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Radioimmunotherapy of Head and Neck Cancer Xenografts Using ¹³¹I-Labeled Antibody L19-SIP for Selective Targeting of Tumor Vasculature

¹ Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands; ² Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland; ³ Research Laboratories of Schering AG, Berlin, Germany; and ⁴ Laboratory of Innovative Therapy, Advanced Biotechnology Center, Istuto Giannina Gaslini, Genova, Italy

Correspondence: For correspondence or reprints contact: Guus A.M.S. van Dongen, PhD, Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, De Boelelaan 1117, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail: gams.vandongen{at}vumc.nl

The extra domain B of fibronectin (ED-B) is a marker of tumor angiogenesis. The human monoclonal antibody (mAb) L19-SIP (80 kDa; SIP is "small immunoprotein") has been selected for targeting of ED-B. The aim of this study was to evaluate the potential of radioimmunotherapy (RIT) with L19-SIP, either alone or in combination with cetuximab, for treatment of head and neck squamous cell carcinoma (HNSCC). Combination with cetuximab was considered because this anti-EGFR (epidermal growth factor receptor) mAb has proven value for the treatment of HNSCC. Methods: HNSCC xenograft lines FaDu and HNX-OE were evaluated for ED-B and EGFR expression. L19-SIP was radiolabeled with 2 candidate radionuclides for RIT, ¹⁷⁷Lu and ¹³¹I (or ¹²⁵I as substitute). The biodistribution of coinjected ¹⁷⁷Lu-L19-SIP and ¹²⁵I-L19-SIP was assessed in FaDu-bearing nude mice, whereas ¹³¹I-L19-SIP was evaluated in both xenograft lines. After labeling with high-dose ¹³¹I (623–789 MBq/mg), the maximum tolerated dose (MTD) was assessed. The efficacy of RIT with injected ¹³¹I-L19-SIP, either alone or in combination with unlabeled cetuximab (1 mg 2 times a week intraperitoneally for 4 wk), was evaluated in both xenograft lines. Results: Xenograft lines expressed both antigens, with similar EGFR expression and the highest ED-B expression in FaDu. Radioiodinated L19-SIP performed better than ¹⁷⁷Lu-L19-SIP and was further exploited. The biodistribution of ¹³¹I-L19-SIP was most favorable in FaDu-bearing mice, with tumor uptake values at 24, 48, and 72 h after injection of 8.6 ± 1.6, 5.8 ± 0.4, and 3.4 ± 0.2 %ID/g (%ID/g is percentage injected dose per gram of tissue), respectively, and ratios of tumor to normal tissues that gradually increased in time, such as for blood from 4.4 ± 1.8 at 24 h to 21.4 ± 1.7 at 72 h, after injection. RIT at the MTD level of 74 MBq caused significant tumor growth delay and improved survival in both lines. Although FaDu was most sensitive for RIT, with size reduction of all tumors, HNX-OE was most sensitive for treatment with cetuximab. The best survival and cure rates were obtained, however, when RIT and cetuximab were combined. Conclusion: RIT with ¹³¹I-L19-SIP appeared efficacious in HNSCC xenografts. The efficacy of RIT was enhanced by combination with cetuximab, without increase of toxicity.

Key Words: radioimmunotherapy • L19-SIP • squamous cell carcinoma • ED-B • angiogenesis

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