Human monoclonal antibodies to domain C of tenascin-C selectively target solid tumors in vivo.
We had previously reported that splice isoforms of tenascin-C containing the extra-domain C are virtually absent in normal adult tissues but are highly abundant in high-grade astrocytomas, with a prominent peri-vascular pattern of expression. We now report that the extra-domain C of tenascin-C is strongly expressed in the majority of lung cancers, with a vascular and stromal pattern of expression. Using antibody phage technology, we have generated a human monoclonal antibody (G11), with a dissociation constant K(D) = 4.2 nM for the human domain C. The G11 antibody, expressed in scFv and in mini-antibody (SIP) format, as well as a scFv-interleukin-2 fusion protein, was then characterized in quantitative biodistribution studies using mice grafted subcutaneously with U87 gliomas, revealing a selective tumor uptake, with tumor/blood ratios up to 11.8:1 at 24 h. A radioiodinated preparation of SIP(G11) was also investigated in a double tracer study using an orthotopic rat glioma model, confirming the antibody's ability to preferentially localize at the tumor site, with tumor/brain ratios superior to the ones observed with (18)F-fluorodeoxyglucose. These tumor-targeting properties, together with the strong immunohistochemical staining of human tumor sections, indicate that the G11 antibody may be used as a portable targeting moiety for the selective delivery of imaging and therapeutic agents to gliomas and lung tumors.
Silacci
Michela
M
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH) Zürich Wolfgang-Paulistrasse 10, Zürich, Switzerland.
Brack
Simon S
SS
Späth
Nicolas
N
Buck
Alfred
A
Hillinger
Sven
S
Arni
Stephan
S
Weder
Walter
W
Zardi
Luciano
L
Neri
Dario
D
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D045744:Cell Line, Tumor; D005910:Glioma / Q000628:therapy; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007700:Kinetics; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D019151:Peptide Library; D017434:Protein Structure, Tertiary; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D019063:Tenascin / Q000737:chemistry*
D000911:Antibodies, Monoclonal; D019151:Peptide Library; D011993:Recombinant Fusion Proteins; D019063:Tenascin