Targeted Reconstitution of Cytokine Activity Upon Antigen Binding Using Split Cytokine Antibody Fusion Proteins

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2016 Jul 13

PMID 27402834

Citations 22

Authors

Dario Venetz

Danil Koovely

Bruce Weder

Dario Neri

Affiliations

Soon will be listed here.

Abstract

The targeted assembly of antibody products upon antigen binding represents a novel strategy for the reconstitution of potent therapeutic activity at the site of disease, sparing healthy tissues. We demonstrate that interleukin-12, a heterodimeric pro-inflammatory cytokine consisting of the disulfide-linked p40 and p35 subunits, can be reconstituted by sequential reassembly of fusion proteins based on antibody fragments and interleukin-12 subunit mutants. Analysis of the immunostimulatory properties of interleukin-12 and its derivatives surprisingly revealed that the mutated p35 subunit partially retained the activity of the parental cytokine, whereas the p40 subunit alone was not able to stimulate T cells or natural killer cells. The concept of stepwise antibody-based reassembly of split cytokines could be useful for the development of other anticancer therapeutics with improved safety and tolerability.

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