Tumor-targeting properties of novel antibodies specific to the large isoform of tenascin-C.
BACKGROUND
The targeted delivery of bioactive molecules with antibodies specific to tumor-associated antigens represents a promising strategy for improving the efficacy of tumor therapy. The large isoform of tenascin-C, an abundant glycoprotein of the tumor extracellular matrix, is strongly overexpressed in adult tissue undergoing tissue remodeling, including wound healing and neoplasia, and has been implicated in a variety of different cancers while being virtually undetectable in most normal adult tissues.


METHODS
We have used antibody phage technology to generate good-quality human recombinant antibodies (F16 and P12) specific to the alternatively spliced domains A1 and D of the large isoform of tenascin-C. The tumor-targeting properties of F16 and P12 were assessed by biodistribution studies in tumor xenografts using the antibodies in small immunoprotein (SIP) format.


RESULTS
SIP(F16) selectively accumulated at the tumor site with 4.5%ID/g at 24 hours in the U87 glioblastoma model but was rapidly cleared from other organs (tumor-to-organ ratios, approximately 10:1). The accumulation of SIP(P12) in the tumor was lower compared with SIP(F16) and persistent levels of radioactivity were observed in the intestine.


CONCLUSIONS
These data suggest that the F16 antibody, specific to domain A1 of tenascin-C, is a promising building block for the development of antibody-based pharmaceuticals in view of its excellent tumor-targeting performance and the strong expression of the antigen in a variety of primary and metastatic tumors.
Brack
Simon S
SS
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology Zürich, Switzerland.
Silacci
Michela
M
Birchler
Manfred
M
Neri
Dario
D
D017398:Alternative Splicing; D000818:Animals; D000906:Antibodies / Q000032:analysis* / Q000276:immunology* / Q000627:therapeutic use; D000917:Antibody Formation; D001932:Brain Neoplasms / Q000276:immunology; D005109:Extracellular Matrix; D005909:Glioblastoma / Q000276:immunology; D007128:Immunoglobulin Fragments; D007135:Immunoglobulin Variable Region; D007150:Immunohistochemistry; D008545:Melanoma / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D020033:Protein Isoforms; D012878:Skin Neoplasms / Q000276:immunology; D019063:Tenascin / Q000737:chemistry / Q000276:immunology*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D000906:Antibodies; D007128:Immunoglobulin Fragments; D007135:Immunoglobulin Variable Region; D020033:Protein Isoforms; D019063:Tenascin