Development of TNKase-specific cleavable peptide-linked radioimmunoconjugates for radioimmunotherapy

Arutselvan Natarajan, Pappanaicken R. Kumaresan, Sally J. DeNardo, Gerald L Denardo, Gary Mirick, Kit Lam

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Radioimmunotherapy (RIT) is a method for selectively delivering radionuclides to cancer cells while reducing the radiation dose to normal tissues. However, because of slow clearance of MAbs, normal tissues also received radiotoxicity. One of the promising strategies is linking on-demand cleavable (ODC) peptides between radiometal chelates and the tumor targeting agents. We have tested this proof-of-concept by using ODC peptides that are designed to be cleaved only by TNKase and are resistant to cleavage by enzymes present in the plasma and the tumor. TNKase-specific peptide linkers using l- and d-amino acids were screened by OBOC combinatorial peptide libraries. One of the best peptides was linked to radiometal chelate and ChL6-MAb to prepare radioimmunoconjugate (RIC). Optimization and characterization of the linker conjugation to MAb show (a) 1-2 peptides linked to each MAb; (b) immunoreactivity >80%; (c) specific activity of the RIC 0.7-1 μCi/μg; (d) RIC stable over 7 days in human plasma; and (e) radiometal-chelated ODC peptide cleaved from the RIC in plasma by TNKase at clinical dose levels of 10 μg/ml. The percent release of radiochelate from RIC was 50% at 24 h and 85% over 72 h in vitro. This novel ODC-linked RIC could be a potential molecule for RIT.

Original languageEnglish (US)
Pages (from-to)4802-4805
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume18
Issue number17
DOIs
StatePublished - Sep 1 2008

Fingerprint

Immunoconjugates
Radioimmunotherapy
Peptides
Tumors
Tissue
Plasma (human)
Plasmas
Peptide Library
Neoplasms
Radioisotopes
Dosimetry
tenecteplase
Cells
Radiation
Amino Acids
Molecules
Enzymes

Keywords

  • ChL6
  • ODC linkers
  • Radioimmunoconjugate
  • Radioimmunotherapy
  • TNKase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Development of TNKase-specific cleavable peptide-linked radioimmunoconjugates for radioimmunotherapy. / Natarajan, Arutselvan; Kumaresan, Pappanaicken R.; DeNardo, Sally J.; Denardo, Gerald L; Mirick, Gary; Lam, Kit.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 18, No. 17, 01.09.2008, p. 4802-4805.

Research output: Contribution to journalArticle

Natarajan, Arutselvan ; Kumaresan, Pappanaicken R. ; DeNardo, Sally J. ; Denardo, Gerald L ; Mirick, Gary ; Lam, Kit. / Development of TNKase-specific cleavable peptide-linked radioimmunoconjugates for radioimmunotherapy. In: Bioorganic and Medicinal Chemistry Letters. 2008 ; Vol. 18, No. 17. pp. 4802-4805.
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