A human mAb specific to oncofetal fibronectin selectively targets chronic skin inflammation in vivo.
The antibody-based targeted delivery of bioactive agents to sites of angiogenesis is an attractive therapeutic strategy for cancer treatment, but is largely unexplored for chronic inflammatory diseases. In this article, we show that the extra domain B (EDB) domain of fibronectin, a marker of angiogenesis, is expressed in psoriatic lesions, and that the anti-EDB human antibody L19 can selectively localize to chronically inflamed skin in vivo. The L19-based delivery of the cytokines IL10 and IL12 did not improve or worsen inflammation in a mouse model of chronic skin inflammation, which overexpressed vascular endothelial growth factor under the control of the keratin-14 promoter. By contrast, the L19-based targeted delivery of the proinflammatory cytokine IL2 or of the photosensitizer Sn(IV) chlorin e6 resulted in an increased swelling and reddening of inflamed skin. These results indicate that antibodies specific to components of the modified extracellular matrix can selectively accumulate at chronically inflamed sites in vivo. This observation now stimulates the search for bioactive molecules which can be fused to antibodies and which may confer a therapeutic benefit as a result of their preferential accumulation in psoriatic lesions and other sites of inflammation.
Trachsel
Eveline
E
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland.
Kaspar
Manuela
M
Bootz
Frank
F
Detmar
Michael
M
Neri
Dario
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000915:Antibody Affinity; D002908:Chronic Disease; D003876:Dermatitis, Atopic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016503:Drug Delivery Systems; D005260:Female; D005353:Fibronectins / Q000276:immunology*; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016753:Interleukin-10 / Q000008:administration & dosage / Q000494:pharmacology; D018664:Interleukin-12 / Q000008:administration & dosage / Q000494:pharmacology; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology; D008027:Light; D008665:Metalloporphyrins / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000494:pharmacology; D012867:Skin / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D000911:Antibodies, Monoclonal; D005353:Fibronectins; D007376:Interleukin-2; D008665:Metalloporphyrins; D017319:Photosensitizing Agents; D042461:Vascular Endothelial Growth Factor A; C121542:oncofetal fibronectin; C069117:tin(IV) chlorin e6; D016753:Interleukin-10; D018664:Interleukin-12