Enhanced therapeutic index of radioimmunotherapy (RIT) in prostate cancer patients: Comparison of radiation dosimetry for 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA)-peptide versus 2IT-DOTA monoclonal antibody linkage for RIT

Sally J. DeNardo, Gerald L Denardo, A. Yuan, Carol M Richman, Robert T O'Donnell, Primo N Lara, David L. Kukis, Arutselvan Natarajan, Kathleen R. Lamborn, Frederik Jacobs, Christine L. Hartmann Siantar

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Purpose: Radioimmunotherapy delivered by radiometal immunoconjugates and followed by marrow support is dose limited by deposition of radioactivity in normal organs. To increase elimination of radioactivity from the liver and body and, thus, minimize hepatic radiation dose, a peptide having a specific cathepsin B cleavage site was placed between the radiometal chelate DOTA (1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid) and the monoclonal antibody m170, and the comparative pharmacokinetics was evaluated in prostate cancer patients. Experimental Design: 111In-DOTA-2IT-m170 and 111In-DOTA-peptide-(GGGF)-m170, representing the same monoclonal antibody and chelate with and without the cleavable linkage, were studied in comparable groups of prostate cancer patients (17 with In-2IT-BAD-m170 and 8 with In-DOTA-peptide-m170). Pharmacokinetics over 7 days, calculated yttrium-90 radiation dosimetry, therapeutic index, and projected maximum tolerated injected yttrium-90 dose were evaluated. Results: The radioimmunoconjugates pharmacokinetics and calculated tumor and normal organ absorbed radiation dose (rads/mCi) were similar, except for a significant decrease in the mean dose to the liver (31%; P < 0.01) and lungs (31%; P < 0.01) with the DOTA-peptide immunoconjugates. Because mean tumor dose was not statistically different, this peptide linkage provided a significant increase in the therapeutic index for this tumor targeting radiopharmaceutical. If marrow support is adequate, the radiation dose historically tolerated by normal organs other than marrow would allow a 30% increase in the administered dose, resulting in a mean dose of 9500 rads to metastatic prostate cancer.

Original languageEnglish (US)
JournalClinical Cancer Research
Volume9
Issue number10 II
StatePublished - Oct 1 2003

Fingerprint

Radiometry
Radioimmunotherapy
Immunoconjugates
Prostatic Neoplasms
Monoclonal Antibodies
Peptides
Yttrium
Pharmacokinetics
Bone Marrow
Radiation
Radioactivity
Liver
Therapeutics
Neoplasms
Cathepsin B
Radiopharmaceuticals
Research Design
cyclen
1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
Lung

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

@article{28f3ed8c167642df99bffc28593911e7,
title = "Enhanced therapeutic index of radioimmunotherapy (RIT) in prostate cancer patients: Comparison of radiation dosimetry for 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA)-peptide versus 2IT-DOTA monoclonal antibody linkage for RIT",
abstract = "Purpose: Radioimmunotherapy delivered by radiometal immunoconjugates and followed by marrow support is dose limited by deposition of radioactivity in normal organs. To increase elimination of radioactivity from the liver and body and, thus, minimize hepatic radiation dose, a peptide having a specific cathepsin B cleavage site was placed between the radiometal chelate DOTA (1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid) and the monoclonal antibody m170, and the comparative pharmacokinetics was evaluated in prostate cancer patients. Experimental Design: 111In-DOTA-2IT-m170 and 111In-DOTA-peptide-(GGGF)-m170, representing the same monoclonal antibody and chelate with and without the cleavable linkage, were studied in comparable groups of prostate cancer patients (17 with In-2IT-BAD-m170 and 8 with In-DOTA-peptide-m170). Pharmacokinetics over 7 days, calculated yttrium-90 radiation dosimetry, therapeutic index, and projected maximum tolerated injected yttrium-90 dose were evaluated. Results: The radioimmunoconjugates pharmacokinetics and calculated tumor and normal organ absorbed radiation dose (rads/mCi) were similar, except for a significant decrease in the mean dose to the liver (31{\%}; P < 0.01) and lungs (31{\%}; P < 0.01) with the DOTA-peptide immunoconjugates. Because mean tumor dose was not statistically different, this peptide linkage provided a significant increase in the therapeutic index for this tumor targeting radiopharmaceutical. If marrow support is adequate, the radiation dose historically tolerated by normal organs other than marrow would allow a 30{\%} increase in the administered dose, resulting in a mean dose of 9500 rads to metastatic prostate cancer.",
author = "DeNardo, {Sally J.} and Denardo, {Gerald L} and A. Yuan and Richman, {Carol M} and O'Donnell, {Robert T} and Lara, {Primo N} and Kukis, {David L.} and Arutselvan Natarajan and Lamborn, {Kathleen R.} and Frederik Jacobs and {Hartmann Siantar}, {Christine L.}",
year = "2003",
month = "10",
day = "1",
language = "English (US)",
volume = "9",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "10 II",

}

TY - JOUR

T1 - Enhanced therapeutic index of radioimmunotherapy (RIT) in prostate cancer patients

T2 - Comparison of radiation dosimetry for 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA)-peptide versus 2IT-DOTA monoclonal antibody linkage for RIT

AU - DeNardo, Sally J.

AU - Denardo, Gerald L

AU - Yuan, A.

AU - Richman, Carol M

AU - O'Donnell, Robert T

AU - Lara, Primo N

AU - Kukis, David L.

AU - Natarajan, Arutselvan

AU - Lamborn, Kathleen R.

AU - Jacobs, Frederik

AU - Hartmann Siantar, Christine L.

PY - 2003/10/1

Y1 - 2003/10/1

N2 - Purpose: Radioimmunotherapy delivered by radiometal immunoconjugates and followed by marrow support is dose limited by deposition of radioactivity in normal organs. To increase elimination of radioactivity from the liver and body and, thus, minimize hepatic radiation dose, a peptide having a specific cathepsin B cleavage site was placed between the radiometal chelate DOTA (1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid) and the monoclonal antibody m170, and the comparative pharmacokinetics was evaluated in prostate cancer patients. Experimental Design: 111In-DOTA-2IT-m170 and 111In-DOTA-peptide-(GGGF)-m170, representing the same monoclonal antibody and chelate with and without the cleavable linkage, were studied in comparable groups of prostate cancer patients (17 with In-2IT-BAD-m170 and 8 with In-DOTA-peptide-m170). Pharmacokinetics over 7 days, calculated yttrium-90 radiation dosimetry, therapeutic index, and projected maximum tolerated injected yttrium-90 dose were evaluated. Results: The radioimmunoconjugates pharmacokinetics and calculated tumor and normal organ absorbed radiation dose (rads/mCi) were similar, except for a significant decrease in the mean dose to the liver (31%; P < 0.01) and lungs (31%; P < 0.01) with the DOTA-peptide immunoconjugates. Because mean tumor dose was not statistically different, this peptide linkage provided a significant increase in the therapeutic index for this tumor targeting radiopharmaceutical. If marrow support is adequate, the radiation dose historically tolerated by normal organs other than marrow would allow a 30% increase in the administered dose, resulting in a mean dose of 9500 rads to metastatic prostate cancer.

AB - Purpose: Radioimmunotherapy delivered by radiometal immunoconjugates and followed by marrow support is dose limited by deposition of radioactivity in normal organs. To increase elimination of radioactivity from the liver and body and, thus, minimize hepatic radiation dose, a peptide having a specific cathepsin B cleavage site was placed between the radiometal chelate DOTA (1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid) and the monoclonal antibody m170, and the comparative pharmacokinetics was evaluated in prostate cancer patients. Experimental Design: 111In-DOTA-2IT-m170 and 111In-DOTA-peptide-(GGGF)-m170, representing the same monoclonal antibody and chelate with and without the cleavable linkage, were studied in comparable groups of prostate cancer patients (17 with In-2IT-BAD-m170 and 8 with In-DOTA-peptide-m170). Pharmacokinetics over 7 days, calculated yttrium-90 radiation dosimetry, therapeutic index, and projected maximum tolerated injected yttrium-90 dose were evaluated. Results: The radioimmunoconjugates pharmacokinetics and calculated tumor and normal organ absorbed radiation dose (rads/mCi) were similar, except for a significant decrease in the mean dose to the liver (31%; P < 0.01) and lungs (31%; P < 0.01) with the DOTA-peptide immunoconjugates. Because mean tumor dose was not statistically different, this peptide linkage provided a significant increase in the therapeutic index for this tumor targeting radiopharmaceutical. If marrow support is adequate, the radiation dose historically tolerated by normal organs other than marrow would allow a 30% increase in the administered dose, resulting in a mean dose of 9500 rads to metastatic prostate cancer.

UR - http://www.scopus.com/inward/record.url?scp=12444272237&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=12444272237&partnerID=8YFLogxK

M3 - Article

C2 - 14506192

AN - SCOPUS:12444272237

VL - 9

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 10 II

ER -