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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.


 

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