期刊
JOURNAL OF BIOTECHNOLOGY
卷 291, 期 -, 页码 17-25出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jbiotec.2018.12.004
关键词
Tumor targeting; Fibronectin; Immunocytokines; Interleukin-12; Linker optimization
Antibody-cytokine fusion proteins are a class of biopharmaceuticals, with the potential to modulate the activity of the immune system at the site of disease. The molecular format used to connect antibody moiety and cytokine payload can have a profound influence on biological activity and pharmacokinetic properties. The optimization of fusion protein format is particularly challenging for heterodimeric cytokines, since various molecular arrangements can be considered. In this article, we have explored the role of linker in a tumor-targeting IL12 fusion protein, based on the L19 antibody, specific to the extra-domain B of fibronectin. In biodistribution studies performed in tumor-bearing mice using radioiodinated protein preparations, fusion of human IL12 at the N-terminus of the L19 antibody in tandem-diabody format led to higher tumor uptake and improved tumor-to-organ ratios, compared to a similar fusion protein featuring L19 in IgG1 format. Moreover, optimization of the amino acid composition in eight variants of the linker connecting the IL12 moiety to the tandem-diabody revealed that a 15-amino acid linker (GSADGGSSAGGSDAG) displayed the best tumor targeting characteristics, with a long residence time at the tumor site and a rapid clearance from blood and normal organs. The product is being developed for industrial and clinical applications.
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