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Publication Abstract from PubMed

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(D) = 2.92 x 10(-10) M), rats (K(D) = 1.68 x 10(-6) M), mice (K(D) = 11.5 x 10(-9) M), and humans (K(D) = 2.83 x 10(-12) 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.

Development and characterization of a fully human antibody targeting SCF/c-kit signaling.,Kim JO, Kim HN, Kim KH, Baek EJ, Park JY, Ha K, Heo DR, Seo MD, Park SG Int J Biol Macromol. 2020 Sep 15;159:66-78. doi: 10.1016/j.ijbiomac.2020.05.045. , Epub 2020 May 11. PMID:32437800^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.