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[Cancer Research 59, 347-352, January 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 347-352, January 15, 1999]
© 1999 American Association for Cancer Research

Biochemistry

Increased Binding Affinity and Valence of Recombinant Antibody Fragments Lead to Improved Targeting of Tumoral Angiogenesis1

Francesca Viti, Lorenzo Tarli, Leonardo Giovannoni, Luciano Zardi and Dario Neri2

Institut für Molekularbiologie und Biophysik, ETH Hönggerberg, CH-8093 Zürich, Switzerland [F. V., L. T., D. N.]; Dipartimento di Biologia Molecolare, Sezíone di Biochimica, Università di Siena, 53100 Siena, Italy [L. G.]; and Istituto Nazionale per la Ricerca sul Cancro/Centro di Biotecnologie Avanzate, 16132 Genova, Italy [L. Z.]

The formation of new blood vessels (angiogenesis) is an important step in tumor progression. Molecules capable of selectively targeting markers of angiogenesis may offer opportunities for the in vivo imaging of aggressive tumors and for the delivery of toxic agents to the tumoral vasculature. Using antibody phage display libraries and combinatorial mutagenesis, we isolated single-chain Fv antibody fragments, which recognize with different affinities the same epitope of the ED-B domain of fibronectin, a marker of angiogenesis. Two single-chain Fv fragments, E1 and L19, with dissociation constants of 41 nM and 0.054 nM, respectively, were investigated for their ability to target F9 murine teratocarcinoma grafted s.c. in nude mice when injected i.v. in either monomeric or homodimeric form (Mr 27,000 and 54,000, respectively). Biodistribution studies, performed at two time points (4 h and 24 h) with radiolabeled samples, showed that the higher affinity antibody targets the tumor significantly better than the lower affinity one, in terms both of tumor:organ ratios and of the amounts of antibody delivered to the tumor. In particular, more than 20% of the injected dose of dimeric L19 accumulated per gram of tumor at 4 h; the tumor:organ ratios at 4 h and 24 h were in the (2.1–8.6):1 and (10.3–29.4):1 range, respectively. This study demonstrates that, although vasculature represents only a small fraction of the total tumor mass, anti-ED-B antibodies can selectively target tumors in vivo and that this process is particularly efficient if very high-affinity binders are used.




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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
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Annual Meeting Education Book Meeting Abstracts Online
Copyright © 1999 by the American Association for Cancer Research.