Improved In Vivo Stability of Radioiodinated Rituximab Using an Iodination Linker for Radioimmunotherapy.
OBJECTIVE
Directly radioiodinated [131I]-rituximab has been developed as a radioimmunotherapeutic agent in patients with CD20-positive B cell non-Hodgkin's lymphoma. However, there are concerns over its in vivo catabolism and deiodination. A novel radioiodination linker, N-(4-isothiocyanatobenzyl)-2-(3-(tributylstannyl)phenyl) acetamide (IBPA), was synthesized for the preparation of stable radioiodinated proteins.


METHODS
The authors evaluated the potential of IBPA as a stable radioiodinated linker for rituximab. [125I]-IBPA was purified and conjugated with rituximab, and in vitro stability testing was performed in serum and liver microsomes. In vivo studies were performed after i.v. injection of [125I]-rituximab or [125I]-IBPA-rituximab to nude mice.


RESULTS
In in vitro studies, [125I]-IBPA-rituximab was stable in serum and liver microsomes. In static scans, high radioactivity was evident in the thyroid following injection of [125I]-rituximab, but low radioactivity was seen in the thyroid following injection of [125I]-IBPA-rituximab. In biodistribution studies, radioactivity uptake in thyroid glands of [125I]-IBPA-rituximab was decreased by approximately sevenfold compared to [125I]-rituximab. In pharmacokinetics, the half-life of [125I]-rituximab was shorter than that of [125I]-IBPA-rituximab in plasma of nude mice.


CONCLUSIONS
The authors demonstrate that [125I]-IBPA-rituximab is more stable to metabolic deiodination in vivo than is [125I]-rituximab. Radioiodination of rituximab using IBPA is thus preferable to direct labeling in terms of in vivo stability.
1 Korea Drug Development Platform using Radio-Isotope (KDePRI), Korea Institute of Radiological and Medical Sciences , Seoul, Korea.|2 School of Life Sciences and Biotechnology, Korea University , Seoul, Korea.
Eun Jung
EJ
Kim
1 Korea Drug Development Platform using Radio-Isotope (KDePRI), Korea Institute of Radiological and Medical Sciences , Seoul, Korea.|3 Department of Molecular Imaging, Korea Institute of Radiological and Medical Sciences , Seoul, Korea.
Byoung Soo
BS
Kim
1 Korea Drug Development Platform using Radio-Isotope (KDePRI), Korea Institute of Radiological and Medical Sciences , Seoul, Korea.
Dan Bee
DB
Choi
2 School of Life Sciences and Biotechnology, Korea University , Seoul, Korea.
Sung-Gil
SG
Chi
3 Department of Molecular Imaging, Korea Institute of Radiological and Medical Sciences , Seoul, Korea.
Tae Hyun
TH
Choi
D000081:Acetamides / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D004355:Drug Stability; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000008:administration & dosage* / Q000737:chemistry; D016393:Lymphoma, B-Cell / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016499:Radioimmunotherapy / Q000379:methods*; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D000069283:Rituximab / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology
D000081:Acetamides; D000970:Antineoplastic Agents; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D000069283:Rituximab
CD20; N-(4-isothiocyanatobenzyl)-2-(3-(tributylstannyl)phenyl) acetamide (IBPA); deiodination; lymphoma; radioimmunotherapy; rituximab