Single-chain TNF, a TNF derivative with enhanced stability and antitumoral activity.
The inflammatory and proapoptotic cytokine TNF possesses a compelling potential as an antitumoral therapeutic agent. Possible target cells include the malignant cells themselves, the tumor vasculature, or the immune system. As the clinical use of TNF is limited by systemic toxicity, targeting strategies using TNF-based fusion proteins are currently used. A major obstacle, however, is that homotrimeric TNF ligands are prone to activity loss due to dissociation into their monomers. In this study, we report the construction of single-chain TNF molecule, a TNF mutant consisting of three TNF monomers fused by short peptide linkers. In comparison to wild-type TNF, single-chain TNF was found to possess increased stability in vitro and in vivo, displayed reduced systemic toxicity yet slightly enhanced antitumoral activity in mouse models. Creation of single-chain variants is a new approach for improvement of functional activity of therapeutics based on TNF family ligands.
University Stuttgart, Institute of Cell Biology and Immunology, Stuttgart, Germany.
Anja
A
Krippner-Heidenreich
Ingo
I
Grunwald
Gudrun
G
Zimmermann
Marie
M
Kühnle
Jeannette
J
Gerspach
Theobald
T
Sterns
Steve D
SD
Shnyder
Jason H
JH
Gill
Daniela N
DN
Männel
Klaus
K
Pfizenmaier
Peter
P
Scheurich
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000138:chemical synthesis*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011489:Protein Denaturation; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000235:genetics; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000138:chemical synthesis; D013816:Thermodynamics; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000138:chemical synthesis* / Q000502:physiology*
D000970:Antineoplastic Agents; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; C521469:micp75TNFR protein, mouse