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Radioimmunotherapy of Solid Tumors by Targeting Extra Domain B Fibronectin: Identification of the Best-Suited Radioimmunoconjugate

Authors' Affiliations: ¹ Schering AG Research Laboratories, Berlin, Germany; ² Forschungszentrum Rossendorf e.V., Institut für Bioorganische und Radiopharmazeutische Chemie, Dresden, Germany; and ³ Philogen S.p.A, Monteriggioni-Siena, Italy

Requests for reprints: Dietmar Berndorff, Schering AG, Research Laboratories, 13342 Berlin, Germany. Phone: 49-30-46817555; Fax: 49-30-46816609. E-mail: dietmar.berndorff{at}schering.de.

Purpose: The expression of extra domain B (ED-B) fibronectin is always associated with angiogenic processes and can be exclusively observed in tissues undergoing growth and/or extensive remodeling. Due to this selective expression, ED-B fibronectin is an interesting target for radioimmunotherapy of malignant diseases. The aim of this study was to identify the most appropriate ED-B-targeting radioimmunoconjugate for the therapy of solid tumors.

Experimental Design: Three ED-B fibronectin-binding human antibody formats of L19 were investigated: dimeric single-chain Fv (50 kDa), "small immunoprotein" (SIP, 80 kDa), and immunoglobulin G1 (IgG1, 150 kDa). These L19 derivatives were either labeled with I-125 or with In-111 (using MX-diethylenetriaminepentaacetic acid, MX-DTPA). Pharmacokinetics and tumor accumulation of the radiolabeled immunoconjugates were investigated in F9 (murine teratocarcinoma) tumor-bearing mice. Subsequently, dosimetry for the corresponding therapeutic isotopes I-13-1 and Y-90 was done. After testing the myelotoxicity of I-131-L19-SIP and I-131-L19-IgG1 in non-tumor-bearing mice, the therapeutic efficacy of these iodinated antibody formats was finally investigated in F9 tumor-bearing mice.

Results: The most favorable therapeutic index was found for I-131-L19-SIP followed by I-131-L19-IgG1. The therapeutic index of all In-111-labeled derivatives was significantly inferior. Considering the bone marrow as the dose-limiting organ, it was calculated that activities of 74 MBq I-131-L19-SIP and 25 MBq I-131-L19-IgG1 could be injected per mouse without causing severe myelotoxicity. The best therapeutic efficacy was observed using I-131-L19-SIP, resulting in significant tumor growth delay and prolonged survival after a single injection.

Conclusion: Compared with other L19-based radioimmunoconjugates, I-131-L19-SIP is characterized by superior antitumor efficacy and toxicity profile in the F9 teratocarcinoma animal model. These results indicate that ED-B fibronectin-targeted radioimmunotherapy using I-131-L19-SIP has potential to be applied to treatment of solid cancers.

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