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Pretargeted 177Lu radioimmunotherapy of carcinoembryonic antigen-expressing human colonic tumors in mice.

AbstractUNLABELLED:
Pretargeted radioimmunotherapy (PRIT) with bispecific antibodies in combination with a radiolabeled peptide reduces the radiation dose to normal tissues, especially the bone marrow. In this study, the optimization, therapeutic efficacy, and toxicity of PRIT of colon cancer with a (177)Lu-labeled peptide was determined in mice with carcinoembryonic antigen (CEA)-expressing human tumors.
METHODS:
To obtain the optimal therapeutic efficacy, several strategies were evaluated to increase the total amount of radioactivity targeted to subcutaneous LS174T colon cancer tumors in BALB/c nude mice. First, the maximum amount of bispecific anti-CEA and antihapten antibody TF2 and the peptide IMP288 that could be targeted was determined. Second, the tumor targeting of repeated administrations of radiolabeled IMP288 was investigated. Mice received 1 TF2 injection, followed by multiple IMP288 injections (3-h interval) or multiple cycles, with each IMP288 administration preceded by a new TF2 injection (72-h interval). PRIT was administered at maximum doses of TF2 and (177)Lu-labeled IMP288 in groups of 9 mice with subcutaneous LS174T tumors. Mice received 1, 2, or 3 successive cycles of treatment (26 MBq/mouse/cycle) or carrier only. The primary endpoint was survival; secondary endpoints were tumor growth, body weight, bone marrow, and renal toxicity.
RESULTS:
The highest amount of radioactivity delivered to a subcutaneous colon tumor was achieved by the administration of 5.0 nmol of TF2 and 0.28 nmol of IMP288 in 3 successive cycles, with each IMP288 preceded by a new TF2 injection (72-h interval). PRIT effectively delayed tumor growth and prolonged survival significantly. Higher activity doses, administered in successive cycles, correlated with longer survival: the median survival of untreated mice was 13 d (range, 6-20 d), whereas that of mice treated with 1, 2, or 3 cycles of PRIT was 24 (range, 24-31 d), 45 (range, 38 ≥ 130 d), and 65 (range, 48 ≥ 130 d) days, respectively. Toxicity was limited: no significant changes in mean body weight were measured. Minimal changes in leukocyte counts were measured at 2 and 3 wk after injection, with full recovery within 7 wk after treatment. Platelet counts were unaffected. Serum creatinine levels were not increased significantly; thus, there was no indication of acute renal toxicity.
CONCLUSION:
This study indicates that PRIT in mice is an effective treatment modality against colon cancer, with limited toxicity.
AuthorsRafke Schoffelen, Winette T A van der Graaf, Gerben Franssen, Robert M Sharkey, David M Goldenberg, William J McBride, Edmund A Rossi, Annemarie Eek, Wim J G Oyen, Otto C Boerman
JournalJournal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 51 Issue 11 Pg. 1780-7 (Nov 2010) ISSN: 1535-5667 [Electronic] United States
PMID21051650 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies, Monoclonal
  • Carcinoembryonic Antigen
  • Haptens
  • Peptides
  • Radioisotopes
  • Lutetium
Topics
  • Animals
  • Antibodies, Monoclonal (immunology)
  • Carcinoembryonic Antigen (immunology, metabolism)
  • Cell Line, Tumor
  • Colonic Neoplasms (metabolism, radiotherapy)
  • Gene Expression Regulation, Neoplastic
  • Haptens (chemistry, immunology)
  • Humans
  • Lutetium (therapeutic use)
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Peptides (adverse effects, chemistry, pharmacokinetics, therapeutic use)
  • Radioimmunotherapy (methods)
  • Radioisotopes

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