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- W2179968303 abstract "Purpose: Radioimmunotherapy (RIT) delivered by radiometal immunoconjugates (RICs) is dose limited by deposition and retention of radioactivity in normal tissues. In order to increase elimination of radioactivity from the liver and body, a peptide having a specific cathepsin B cleavage site was placed between the radiometal chelate, 111In-DOTA, and the panadenocarcinoma monoclonal antibody (MAb), m170. Experimental design: Indium-111 (111In)-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA)-2-iminothiolane (2IT)-m170 and 111In-DOTA-peptide-m170, representing the same MAb and chelate without and with a cleavable linkage, were studied in athymic mice and patients with breast or prostate cancer. Pharmacokinetics, cumulated activities and therapeutic indices (TI), were evaluated. Cumulated activities in the liver and tumors were calculated and used as a surrogate for radiation dose. Results: Except for liver, the pharmacokinetics of 111In-DOTA-peptide-m170 were similar to those of the 111In-2IT-2-[p(bromoacetamido)benzyl]-1,4,7,10-tetraazocyclododecane-N,N′,N″,N‴-tetraacetic acid-m170 (111In-2IT-BAD-m170) in mice and patients. Liver cumulated activities for 111In-DOTA-peptide-m170 were consistently decreased when compared to those for 111In-2IT-BAD-m170, reductions varying between 22-30%. Cumulated activities for 111In-DOTA-peptide-m170 in the malignant tumors of the patients were as great as those for 111In-2IT-BAD-m170, so that the tumor-to-liver cumulated activity ratios (therapeutic indices) were better for 111In-DOTA-peptide-m170. Conclusions: A cathepsin-B-cleavable peptide used to link chelated 111In to MAb, m170, reduced liver cumulated activity (radiation dose) and improved the TI. This novel linker illustrates the importance of linker technology in the development of safer RICs for cancer therapy." @default.
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- W2179968303 date "2004-02-01" @default.
- W2179968303 modified "2023-09-23" @default.
- W2179968303 title "Evaluation of a Cathepsin-Cleavable Peptide Linked Radioimmunoconjugate of a Panadenocarcinoma MAb, m170, in Mice and Patients" @default.
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- W2179968303 doi "https://doi.org/10.1089/108497804773391720" @default.
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