-kit signaling.
Int.J.Biol.Macromol., 159:66-78, 2020

PubMed Abstract: CD117/c-kit, a tyrosine kinase receptor, plays a critical role in hematopoiesis, pigmentation, and fertility. The overexpression and activation of c-kit are thought to promote tumor growth and have been reported in various cancers, including leukemia, glioblastoma and mastocytosis. To disrupt the SCF/c-kit signaling axis in cancer, we generated a c-kit antagonist human antibody (NN2101) that binds to domain 2/3 of c-kit. This completely blocked the SCF-mediated phosphorylation of c-kit and inhibited TF-1 cell proliferation, erythroleukemia. In addition, the examination of binding affinity using surface plasmon resonance (SPR) assay showed that NN2101 can bind to c-kit of monkeys (K = 2.92 × 10 M), rats (K = 1.68 × 10 M), mice (K = 11.5 × 10 M), and humans (K = 2.83 × 10 M). We showed that NN2101 does not cause antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. The immunogenicity of NN2101 was similar to that of bevacizumab. Furthermore, the crystal structure of NN2101 Fab was determined and the structure of NN2101 Fab:c-kit complex was modeled. Structural information, as well as mutagenesis results, revealed that NN2101 can bind to the SCF-binding regions of c-kit. Collectively, we generated a c-kit neutralizing human antibody (NN2101) for the treatment of erythroleukemia and characterized its biophysical properties. NN2101 can potentially be used as a therapeutic antibody to treat different cancers.

PubMed: 32437800
DOI: 10.1016/j.ijbiomac.2020.05.045

Experimental method

X-RAY DIFFRACTION (1.9 Å)