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A novel anti-cancer L19-interleukin-12 fusion protein with an optimized peptide linker efficiently localizes in vivo at the site of tumors.

07:00 EST 23rd December 2018 | BioPortfolio

Summary of "A novel anti-cancer L19-interleukin-12 fusion protein with an optimized peptide linker efficiently localizes in vivo at the site of tumors."

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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This article was published in the following journal.

Name: Journal of biotechnology
ISSN: 1873-4863
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Medical and Biotech [MESH] Definitions

A receptor for INTERLEUKIN-33 that is related structurally to the interleukin-1 receptor. It contains three extracellular IMMUNOGLOBULIN-LIKE DOMAIN regions and associates with INTERLEUKIN-1 RECEPTOR ACCESSORY PROTEIN upon binding IL-33 to initiate signaling. It may function in the response of HELPER T CELLS to INFLAMMATION.

An interleukin-1 receptor subtype that is involved in signaling cellular responses to INTERLEUKIN-1ALPHA and INTERLEUKIN-1BETA. The binding of this receptor to its ligand causes its favorable interaction with INTERLEUKIN-1 RECEPTOR ACCESSORY PROTEIN and the formation of an activated receptor complex.

A protein that takes part in the formation of active interleukin-1 receptor complex. It binds specifically to INTERLEUKIN-1 and the INTERLEUKIN-1 RECEPTOR TYPE I at the cell surface to form a heterotrimeric complex that brings its cytoplasmic domain into contact with the cytoplasm domain of the TYPE-I INTERLEUKIN-1 RECEPTOR. Activation of intracellular signal transduction pathways from the receptor is believed to be driven by this form of cytoplasmic interaction.

An interleukin receptor subunit that was originally discovered as a component of the INTERLEUKIN 2 RECEPTOR. It was subsequently found to be a component of several other receptors including the INTERLEUKIN 4 RECEPTOR, the INTERLEUKIN 7 RECEPTOR, the INTERLEUKIN-9 RECEPTOR, the INTERLEUKIN-15 RECEPTOR, and the INTERLEUKIN-21 RECEPTOR. Mutations in the gene for the interleukin common gamma chain have been associated with X-LINKED COMBINED IMMUNODEFICIENCY DISEASES.

A heterodimeric protein that is a cell surface antigen associated with lymphocyte activation. The initial characterization of this protein revealed one identifiable heavy chain (FUSION REGULATORY PROTEIN 1, HEAVY CHAIN) and an indeterminate smaller light chain. It is now known that a variety of light chain subunits (FUSION REGULATORY PROTEIN 1, LIGHT CHAINS) can dimerize with the heavy chain. Depending upon its light chain composition a diverse array of functions can be found for this protein. Functions include: type L amino acid transport, type y+L amino acid transport and regulation of cellular fusion.

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