89Zr-Labeled Versus 124I-Labeled αHER2 Fab with Optimized Plasma Half-Life for High-Contrast Tumor Imaging In Vivo

被引:0
作者
Mendler, Claudia T. [1 ,2 ,3 ]
Gehring, Torben [1 ,2 ]
Wester, Hans-Juergen [4 ]
Schwaiger, Markus [3 ]
Skerra, Arne [1 ,2 ]
机构
[1] Tech Univ Munich, Munich Ctr Integrated Prot Sci CIPS M, D-85350 Freising Weihenstephan, Germany
[2] Tech Univ Munich, Lehrstuhl Biol Chem, D-85350 Freising Weihenstephan, Germany
[3] Tech Univ Munich, Klinikum Rechts Isar, Nukl Med Klin & Poliklin, D-80290 Munich, Germany
[4] Tech Univ Munich, Pharmazeut Radiochem, Garching, Germany
关键词
Fab; HER2; PASylation; plasma half-life; PET; MONOCLONAL-ANTIBODIES; BIFUNCTIONAL CHELATE; RENAL UPTAKE; FRAGMENTS; PHARMACOKINETICS; ZIRCONIUM-89; IMMUNOPET; PEPTIDES; ZR-89-TRASTUZUMAB; THERAPY;
D O I
暂无
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
Immuno-PET imaging of the tumor antigen HER2/neu allows for the noninvasive detection and monitoring of oncogene expression; such detection and monitoring are of prognostic value in patients with breast cancer. Compared with the full-size antibody trastuzumab, smaller protein tracers with more rapid blood clearance permit higher imaging contrast at earlier time points. Antigen-binding fragments (Fabs) of antibodies with moderately prolonged circulation achieved through the genetic fusion with a long, conformationally disordered chain of the natural amino acids Pro, Ala, and Ser (PASylation)-a biologic alternative to chemical conjugation with polyethylene glycol, PEG-offer a promising tracer format with improved pharmacokinetics for in vivo imaging. Recently, the transition metal radionuclide Zr-89 has attracted increasing interest for immuno-PET studies, complementing the conventional halogen radionuclide I-124. Methods: To allow direct comparison of these 2 radioactive labels for the same protein tracer, the recombinant alpha HER2 Fab fused with 200 Pro, Ala, and Ser (PAS(200)) residues was either conjugated with I-124 via an iodination reagent or coupled with deferoxamine (Df) and complexed with Zr-89. After confirmation of the stability of both radioconjugates and quality control in vitro, immuno-PET and biodistribution studies were performed with CD1-Foxn1(nu) mice bearing HER2-positive human tumor xenografts. Results: Zr-89.Df-Fab-PAS(200) and I-124-Fab-PAS(200) showed specific tumor uptake of 11 and 2.3 percentage injected dose per gram 24 h after injection, respectively; both led to high tumor-to-blood (3.6 and 4.4, respectively) and tumor-to-muscle (20 and 43, respectively) ratios. With regard to off-target accumulation, overt I-124 activity was seen in the thyroid, as expected, whereas high kidney uptake was evident for Zr-89; the latter was probably due to glomerular filtration and reabsorption of the protein tracer in proximal tubular cells. Conclusion: Both Zr-89- and I-124-labeled versions of alpha HER2 Fab-PAS(200) allowed PET tumor imaging with high contrast. With its residualizing radiometal, the tracer Zr-89.Df-Fab-PAS(200) showed better in vivo stability and higher tumor uptake.
引用
收藏
页码:1112 / 1118
页数:7
相关论文
共 31 条
[1]   In Vivo and In Vitro Studies on Renal Uptake of Radiolabeled Affibody Molecules for Imaging of HER2 Expression in Tumors [J].
Altai, Mohamed ;
Varasteh, Zohreh ;
Andersson, Karl ;
Eek, Annemarie ;
Boerman, Otto ;
Orlova, Anna .
CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS, 2013, 28 (03) :187-195
[2]   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
[3]   Radiation Dosimetry of 89Zr-Labeled Chimeric Monoclonal Antibody U36 as Used for Immuno-PET in Head and Neck Cancer Patients [J].
Boerjesson, Pontus K. E. ;
Jauw, Yvonne W. S. ;
de Bree, Remco ;
Roos, Jan C. ;
Castelijns, Jonas A. ;
Leemans, C. Rene ;
van Dongen, Guus A. M. S. ;
Boellaard, Ronald .
JOURNAL OF NUCLEAR MEDICINE, 2009, 50 (11) :1828-1836
[4]   Enhanced Tumor Retention of a Radiohalogen Label for Site-Specific Modification of Antibodies [J].
Boswell, C. Andrew ;
Marik, Jan ;
Elowson, Michael J. ;
Reyes, Noe A. ;
Ulufatu, Sheila ;
Bumbaca, Daniela ;
Yip, Victor ;
Mundo, Eduardo E. ;
Majidy, Nicholas ;
Van Hoy, Marjie ;
Goriparthi, Saritha N. ;
Trias, Anthony ;
Gill, Herman S. ;
Williams, Simon P. ;
Junutula, Jagath R. ;
Fielder, Paul J. ;
Khawli, Leslie A. .
JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (23) :9418-9426
[5]   The sodium/iodide symporter: State of the art of its molecular characterization [J].
Darrouzet, Elisabeth ;
Lindenthal, Sabine ;
Marcellin, Didier ;
Pellequer, Jean-Luc ;
Pourcher, Thierry .
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 2014, 1838 (01) :244-253
[6]   Imaging tumors with an albumin-binding Fab, a novel tumor-targeting agent [J].
Dennis, Mark S. ;
Jin, Hongkui ;
Dugger, Debra ;
Yang, Renhui ;
McFarland, Leanne ;
Ogasawara, Annie ;
Williams, Simon ;
Cole, Mary J. ;
Ross, Sarajane ;
Schwall, Ralph .
CANCER RESEARCH, 2007, 67 (01) :254-261
[7]   Biodistribution of 89Zr-trastuzumab and PET Imaging of HER2-Positive Lesions in Patients With Metastatic Breast Cancer [J].
Dijkers, E. C. ;
Munnink, T. H. Oude ;
Kosterink, J. G. ;
Brouwers, A. H. ;
Jager, P. L. ;
de Jong, J. R. ;
van Dongen, G. A. ;
Schroder, C. P. ;
Lub-de Hooge, M. N. ;
de Vries, E. G. .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 2010, 87 (05) :586-592
[8]   Development and Characterization of Clinical-Grade 89Zr-Trastuzumab for HER2/neu ImmunoPET Imaging [J].
Dijkers, Eli C. F. ;
Kosterink, Jos G. W. ;
Rademaker, Anna P. ;
Perk, Lars R. ;
van Dongen, Guus A. M. S. ;
Bart, Joost ;
de Jong, Johan R. ;
de Vries, Elisabeth G. E. ;
Lub-de Hooge, Marjolijn N. .
JOURNAL OF NUCLEAR MEDICINE, 2009, 50 (06) :974-981
[9]   Image-Quality Assessment for Several Positron Emitters Using the NEMA NU 4-2008 Standards in the Siemens Inveon Small-Animal PET Scanner [J].
Disselhorst, Jonathan A. ;
Brom, Maarten ;
Laverman, Peter ;
Slump, Cornelius H. ;
Boerman, Otto C. ;
Oyen, Wim J. G. ;
Gotthardt, Martin ;
Visser, Eric P. .
JOURNAL OF NUCLEAR MEDICINE, 2010, 51 (04) :610-617
[10]   Preoperative characterisation of clear-cell renal carcinoma using iodine-124-labelled antibody chimeric G250 (124I-cG250) and PET in patients with renal masses:: a phase I trial [J].
Divgi, Chaitanya R. ;
Pandit-Taskar, Neeta ;
Jungbluth, Achim A. ;
Reuter, Victor E. ;
Gonen, Mithat ;
Ruan, Shutian ;
Pierre, Christine ;
Nagel, Andrew ;
Pryma, Daniel A. ;
Humm, John ;
Larson, Steven M. ;
Old, Lloyd J. ;
Russo, Paul .
LANCET ONCOLOGY, 2007, 8 (04) :304-310