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Bispecific Antibody Pretargeting of Tumor Neovasculature for Improved Systemic Radiotherapy of Solid Tumors

Authors' Affiliations: ¹ Schering AG, Research Laboratories, Berlin, Germany; ² IBC Pharmaceuticals, Inc.; ³ Immunomedics, Inc., Morris Plains, New Jersey; ⁴ Forschungszentrum Rossendorf eV, Institut für Bioorganische und Radiopharmazeutische Chemie, Dresden, Germany; and ⁵ Center for Molecular Medicine and Immunology, Belleville, New Jersey

Requests for reprints: Dieter Moosmayer, Schering AG Research Laboratories, Protein Chemistry, Muellerstrasse 178, 13342 Berlin, Germany. Phone: 49-30-468-17038; Fax: 49-30-468-16707; E-mail: dieter.moosmayer{at}schering.de.

Purpose: Extra domain B (ED-B) fibronectin is a specific tumor matrix marker for targeting angiogenesis in solid tumors. In this study, the radiotherapeutic potential of the directly radioiodinated divalent anti-ED-B antibody fragment, L19 small immunoprotein (L19-SIP; 75,000 Da), was compared with a pretargeting approach using the bispecific antibody AP39xm679 (bsMAb; 75,000 Da).

Experimental Design: The bsMAb was prepared by coupling an anti-ED-B single-chain Fv (AP39) to the Fab' of the murine antibody m679, which binds to the small peptidic hapten histamine-succinyl-glycine (HSG). As an effector molecule for the pretargeting approach, the ¹¹¹In-labeled HSG-DOTA complex was injected 25 or 41 hours after the bsMAb. The kinetics of both the iodinated bsMAb and the pretargeted ¹¹¹In-labeled HSG hapten were investigated in mice bearing human glioblastoma xenografts (U251) and compared with the kinetics and tumor accumulation of radioiodinated L19-SIP. ¹¹¹In and ¹²⁵I were used as surrogate marker for the therapeutic radioisotopes ⁹⁰Y/¹⁷⁷Lu and ¹³¹I, respectively.

Results: Tumor uptake of the pretargeted ¹¹¹In-labeled peptide was significantly higher than ¹²⁵I-L19-SIP over 7 days. At the calculated maximally tolerated dose for each agent (with the kidney being the dose-limiting organ for pretargeting and the bone marrow for direct targeting), a mouse tumor dose of 146 Gy could be given by pretargeting versus 45 Gy delivered by the direct approach.

Conclusions: These data suggest that pretargeting of ED-B with AP39xm679 and subsequent injection of the ⁹⁰Y-hapten-peptide would improve the therapeutic efficacy in solid tumors by >3-fold compared with directly radiolabeled ¹³¹I-L19-SIP.

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