Evaluation of a Cathepsin-Cleavable Peptide Linked Radioimmunoconjugate of a Panadenocarcinoma MAb, m170, in Mice and Patients

Gerald L Denardo, Sally J. DeNardo

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)85-92
Number of pages8
JournalCancer Biotherapy and Radiopharmaceuticals
Volume19
Issue number1
DOIs
StatePublished - 2004

Fingerprint

Immunoconjugates
Cathepsins
Monoclonal Antibodies
Peptides
Liver
Cathepsin B
Radioactivity
Neoplasms
Pharmacokinetics
Radiation
Radioimmunotherapy
Indium
Therapeutics
Nude Mice
indium-111-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
Prostatic Neoplasms
Research Design
methyl 4-mercaptobutyrimidate
Breast Neoplasms
Technology

Keywords

  • Antibody
  • Cancer
  • Indium-111
  • Linker
  • Radioimmunotherapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology

Cite this

@article{855ae1b9c4ae4623b21d6381e13b1e6d,
title = "Evaluation of a Cathepsin-Cleavable Peptide Linked Radioimmunoconjugate of a Panadenocarcinoma MAb, m170, in Mice and Patients",
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.",
keywords = "Antibody, Cancer, Indium-111, Linker, Radioimmunotherapy",
author = "Denardo, {Gerald L} and DeNardo, {Sally J.}",
year = "2004",
doi = "10.1089/108497804773391720",
language = "English (US)",
volume = "19",
pages = "85--92",
journal = "Cancer Biotherapy and Radiopharmaceuticals",
issn = "1084-9785",
publisher = "Mary Ann Liebert Inc.",
number = "1",

}

TY - JOUR

T1 - Evaluation of a Cathepsin-Cleavable Peptide Linked Radioimmunoconjugate of a Panadenocarcinoma MAb, m170, in Mice and Patients

AU - Denardo, Gerald L

AU - DeNardo, Sally J.

PY - 2004

Y1 - 2004

N2 - 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.

AB - 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.

KW - Antibody

KW - Cancer

KW - Indium-111

KW - Linker

KW - Radioimmunotherapy

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U2 - 10.1089/108497804773391720

DO - 10.1089/108497804773391720

M3 - Article

C2 - 15068616

AN - SCOPUS:1542743561

VL - 19

SP - 85

EP - 92

JO - Cancer Biotherapy and Radiopharmaceuticals

JF - Cancer Biotherapy and Radiopharmaceuticals

SN - 1084-9785

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