Cancer Immunology, Immunotherapy

, Volume 52, Issue 9, pp 576–582

Safety, biodistribution, pharmacokinetics, and immunogenicity of 99mTc-labeled humanized monoclonal antibody BIWA 4 (bivatuzumab) in patients with squamous cell carcinoma of the head and neck

Authors

  • David R. Colnot
    • Department of Otolaryngology/Head and Neck SurgeryVU University Medical Center
  • Jan C. Roos
    • Department of Nuclear MedicineVU University Medical Center
  • Remco de Bree
    • Department of Otolaryngology/Head and Neck SurgeryVU University Medical Center
  • Abraham J. Wilhelm
    • Department of Nuclear MedicineVU University Medical Center
  • J. Alain Kummer
    • Department of PathologyVU University Medical Center
  • Gertraud Hanft
    • Boehringer Ingelheim Pharma
  • Karl-Heinz Heider
    • Boehringer Ingelheim Austria
  • Gerd Stehle
    • Boehringer Ingelheim Pharma
  • Gordon B. Snow
    • Department of Otolaryngology/Head and Neck SurgeryVU University Medical Center
    • Department of Otolaryngology/Head and Neck SurgeryVU University Medical Center
Original Article

DOI: 10.1007/s00262-003-0396-5

Cite this article as:
Colnot, D.R., Roos, J.C., de Bree, R. et al. Cancer Immunol Immunother (2003) 52: 576. doi:10.1007/s00262-003-0396-5

Abstract

Previous studies have shown the potential of murine and chimeric anti-CD44v6 monoclonal antibodies (MAbs) for radioimmunotherapy (RIT) of head and neck squamous cell carcinoma (HNSCC). A limitation of these MAbs, however, appeared to be their immunogenicity. Therefore, humanized monoclonal antibody BIWA 4 (bivatuzumab), with an intermediate affinity for CD44v6, was recently selected. As a prelude to RIT, we evaluated the safety, tumor-targeting potential, pharmacokinetics, and immunogenicity of technetium-99m-labeled BIWA 4 in patients undergoing operations for primary HNSCC in this study. Ten patients were treated at BIWA 4 dose levels of 25 mg (n=3), 50 mg (n=4), and 100 mg (n=3). Patients received 2 mg of 750 MBq 99mTc-BIWA 4, together with 23-, 48-, and 98-mg unlabeled BIWA 4, respectively. Radioimmunoscintigraphy (RIS) was performed within 1 h and after 21 h, and patients underwent surgery at 48 h after injection. Biodistribution of 99mTc-BIWA 4 was evaluated by radioactivity measurements in blood, bone marrow, and in biopsies of a surgical specimen obtained 48 h after injection. BIWA 4 concentration in blood was assessed by ELISA and high performance liquid chromatography and related to soluble CD44v6 levels in serum samples. The development of human anti–human antibody (HAHA) responses was determined. Administration of 99mTc-BIWA 4 was well tolerated by all patients and no HAHA responses were observed. A mean t1/2 in plasma of 54.8±11.5 h, 76.1±21.8 h, and 68.5±21.2 h was found for the 25-, 50-, and 100-mg dose group, respectively. No complex formation of BIWA 4 with soluble CD44v6 in blood was observed. RIS showed targeting of primary tumors and lymph node metastases in 8 of 10 and 1 of 5 patients, respectively. The highest tumor uptake and tumor to nontumor ratios were observed for the 50-mg dose group. Tumor uptake was 12.9±5.9, 26.2±3.1, and 15.4±1.9% of the injected dose (ID)/kg for the 25-, 50-, and 100-mg dose group, respectively, while the tumor to bone marrow ratios for these groups were 1.7±0.5, 3.2±1.1, and 2.0±0.6, respectively. Conclusion: 99mTc-BIWA 4 can safely be administered to patients with HNSCC, with absence of detectable HAHA responses. The 50-mg dose level showed the highest tumor uptake and tumor to nontumor ratios. These findings support the use of BIWA 4 for RIT studies in patients with HNSCC.

Keywords

99mTc-BIWA 4CD44RadioimmunotherapyHumanized monoclonal antibodiesSquamous cell carcinomaHead and neck cancer

Copyright information

© Springer-Verlag 2003