Pretargeted radioimmunotherapy of mesothelin-expressing cancer using a tetravalent single-chain Fv-streptavidin fusion protein.

Abstract

UNLABELLED:

Mesothelin is a glycoprotein that is overexpressed in several human tumors, including mesotheliomas and ovarian cancers, and has been identified as a potential target for therapy. We evaluated the biodistribution and tumor-targeting ability of an antimesothelin tetravalent single-chain Fv-streptavidin fusion protein (SS1scFvSA) in mice.

METHODS:

SS1scFvSA was labeled with 125I or 111In for evaluation of internalization in vitro and for optimization of its biodistribution. The A431-K5 mesothelin transfected cell line was used as the target. We used a 3-step pretargeting approach consisting of injections of (i) SS1scFvSA, followed 20 h later by (ii) a synthetic clearing agent, and (iii) 4 h later, radiolabeled (111In, 88Y/90Y, or 177Lu) 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-biotin. To optimize the tumor uptake, the effect of the specific activity of 111In-DOTA-biotin was evaluated.

RESULTS:

Approximately 60% of SS1sc FvSA internalized within 6 h. The optimal dose of SS1scFvSA for pretargeting was 600 microg. Decreasing the specific activity of DOTA-biotin by administering 0.1-5 microg of DOTA-biotin resulted in tumor uptake decreasing from 31.8 to 5.5 %ID/g (percentage injected dose per gram) at 2 h. Pretargeted therapy of A431-K5 tumor with 90Y doses of 11.1-32.4 MBq resulted in a dose-dependent tumor response. With 32.4 MBq, 86% of mice survived tumor free for 110 d. All nontreated mice died, with a median survival of 16 d.

CONCLUSION:

SS1scFvSA localized in the mesothelin-expressing tumor, resulting in a high accumulation of radiolabeled DOTA-biotin. The specific activity of DOTA-biotin had a significant effect on its tumor uptake. Therapeutic tumor doses were obtained without dose-limiting toxicity.

• Authors: Noriko Sato, Raffit Hassan, Donald B Axworthy, Karen J Wong, Sarah Yu, Louis J Theodore, Yukang Lin, Luke Park, Martin W Brechbiel, Ira Pastan, Chang H Paik, Jorge A Carrasquillo
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 46 Issue 7 Pg. 1201-9 (Jul 2005) ISSN: 0161-5505 [Print] United States
• PMID: 16000290 (Publication Type: Journal Article)

Chemical References

• GPI-Linked Proteins
• Immunoglobulin Fragments
• Iodine Radioisotopes
• Membrane Glycoproteins
• Msln protein, mouse
• Radiopharmaceuticals
• Recombinant Fusion Proteins
• Streptavidin
• Mesothelin

Topics

• Animals
• Carcinoma, Squamous Cell (metabolism, radiotherapy)
• Cell Line, Tumor
• Drug Delivery Systems (methods)
• Female
• GPI-Linked Proteins
• Humans
• Immunoglobulin Fragments (metabolism, therapeutic use)
• Iodine Radioisotopes (pharmacokinetics, therapeutic use)
• Membrane Glycoproteins (metabolism)
• Mesothelin
• Metabolic Clearance Rate
• Mice
• Mice, Nude
• Organ Specificity
• Radioimmunotherapy (methods)
• Radiopharmaceuticals (pharmacokinetics, therapeutic use)
• Recombinant Fusion Proteins (pharmacokinetics, therapeutic use)
• Streptavidin (pharmacokinetics, therapeutic use)
• Survival Analysis
• Tissue Distribution
• Treatment Outcome