Evaluation of Radiolabeled Girentuximab In Vitro and In Vivo.

Basaco, Tais; Pektor, Stefanie; Bermudez, Josue M.; Meneses, Niurka; Heller, Manfred; Galván, José A.; Frias Boligan, Kayluz; Schürch, Stefan; von Gunten, Stephan; Türler, Andreas; Miederer, Matthias (2018). Evaluation of Radiolabeled Girentuximab In Vitro and In Vivo. Pharmaceuticals, 11(4) MDPI 10.3390/ph11040132

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Girentuximab (cG250) targets carbonic anhydrase IX (CAIX), a protein which is expressed on the surface of most renal cancer cells (RCCs). cG250 labeled with Lu has been used in clinical trials for radioimmunotherapy (RIT) of RCCs. In this work, an extensive characterization of the immunoconjugates allowed optimization of the labeling conditions with Lu while maintaining immunoreactivity of cG250, which was then investigated in in vitro and in vivo experiments. cG250 was conjugated with S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (DOTA(SCN)) by using incubation times between 30 and 90 min and characterized by mass spectrometry. Immunoconjugates with five to ten DOTA(SCN) molecules per cG250 molecule were obtained. Conjugates with ratios less than six DOTA(SCN)/cG250 had higher in vitro antigen affinity, both pre- and postlabeling with Lu. Radiochemical stability increased, in the presence of sodium ascorbate, which prevents radiolysis. The immunoreactivity of the radiolabeled cG250 tested by specific binding to SK-RC-52 cells decreased when the DOTA content per conjugate increased. The in vivo tumor uptake was < 10% ID/g and independent of the total amount of protein in the range between 5 and 100 µg cG250 per animal. Low tumor uptake was found to be due to significant necrotic areas and heterogeneous CAIX expression. In addition, low vascularity indicated relatively poor accessibility of the CAIX target.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Thromboselabor Kinderklinik (discontinued)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Service Sector > Institute of Pathology
08 Faculty of Science > Departement of Chemistry and Biochemistry
04 Faculty of Medicine > Service Sector > Institute of Pathology > Tumour Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Services > Core Facility Massenspektrometrie- und Proteomics-Labor

UniBE Contributor:

Basaco Bernabeu, Tais; Moreno Bermudez, Josue Manuel; Meneses Moreno, Niurka; Heller, Manfred; Galván Hernández, José Alberto; Frias Boligan, Kayluz; Schürch, Stefan; von Gunten, Stephan and Türler, Andreas

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

1424-8247

Publisher:

MDPI

Language:

English

Submitter:

Marla Rittiner

Date Deposited:

20 Dec 2018 09:22

Last Modified:

19 Mar 2019 10:01

Publisher DOI:

10.3390/ph11040132

PubMed ID:

30487460

Uncontrolled Keywords:

177Lu-radiopharmaceuticals carbonic anhydrase IX girentuximab radioimmunotherapy renal cell carcinomas

BORIS DOI:

10.7892/boris.122541

URI:

https://boris.unibe.ch/id/eprint/122541

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