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J Nucl Med. 2008; 49 (Supplement 1):140P
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Radiopharmaceutical Chemistry: New Chemistry-Oncology

New Chemistry-Oncology III: Other

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

Arutselvan Natarajan1, Pappanaicken Kumaresan1, Sally DeNardo1, Gary Mirick1, Gerald DeNardo1 and Kit Lam1

1 Internal Medicine, UC Davis, Sacramento, California

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Objectives: Radioimmunotherapy (RIT) is a method to more selectively deliver radionuclides to cancer cells. However, normal tissues get irradiated during the slow blood clearance of the MAbs."On demand" cleavable (ODC) peptide linker strategy was used to connect the radiometal chelates to the tumor targeting agents. We have tested this concept by using ODC peptides cleavable only by TNKase, an approved thrombolytic drug, and resistant to cleavage by enzymes present in plasma, normal tissue and tumor.

Methods: TNKase-specific peptide linkers were screened by "one-bead-one-compound" (OBOC) peptide libraries. A selected set of peptides were synthesized to link the DOTA chelate at an ‘optimal distance" with an amino-oxy functionality for conjugation to a breast cancer targeting monoclonal antibody (ChL6). Hundreds of these ODC peptide linkages, further screened for TNKase-specific susceptibility were linked to ChL6 by amino-oxy and keto ligation to prepare radioimmunoconjugates (RICs) which were characterized using mass spectrometry, HPLC, CAE, TLC, immunoreactivity and plasma stability.

Results: Optimization of the linker conjugation to MAb was carried out to control the linkers in such a way to meet the following criteria: a) 1-3 peptides linked to each MAb; b) immunoreactivity >80%; C) specific activities of the RICs were 0.7-1µCi/µg; d) RICs were stable over 7 days in human plasma; and, e) radiometal chelated ODC peptide cleaved from RIC >80% with 100µg of TNKase in 24 h; 50% with 10µg TNKase in human plasma.

Conclusions: Novel ODC-linked RICs were prepared for RIT. Radiometal was efficiently cleaved from the RIC in plasma by TNKase at levels of 10 µg/mL corresponding to clinical doses.

Research Support: NIH PO1 grant CA47829





This Article
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Google Scholar
Right arrow Articles by Natarajan, A.
Right arrow Articles by Lam, K.
PubMed
Right arrow Articles by Natarajan, A.
Right arrow Articles by Lam, K.