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

  • David R. Colnot
  • Jan C. Roos
  • Remco de Bree
  • Abraham J. Wilhelm
  • J. Alain Kummer
  • Gertraud Hanft
  • Karl-Heinz Heider
  • Gerd Stehle
  • Gordon B. Snow
  • Guus A. M. S. van Dongen
Original Article


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.


99mTc-BIWA 4 CD44 Radioimmunotherapy Humanized monoclonal antibodies Squamous cell carcinoma Head and neck cancer 


  1. 1.
    Bosslet K, Steinstrasser A, Schwarz A, Harthus HP, Luben G, Kuhlmann L, Sedlacek HH (1988) Quantitative considerations supporting the irrelevance of circulating serum CEA for the immunoscintigraphic visualization of CEA expressing carcinomas. Eur J Nucl Med 14:523–528PubMedGoogle Scholar
  2. 2.
    Caron PC, Jurcic JG, Scott AM, Finn RD, Divgi CR, Graham MC, Jureidini IM, Sgouros G, Tyson D, Old LJ, Larson SM, Scheinberg DA (1994) A phase IB trial of humanized monoclonal antibody M195 (anti-CD33) in myeloid leukemia: specific targeting without immunogenicity. Blood 83:1760–1768PubMedGoogle Scholar
  3. 3.
    Colnot DR, Ossenkoppele GJ, Roos JC, Quak JJ, de Bree R, Borjesson PK, Huijgens PC, Snow GB, Van Dongen GAMS (2002) Reinfusion of unprocessed, granulocyte colony-stimulating factor-stimulated whole blood allows dose escalation of 186Re-labeled chimeric monoclonal antibody U36 radioimmunotherapy in a phase I dose escalation study. Clin Cancer Res 8:3401–3406PubMedGoogle Scholar
  4. 4.
    Colnot DR, Quak JJ, Roos JC, Van Lingen A, Wilhelm AJ, Van Kamp GJ, Huijgens PC, Snow GB, Van Dongen GAMS (2000) Phase I therapy study of Rhenium-186-labeled chimeric monoclonal antibody U36 in patients with squamous cell carcinoma of the head and neck. J Nucl Med 41:1999–2010PubMedGoogle Scholar
  5. 5.
    De Bree R, Roos JC, Plaizier MA, Quak JJ, Van Kamp GJ, Den Hollander W, Snow GB, Van Dongen GAMS (1997) Selection of monoclonal antibody E48 IgG or U36 IgG for adjuvant radioimmunotherapy in head and neck cancer patients. Brit J Cancer 75:1049–1060Google Scholar
  6. 6.
    De Bree R, Roos JC, Quak JJ, Den Hollander W, Snow GB, Van Dongen GAMS (1995) Radioimmunoscintigraphy and biodistribution of 99mTc-labeled monoclonal antibody U36 in patients with head and neck cancer. Clin Cancer Res 1:591–598PubMedGoogle Scholar
  7. 7.
    DeNardo SJ, Kramer EL, O'Donnell RT, Richman CM, Salako QA, Shen S, Noz M, Glenn SD, Ceriani RL, DeNardo GL (1997) Radioimmunotherapy for breast cancer using indium-111/yttrium-90 BrE-3: results of a phase I clinical trial. J Nucl Med 38:1180–1185PubMedGoogle Scholar
  8. 8.
    Heider K-H, Mulder J-WR, Ostermann E, Susani S, Patzelt E, Pals ST, Adolf GR (1995) Splice variants of the cell surface glycoprotein CD44 associated with metastatic tumor cells are expressed in normal tissues of humans and cynomolgus monkeys. Eur J Cancer 31A:2385–2391CrossRefPubMedGoogle Scholar
  9. 9.
    Heider K-H, Sproll M, Susani S, Patzelt E, Beaumier PL, Ostermann E, Ahorn H, Adolf GR (1996) Characterization of a high-affinity monoclonal antibody specific for CD44v6 as candidate for immunotherapy of squamous cell carcinomas. Cancer Immunol Immunother 43:245–253CrossRefPubMedGoogle Scholar
  10. 10.
    Himmler A, Maurer-Fogy I, Kronke M, Scheurich P, Pfizenmaier K, Lantz M, Olsson I, Hauptmann R, Stratowa C, Adolf GR (1990) Molecular cloning and expression of human and rat tumor necrosis factor receptor chain (p60) and its soluble derivative, tumor necrosis factor-binding protein. DNA Cell Biol 9:705–715Google Scholar
  11. 11.
    Hnatowich DJ, Griffin TW, Kosciuczyk C, Rusckowski M, Childs RL, Mattis JA, Shealy D, Doherty PW (1985) Pharmacokinetics of an indium-111-labeled monoclonal antibody in cancer patients. J Nucl Med 26:849–858PubMedGoogle Scholar
  12. 12.
    Jung K, Lein MWS, Schnorr D, Henke W, Loening S (1996) Soluble CD44 molecules in serum of patients with prostate cancer and benign prostatic hyperplasia. Eur J Cancer 32A:627–630CrossRefPubMedGoogle Scholar
  13. 13.
    Kaminski MS, Estes J, Zasadny KR, Francis IR, Ross CW, Tuck M, Regan D, Fisher. S., Gutierrez J, Kroll S, Stagg R, Tidmarsch G, Wahl RL (2000) Radioimmunotherapy with iodine 131-I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience. Blood 96:1259–1266PubMedGoogle Scholar
  14. 14.
    Kittl EM, Ruckser R, Reich-Weichselbraun I, Hinterberger W, Bauer K (1997) Significant elevation of tumor-associated isoforms of soluble CD44 in serum of normal individuals caused by cigarette smoking. Eur J Clin Chem Clin Biochem 35:81–84PubMedGoogle Scholar
  15. 15.
    Kramer EL, DeNardo SJ, Liebes L, Kroger LA, Noz ME, Mizrachi H, Salako QA, Furmanski P, Glenn SD, DeNardo GL (1993) Radioimmunolocalization of metastatic breast carcinoma using indium-111-methyl benzyl DTPA BrE-3 monoclonal antibody: phase I study. J Nucl Med 34:1067–1074PubMedGoogle Scholar
  16. 16.
    Kramer EL, Liebes L, Wasserheit C, Noz ME, Blank EW, Zabalegui A, Melamed J, Furmanski P, Peterson JA, Ceriani RL (1998) Initial clinical evaluation of radiolabeled MX-DTPA humanized BrE-3 antibody in patients with advanced breast cancer. Clin Cancer Res 4:1679–1688PubMedGoogle Scholar
  17. 17.
    Kugelman LC, Ganguly S, Haggerty JG, Weissman SM, Milstone LM (1992) The core protein of epican, a heparan sulfate proteoglycan on keratinocytes, is an alternative form of CD44. J Invest Dermatol 99:886–891PubMedGoogle Scholar
  18. 18.
    Parkin DM, Bray F, Ferlay J, Pisani P (2001) Estimating the world cancer burden: Globocan 2000. Int J Cancer 94:153–156CrossRefPubMedGoogle Scholar
  19. 19.
    Press OW, Eary JF, Gooley T, Gopal AK, Liu S, Rajendran JG, Maloney DG, Petersdorf S, Bush SA, Durack LD, Martin PJ, Fisher DR, Wood B, Borrow JW, Porter B, Smith JP, Matthews DC, Appelbaum FR, Bernstein ID (2000) A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas. Blood 96:2934–2942PubMedGoogle Scholar
  20. 20.
    Ritter G, Cohen LS, Williams C Jr, Richards EC, Old LJ, Welt S (2001) Serological analysis of human anti-human antibody responses in colon cancer patients treated with repeated doses of humanized monoclonal antibody A33. Cancer Res 61:6851–6859PubMedGoogle Scholar
  21. 21.
    Schwartz MA, Lovett DR, Redner A, Finn RD, Graham MC, Divgi CR, Dantis L, Gee TS, Andreeff M, Old LJ (1993) Dose-escalation trial of M195 labeled with iodine 131 for cytoreduction and marrow ablation in relapsed or refractory myeloid leukemias. J Clin Oncol 11:294–303PubMedGoogle Scholar
  22. 22.
    Stroomer JW, Roos JC, Sproll M, Quak JJ, Heider KH, Wilhelm BJ, Castelijns JA, Meyer R, Kwakkelstein MO, Snow GB, Adolf GR, Van Dongen GAMS (2000) Safety and biodistribution of 99m-Technetium-labeled anti-CD44v6 monoclonal antibody BIWA 1 in head and neck cancer patients. Clin Cancer Res 6:3046-3055PubMedGoogle Scholar
  23. 23.
    Van Gog FB, Visser GWM, Stroomer JWG, Roos JC, Snow GB, Van Dongen GAMS (1997) High dose rhenium-186 labeling of monoclonal antibodies for clinical application. Pitfalls and solutions. Cancer 80:2360–2370CrossRefPubMedGoogle Scholar
  24. 24.
    Van Hal NLW, Van Dongen GAMS, Rood-Knippels EMC, Van der Valk P, Snow GB, Brakenhoff RH (1996) Monoclonal antibody U36, a suitable candidate for clinical immunotherapy of squamous cell carcinoma, recognizes a CD44 isoform. Int J Cancer 68:520–527CrossRefPubMedGoogle Scholar
  25. 25.
    Verel I, Heider K-H, Siegmund M, Ostermann E, Patzelt E, Sproll M, Snow GB, Adolf GR, Van Dongen GAMS (2002) Tumor targeting properties of monoclonal antibodies with different affinity for target antigen CD44V6 in nude mice bearing head-and-neck cancer xenografts. Int J Cancer 99:396–402CrossRefPubMedGoogle Scholar
  26. 26.
    Welt S, Scott AM, Divgi CR, Kemeny NE, Finn RD, Daghighian F, Stgermain J, Richards EC, Larson SM, Old LJ (1996) Phase I/II study of 125-I labeled monoclonal antibody A33 in patients with advanced colorectal cancer. J Clin Oncol 14:1787–1797PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • David R. Colnot
    • 1
  • Jan C. Roos
    • 2
  • Remco de Bree
    • 1
  • Abraham J. Wilhelm
    • 2
  • J. Alain Kummer
    • 3
  • Gertraud Hanft
    • 4
  • Karl-Heinz Heider
    • 5
  • Gerd Stehle
    • 4
  • Gordon B. Snow
    • 1
  • Guus A. M. S. van Dongen
    • 1
  1. 1.Department of Otolaryngology/Head and Neck SurgeryVU University Medical CenterAmsterdamThe Netherlands
  2. 2.Department of Nuclear MedicineVU University Medical CenterAmsterdamThe Netherlands
  3. 3.Department of PathologyVU University Medical CenterAmsterdamThe Netherlands
  4. 4.Boehringer Ingelheim PharmaBiberach an der RissGermany
  5. 5.Boehringer Ingelheim AustriaViennaAustria

Personalised recommendations