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1.
J Biol Chem ; 289(12): 8493-507, 2014 Mar 21.
Article in English | MEDLINE | ID: mdl-24474690

ABSTRACT

Targeting effector molecules to tumor cells is a promising mode of action for cancer therapy and diagnostics. Binding proteins with high affinity and specificity for a tumor target that carry effector molecules such as toxins, cytokines, or radiolabels to their intended site of action are required for these applications. In order to yield high tumor accumulation while maintaining low levels in healthy tissues and blood, the half-life of such conjugates needs to be in an optimal range. Scaffold-based binding molecules are small proteins with high affinity and short systemic circulation. Due to their low molecular complexity, they are well suited for combination with effector molecules as well as half-life extension technologies yielding therapeutics with half-lives adapted to the specific therapy. We have identified ubiquitin as an ideal scaffold protein due to its outstanding biophysical and biochemical properties. Based on a dimeric ubiquitin library, high affinity and specific binding molecules, so-called Affilin® molecules, have been selected against the extradomain B of fibronectin, a target almost exclusively expressed in tumor tissues. Extradomain B-binding molecules feature high thermal and serum stability as well as strong in vitro target binding and in vivo tumor accumulation. Application of several half-life extension technologies results in molecules of largely unaffected affinity but significantly prolonged in vivo half-life and tumor retention. Our results demonstrate the utility of ubiquitin as a scaffold for the generation of high affinity binders in a modular fashion, which can be combined with effector molecules and half-life extension technologies.


Subject(s)
Fibronectins/metabolism , Neoplasms/metabolism , Ubiquitin/metabolism , Animals , Cell Line , Humans , Mice , Models, Molecular , Peptide Library , Protein Binding , Protein Engineering , Protein Structure, Tertiary , Ubiquitin/chemistry , Ubiquitin/genetics , Ubiquitin/pharmacokinetics
2.
EMBO Rep ; 4(5): 511-6, 2003 May.
Article in English | MEDLINE | ID: mdl-12717455

ABSTRACT

Obesity is a metabolic disorder related to improper control of energy uptake and expenditure, which results in excessive accumulation of body fat. Initial insights into the genetic pathways that regulate energy metabolism have been provided by a discrete number of obesity-related genes that have been identified in mammals. Here, we report the identification of the adipose (adp) gene, the mutation of which causes obesity in Drosophila. Loss of adp activity promotes increased fat storage, which extends the lifespan of mutant flies under starvation conditions. By contrast, adp gain-of-function causes a specific reduction of the fat body in Drosophila. adp encodes an evolutionarily conserved WD40/tetratricopeptide-repeat-domain protein that is likely to represent an intermediate in a novel signalling pathway.


Subject(s)
Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Fat Body/metabolism , Mutation , Obesity/genetics , Proteins/genetics , Triglycerides/metabolism , Amino Acid Sequence , Animals , Cloning, Molecular , DNA, Complementary/chemistry , Drosophila Proteins/biosynthesis , Drosophila Proteins/genetics , Energy Metabolism/genetics , Evolution, Molecular , Larva/genetics , Larva/metabolism , Molecular Sequence Data , Obesity/metabolism , Phenotype , Proteins/metabolism , Sequence Alignment , Triglycerides/genetics
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