Targeted Reconstitution of Cytokine Activity upon Antigen Binding using Split Cytokine Antibody Fusion Proteins.
- Venetz D From the Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 1-5/10, CH-8093 Zürich, Switzerland dario.venetz@pharma.ethz.ch.
- Koovely D From the Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 1-5/10, CH-8093 Zürich, Switzerland.
- Weder B From the Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 1-5/10, CH-8093 Zürich, Switzerland.
- Neri D From the Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 1-5/10, CH-8093 Zürich, Switzerland dario.neri@pharma.ethz.ch.
- 2016-07-13
Published in:
- The Journal of biological chemistry. - 2016
activity reconstitution
activity-on-demand
antibody
cancer
cytokine
immunotherapy
interleukin-12
pharmacology
split protein
tumor targeting
Animals
Antibodies
Humans
Interleukin-12 Subunit p35
Interleukin-12 Subunit p40
Mice
Recombinant Fusion Proteins
English
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.
- Language
-
- English
- Open access status
- bronze
- Identifiers
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- DOI 10.1074/jbc.M116.737734
- PMID 27402834
- Persistent URL
- https://sonar.ch/global/documents/36738
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