title: Improved renal clearance and tumor targeting of 99mTc-labeled anti-Tac monoclonal antibody Fab by chemical modifications.
abstract: This study was undertaken to improve the renal clearance and tumor targeting properties of 99mTc-labeled humanized anti-Tac (HuTac) monoclonal antibody Fab fragments using two chemical approaches: 1) labeling with a renal secretion agent 99mTc-mercaptoacetyltriglycine (MAG3) and 2) lowering its isoelectric point (pI) by acylation. HuTac Fab (3.3 mg/mL) was reacted with a trifluorophenyl ester (TFP) of 99mTc-MAG3 alone or was additionally reacted with TFP-glycolate to reduce the pI. In Balb/c mice, 99mTc-MAG3-Fab (pI > 9.3) rapidly accumulated in the kidneys (177% injected dose [ID]/g at 15 min) and then gradually cleared out of the kidneys. In contrast, the glycolation (pI 4.6 approximately 6.6) drastically reduced the renal uptake (31% ID/g) and also the whole-body retention (82% ID vs 101% for the nonglycolated) at 15 min, indicating that the glycolated 99mTc-MAG3-Fab (pI 4.6 approximately 6.6) was rapidly excreted. The glycolated remained in the blood longer than the nonglycolated (1.2% vs 0.3% ID/g at 360 min), but this effect was less drastic than the effect shown on the renal uptake. In nude mice bearing receptor-positive (ATAC4) tumors, the glycolated 99mTc-MAG3-Fab increased the peak tumor uptake to 14.8% ID/g from 8.3% ID/g for 99mTc-MAG3-Fab, whereas the glycolation resulted in a drastic reduction of the renal uptake at 15 min. We demonstrated that the renal clearance and the tumor targeting of Fab could be optimized by chemical modifications.
authors.affiliation: Department of Nuclear Medicine, Warren G. Magnuson Clinical Center, Bethesda, Maryland 20892, USA.
authors.forename: Meyoung-kon
authors.initials: MK
authors.lastname: Kim
authors.forename: Hyeh-Jean
authors.initials: HJ
authors.lastname: Jeong
authors.forename: Chih-Hao K
authors.initials: CH
authors.lastname: Kao
authors.forename: Zhengsheng
authors.initials: Z
authors.lastname: Yao
authors.forename: David S
authors.initials: DS
authors.lastname: Paik
authors.forename: Jae Eun
authors.initials: JE
authors.lastname: Pie
authors.forename: Hisataka
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Carrasquillo
authors.forename: Chang H
authors.initials: CH
authors.lastname: Paik
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D005260:Female; D006016:Glycolates / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism*; D007457:Iodine Radioisotopes / Q000097:blood / Q000652:urine; D007668:Kidney / Q000378:metabolism*; D008239:Lysine / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D017263:Technetium Tc 99m Mertiatide / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D006016:Glycolates; D007140:Immunoglobulin Fab Fragments; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D017263:Technetium Tc 99m Mertiatide; D008239:Lysine