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Nuklearmedizin 2010; 49(03): 97-105
DOI: 10.3413/nukmed-0258
Original article
Schattauer GmbH

Development of anti-CD30 radioimmunoconstructs (RICs) for treatment of Hodgkin's lymphoma

Studies with cell lines and animal studiesEntwicklung von Anti-CD30-Radioimmunkon-strukten zur Behandlung des Hodgkin-LymphomsStudien an Zellkulturen und Tieren
M. Dietlein
1   Department of Nuclear Medicine, University of Cologne, Germany
,
S. M. Börner   *
1   Department of Nuclear Medicine, University of Cologne, Germany
,
T. Fischer
1   Department of Nuclear Medicine, University of Cologne, Germany
,
H. Hansen
2   Department of Internal Medicine I, University of Cologne, Germany
,
R. Schnell
2   Department of Internal Medicine I, University of Cologne, Germany
,
B. Zimmermanns
1   Department of Nuclear Medicine, University of Cologne, Germany
,
S. Tawadros
2   Department of Internal Medicine I, University of Cologne, Germany
,
A. Engert
2   Department of Internal Medicine I, University of Cologne, Germany
,
O. Staak
2   Department of Internal Medicine I, University of Cologne, Germany
,
E. Pogge von Strandmann
2   Department of Internal Medicine I, University of Cologne, Germany
,
C. Kobe
1   Department of Nuclear Medicine, University of Cologne, Germany
,
H. Schicha
1   Department of Nuclear Medicine, University of Cologne, Germany
,
K. Schomäcker
1   Department of Nuclear Medicine, University of Cologne, Germany
› Author Affiliations
Further Information

Publication History

received: 20 June 2009

accepted in revised form: 22 January 2010

Publication Date:
24 January 2018 (online)

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Summary

Objectives: Comparison of the binding affinity to a CD30-positive Hodgkin lymphoma (HL) cell line and biodistribution in HL bearing mice of new anti-CD30 radioimmunoconjugates (RICs) of varying structure and labelling nuclides. Methods: The antibodies Ki-4 and 5F11 were radioiodinated by the chloramine T method or labelled with 111In via p-NCSBenzyl- DOTA. In addition, the Ki-4-dimer was investigated in the iodinated form. The RICs were analyzed for retained immunoreactivity by immunochromatography. In-vitro binding studies were performed on CD30-positive L540 cell lines. For in-vivo biodistribution studies, SCID mice bearing human HL xenografts were injected with the various radioimmunoconjugates. After 24 h, activities in the organs and tumour were measured for all 5 RICs. Tumour-free animals were studied in the same way with 131I- Ki-4 24 h p. i. The three RICs with the highest tumour/background ratios 24 h p.i. (131I-Ki-4, 131I–5F11, 111In-bz- DOTA-Ki-4) were analysed further at 48 h and 72 h. Results: All the RICs were successfully labelled with high specific activities (28–47 TBq/ mmol) and sufficient radiochemical yields (> 80%). Scatchard plot analysis proved high tumour affinity (KD = 20–220 nmol/l). In-vivo tumour accumulation in % of injected dose per g tissue (%ID/g) lay between 2.6 (131I-5F11) and 12.3 % ID/g (131I-Ki-4) with permanently high background in blood. Tumour/blood-ratios of all RICs were below one at all time points. Conclusions: In-vitro tumour cell affinities of all RICs were promising. However, in-vivo biokinetics tested in the mouse model did not meet expectations. This highlights the importance of developing and testing further new anti-CD30 conjugates.

Zusammenfassung

Ziel: Vergleichende Testung neuer Anti- CD30-Radioimmunkonjugate (RIK) hinsichtlich ihrer Bindungsaffinität an CD30-positive Hodgkin-Lymphom(HL)-Zelllinien und hinsichtlich ihrer Biodistribution in HL-tragenden Mäusen. Variiert wurden Markierungsnuklide und Antikörperstruktur. Methode: Die Antikörper Ki-4 und 5F11 wurden mittels Chloramin- T-Methode iodiert oder über p-NCS-Benzyl- DOTA (5F11) mit 111In markiert. Zusätzlich wurde iodiertes Ki-4 als Dimer getestet. Die Immunchromatographie diente zur Analyse der Immunreaktivität der RIK. Für In-vitro-Bindungsstudien kamen CD30-positive L540- Zelllinien zum Einsatz. Die In-vivo-Biodistribution wurde an SCID-Mäusen mit implantiertem HL untersucht. Die Aktivität in den Organen und im Tumor wurde für alle fünf RIK 24 h p. i. gemessen. Mäuse ohne Tumorimplantat wurden nach 131I-Ki-4-Injektion 24 h p. i. gemessen. Für die drei RIK mit den höchsten Tumor/ Untergrund-Verhältnissen 24 h p. i. (131IKi- 4, 131I-5F11, 111In-bz-DOTA-Ki-4) wurden zusätzliche Messwerte nach 48 h und 72 h erhoben. Ergebnisse: Alle RIK wurden mit hoher spezifischer Aktivität (28–47 TBq/mmol) und genügender radiochemischer Ausbeute (> 80%) markiert. Scatchard-Plot-Analysen belegten eine hohe Tumoraffinität (KD = 20–220 nmol/l). Die In-vivo-Tumoranreicherung lag zwischen 2,6% (131I-5F11) und 12,3% (131I-Ki-4) bei anhaltend hoher Blutaktivität. Der Quotient Tumor/Blut lag für alle RIK zu allen Messzeitpunkten unter 1. Schlussfolgerung: Die Affinitäten der RIK zu den Tumorzelllinien waren vielversprechend. Jedoch konnte die im Mausmodell getestete Biokinetik nicht diese Erwartungen erfüllen. Es gilt, neue Anti-CD30-Konjugate zu testen.

Keywords

Hodgkin's lymphoma - radioimmunotherapy - anti-CD30 - radioimmunoconjugates - Ki-4

Schlüsselwörter

Hodgkin Lymphom (HL) - Radioimmuntherapie (RIT) - anti-CD30 - Radioimmunkonjugat (RIK) - Ki-4

* The experiments forming the basis of this study were carried out as part of the dissertation of S. M. Börner, and the results are likewise taken from her dissertation.


 

  • References

  • 1 Adams GP, Schier R, McCall AM. et al. High affinity restricts the localization and tumor penetration of single-chain fv antibody molecules. Cancer Res 2001; 61: 4750-4755.
    PubMedGoogle Scholar
  • 2 Borchmann P, Schnell R, Engert A. Immunotherapy of Hodgkin's lymphoma. Eur J Haematol Suppl 2005; 66: 159-165.
    Google Scholar
  • 3 Brice P. Managing relapsed and refractory Hodgkin lymphoma. Br J Haematol 2008; 141: 3-13.
    CrossrefPubMedGoogle Scholar
  • 4 Dahle J, Krogh C, Melhus KB. et al. A one-step method for determining the maximum number of bound antibodies, and the affinity and association rate constants for antibody binding. Nucl Med Commun 2007; 28: 742-747.
    CrossrefPubMedGoogle Scholar
  • 5 Decristoforo C, Hernandez Gonzalez I, Carlsen J. et al. 68Ga- and 111In-labelled DOTA-RGD peptides for imaging of alphavbeta3 integrin expression. Eur J Nucl Med Mol Imaging 2008; 35: 1507-1515.
    CrossrefPubMedGoogle Scholar
  • 6 Diehl V, Kirchner HH, Schaadt M. et al. Hodgkin's disease: establishment and characterization of four in vitro cell lines. J Cancer Res Clin Oncol 1981; 101: 111-124.
    CrossrefPubMedGoogle Scholar
  • 7 Diehl V, Kirchner HH, Burrichter H. et al. Characteristics of Hodgkin's disease-derived cell lines. Cancer Treat Rep 1982; 66: 615-632.
    Google Scholar
  • 8 Diehl V, Engert A, Re D. New strategies for the treatment of advanced-stage Hodgkin's lymphoma. Hematol Oncol Clin North Am 2007; 21: 897-914.
    CrossrefPubMedGoogle Scholar
  • 9 Eichenauer DA, Simhadri VL, von Strandmann EP. et al. ADAM10 inhibition of human CD30 shedding increases specificity of targeted immunotherapy in vitro. Cancer Res 2007; 67: 332-338.
    CrossrefPubMedGoogle Scholar
  • 10 Faivre-Chauvet A, Chatal JF. Radioimmunotherapy with yttrium-90 labelled ibritumomab-tiuxetan (Zevalin). EJHP Practice 2005; 4: 55-56.
    Google Scholar
  • 11 Falini B, Flenghi L, Fedeli L. et al. In vivo targeting of Hodgkin and Reed-Sternberg cells of Hodgkin's disease with monoclonal antibody Ber-H2 (CD30): immunohistological evidence. Br J Haematol 1992; 82: 38-45.
    CrossrefPubMedGoogle Scholar
  • 12 Fischer M, Grünwald F, Knapp WH. et al. Leitlinie für die Radioimmuntherapie des CD20-positiven follikulären B-Zell-Non-Hodgkin-Lymphoms. Nuklearmedizin 2009; 48: 215-220.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Goldenberg DM. Targeted Therapy of cancer with radiolabeled antibodies. J Nucl Med 2002; 43: 693-713.
    PubMedGoogle Scholar
  • 14 Govindan SV, Shih LB, Goldenberg DM. et al. 90Y- labeled complementarity-determining-region- grafted monoclonal antibodies for radioimmuno- therapy: radiolabeling and animal biodistribution studies. Bioconjug Chem 1998; 9: 773-782.
    CrossrefPubMedGoogle Scholar
  • 15 Greenwood FC, Hunter WM, Glover JS. The preparation of 131I -labelled human growth hormone of high specific radioactivity. Biochem J 1963; 89: 114-123.
    CrossrefPubMedGoogle Scholar
  • 16 Hansen HP, Kisseleva T, Kobarg J. et al. A zinc metalloproteinase is responsible for the release of CD30 on human tumor cell lines. Int J Cancer 1995; 63: 750-756.
    CrossrefPubMedGoogle Scholar
  • 17 Hansen HP, Recke A, Reineke U. et al. Ectodomain shedding of CD30 is specifically regulated by peptide motifs in its cystine-rich domains 2 and 5. FASEB J 2004; 18: 893-895.
    CrossrefPubMedGoogle Scholar
  • 18 Hirsch B, Brauer J, Fischdick M. et al. Anti-CD30 human IL-2 fusion proteins display strong and specific cytotoxicity in vivo. Curr Drug Targets 2009; 10: 110-117.
    CrossrefPubMedGoogle Scholar
  • 19 Hnatowich DJ. Label stability in serum of four radionuclides on DTPA-coupled antibodies-an evaluation. Int J Rad Appl Instrum B 1986; 13: 353-358.
    CrossrefPubMedGoogle Scholar
  • 20 Horie R, Watanabe T. CD30: expression and function in health and disease. Semin Immunol 1998; 10: 457-470.
    CrossrefPubMedGoogle Scholar
  • 21 Horn-Lohrens O, Tiemann M, Lange H. et al. Shedding of the soluble form of CD30 from the Hodg- kin-analogous cell line L540 is strongly inhibited by a new CD30-specific antibody (Ki-4). Int J Cancer 1995; 60: 539-544.
    CrossrefPubMedGoogle Scholar
  • 22 International Commission on Radiological Protection. Radiation dose to patients from radiophar-maceuticals. A report of a Task Group of Committee 2 of the International Commission on Radiological Protection. Ann ICRP 1987; 18: 1-377.
    CrossrefPubMedGoogle Scholar
  • 23 Jacene HA, Filice R, Kasecamp W, Wahl RL. Comparison of 90Y-ibritumomab tiuxetan and 131I- tositumomab in clinical practice. J Nucl Med 2007; 48: 1767-1776.
    CrossrefPubMedGoogle Scholar
  • 24 Kasamon YL, Ambinder RF. Immunotherapies for Hodgkin's lymphoma. Crit Rev Oncol Hematol 2008; 66: 135-144.
    CrossrefPubMedGoogle Scholar
  • 25 Kiraly FJ, Kletting P, Reske S, Glatting G. Modellierung der Radioimmuntherapie mit anti- CD45-Antikörpern zur Verbesserung der Biodistribution. Nuklearmedizin 2009; 48: 113-119.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Kobe C, Dietlein M, Mauz-Körholz C. et al. FDG- PET beim Hodgkin-Lymphom. Nuklearmedizin 2008; 47: 235-238.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Kumar SR, Deutscher SL. 111In-labeled galectin- 3-targeting peptide as a SPECT agent for imaging breast tumors. J Nucl Med 2008; 49: 796-803.
    CrossrefPubMedGoogle Scholar
  • 28 Matthey B, Engert A, Barth S. Recombinant immunotoxins for the treatment of Hodgkin's disease. Int J Mol Med 2000; 6: 509-514.
    PubMedGoogle Scholar
  • 29 Matthey B, Borchmann P, Schnell R. et al. Metallo- proteinase inhibition augments antitumor efficacy of the anti-CD30 immunotoxin Ki-3(scFv)-ETA' against human lymphomas in vivo. Int J Cancer 2004; 111: 568-574.
    CrossrefPubMedGoogle Scholar
  • 30 Meredith RF, Buchsbaum DJ. Pretargeted radio-immunotherapy. Int J Radiat Oncol Biol Phys 2006; 66 (2 Suppl) S57-59.
    PubMedGoogle Scholar
  • 31 Mohsin H, Fitzsimmons J, Shelton T. et al. Preparation and biological evaluation of 111In-, 177Lu- and 90Y-labeled DOTA analogues conjugated to B72.3. Nucl Med Biol 2007; 34: 493-502.
    CrossrefPubMedGoogle Scholar
  • 32 Paganelli G, Bartolomei M, Grana C. Radio- immunotherapy of brain tumor. Neurol Res 2006; 28: 518-522.
    CrossrefPubMedGoogle Scholar
  • 33 Rudnick SI, Adams GP. Affinity and avidity in antibody-based tumor targeting. Cancer Biother Radiopharm 2009; 24: 155-161.
    CrossrefPubMedGoogle Scholar
  • 34 Sausville EA, Burger AM. Contributions of human tumor xenografts to anticancer drug development. Cancer Res 2006; 66: 3351-3354.
    CrossrefPubMedGoogle Scholar
  • 35 Scatchard O. The attractions of proteins for small molecules and ions. Ann NY Acad Sci 1949; 51: 660-672.
    CrossrefGoogle Scholar
  • 36 Schnell R, Staak O, Borchmann P. et al. A Phase I study with an anti-CD30 ricin A-chain immuno- toxin (Ki-4.dgA) in patients with refractory CD30+ Hodgkin's and non-Hodgkin's lymphoma. Clin Cancer Res 2002; 8: 1779-1786.
    PubMedGoogle Scholar
  • 37 Schnell R, Dietlein M, Staak JO. et al. Treatment of refractory Hodgkin's lymphoma patients with an iodine-131-labeled murine anti-CD30 monoclonal antibody. J Clin Oncol 2005; 23: 4669-4678.
    CrossrefPubMedGoogle Scholar
  • 38 Schnell R, Dietlein M, Schomäcker K. et al. Yt- trium-90 ibritumomab tiuxetan-induced complete remission in a patient with classical lymphocyte- rich Hodgkin's Lymphoma. Onkologie 2008; 31: 49-51.
    CrossrefPubMedGoogle Scholar
  • 39 Schnitzer B. Hodgkin lymphoma. Hematol Oncol Clin North Am 2009; 23: 747-768.
    CrossrefPubMedGoogle Scholar
  • 40 Stein H, Gerdes J, Schwab U. et al. Identification of Hodgkin and Sternberg-reed cells as a unique cell type derived from a newly-detected small-cell population. Int J Cancer 1982; 30: 445-459.
    CrossrefPubMedGoogle Scholar
  • 41 Stein H, Schwarting R, Dallenbach F, Dienemann D. Immunology of Ho dgkin and Reed-Sternberg cells. Recent Results Cancer Res 1989; 117: 14-26.
    PubMedGoogle Scholar
  • 42 Tur MK, Neef I, Jäger G. et al. Immunokinases, a novel class of immunotherapeutics for targeted cancer therapy. Curr Pharm Des 2009; 15: 2693-2699.
    CrossrefPubMedGoogle Scholar
  • 43 Von Kalle C, Wolf J, Becker A. et al. Growth of Hodgkin cell lines in severely combined immuno- deficient mice. Int J Cancer 1992; 52: 887-891.
    CrossrefPubMedGoogle Scholar
  • 44 Vriesendorp HM, Quadri SM, Wyllie CT. et al. Fractionated radiolabeled antiferritin therapy for patients with recurrent Hodgkin's disease. Clin Cancer Res 1999; 5: 3324-3329.
    Google Scholar
  • 45 Wildes TM, Bartlett NL. Drug development for recurrent and refractory classical Hodgkin lymphoma. Leuk Lymphoma 2009; 50: 529-540.
    CrossrefPubMedGoogle Scholar
  • 46 Wong JY. Basic immunology of antibody targeted radiotherapy. Int J Radiat Oncol Biol Phys 2006; 66 (2 Suppl) S8-S14.
    PubMedGoogle Scholar
  • 47 Zhang M, Yao Z, Zhang Z. et al. The anti-CD25 monoclonal antibody 7G7/B6, armed with the alpha-emitter 211At, provides effective radioimmu- notherapy for a murine model of leukemia. Cancer Res 2006; 66: 8227-8232.
    CrossrefPubMedGoogle Scholar