Development and preclinical characterisation of 99mTc-labelled Affibody molecules with reduced renal uptake

被引:72
作者
Ekblad, Torun [5 ]
Tran, Thuy [1 ]
Orlova, Anna [1 ,2 ]
Widstrom, Charles [3 ]
Feldwisch, Joachim [1 ,2 ]
Abrahmsen, Lars [2 ]
Wennborg, Anders [2 ]
Karlstrom, Amelie Eriksson [5 ]
Tolmachev, Vladimir [1 ,2 ,4 ]
机构
[1] Uppsala Univ, Rudbeck Lab, Unit Biomed Radiat Sci, Uppsala, Sweden
[2] Affibody AB, Bromma, Sweden
[3] Univ Uppsala Hosp, Dept Oncol, Sect Hosp Phys, S-75185 Uppsala, Sweden
[4] Uppsala Univ, Nucl Med Unit, Dept Med Sci, Uppsala, Sweden
[5] Royal Inst Technol, Sch Biotechnol, Stockholm, Sweden
基金
瑞典研究理事会;
关键词
Affibody molecule; HER2; Renal uptake; Technetium-99m; Tumour targeting;
D O I
10.1007/s00259-008-0845-7
中图分类号
R8 [特种医学]; R445 [影像诊断学];
学科分类号
1002 ; 100207 ; 1009 ;
摘要
Purpose Affibody molecules are low molecular weight proteins (7 kDa), which can be selected to bind to tumour-associated target proteins with subnanomolar affinity. Because of rapid tumour localisation and clearance from nonspecific compartments, Affibody molecules are promising tracers for molecular imaging. Earlier, Tc-99m-labelled Affibody molecules demonstrated specific targeting of tumour xenografts. However, the biodistribution was suboptimal either because of hepatobiliary excretion or high renal uptake of the radioactivity. The goal of this study was to optimise the biodistribution of Affibody molecules by chelator engineering. Materials and methods Anti-HER2 Z(HER2:342) Affibody molecules, carrying the mercaptoacetyl-glutamyl-serylglutamyl (maESE), mercaptoacetyl-glutamyl-glutamyl-seryl (maEES) and mercaptoacetyl-seryl-glutamyl-glutamyl (maSEE) chelators, were prepared by peptide synthesis and labelled with Tc-99m. The tumour-targeting capacity of these conjugates was compared with each other and with the best previously available conjugate, Tc-99m-maEEE-Z(HER2:342), in nude mice bearing SKOV-3 xenografts. The tumour-targeting capacity of the most promising conjugate, Tc-99m-maESE-Z(HER2:342), was compared with radioiodinated Z(HER2:342). Results All novel conjugates demonstrated successful tumour targeting and a low degree of hepatobiliary excretion. The renal uptakes of serine-containing conjugates, 33 +/- 5, 68 +/- 21 and 71 +/- 10% IA/g, for Tc-99m-maESE-Z(HER2:342), Tc-99m-maEES-Z(HER2:342) and Tc-99m-maSEE-Z(HER2:342), respectively, were significantly reduced in comparison with Tc-99m-maEEE-Z(HER2:342) (102 +/- 13% IA/g). For (99m)TcmaESE-Z(HER2:342), a tumour uptake of 9.6 +/- 1.8% IA/g and a tumour-to-blood ratio of 58 +/- 6 were reached at 4 h p.i. Conclusions A combination of serine and glutamic acid residues in the chelator sequence confers increased renal excretion and relatively low renal uptake of Tc-99m-labelled Affibody molecules. In combination with preserved targeting capacity, this improved imaging of targets in abdominal area.
引用
收藏
页码:2245 / 2255
页数:11
相关论文
共 33 条
[1]   Pharmacokinetics and biodistribution of genetically engineered antibodies [J].
Batra, SK ;
Jain, M ;
Wittel, UA ;
Chauhan, SC ;
Colcher, D .
CURRENT OPINION IN BIOTECHNOLOGY, 2002, 13 (06) :603-608
[2]  
BAUM R, 2006, J NUCL MED S1, V47, pP108
[3]  
Béhé M, 2005, J NUCL MED, V46, P1012
[4]   Reducing the renal uptake of radiolabeled antibody fragments and peptides for diagnosis and therapy: present status, future prospects and limitations [J].
Behr, TM ;
Goldenberg, DM ;
Becker, W .
EUROPEAN JOURNAL OF NUCLEAR MEDICINE, 1998, 25 (02) :201-212
[5]  
Behr TM, 2001, Q J NUCL MED, V45, P189
[6]   Engineering novel binding proteins from nonimmunoglobulin domains [J].
Binz, HK ;
Amstutz, P ;
Plückthun, A .
NATURE BIOTECHNOLOGY, 2005, 23 (10) :1257-1268
[7]   Development of radioimmunotherapeutic and diagnostic antibodies: an inside-out view [J].
Boswell, C. Andrew ;
Brechbiel, Martin W. .
NUCLEAR MEDICINE AND BIOLOGY, 2007, 34 (07) :757-778
[8]  
Britz-Cunningham SH, 2003, J NUCL MED, V44, P1945
[9]   Effects of intravenous amino acid administration with Y-90 DOTA-Phe1-Ty3-octreotide (SMT487 [OctreoTher™]) treatment [J].
Bushnell, D ;
Menda, Y ;
O'Dorisio, T ;
Madsen, M ;
Miller, S ;
Carlisle, T ;
Squires, S ;
Kahn, D ;
Walkner, W ;
Connolly, M ;
O'Dorisio, S ;
Karwal, M ;
Ponto, J ;
Bouterfa, H .
CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS, 2004, 19 (01) :35-41
[10]   Efficient tumor targeting by single-domain antibody fragments of camels [J].
Cortez-Retamozo, V ;
Lauwereys, M ;
Gh, GH ;
Gobert, M ;
Conrath, K ;
Muyldermans, S ;
De Baetselier, P ;
Revets, H .
INTERNATIONAL JOURNAL OF CANCER, 2002, 98 (03) :456-462