BIOTINYLATED AND CHELATED POLY-L-LYSINE AS EFFECTOR FOR PRETARGETING IN CANCER THERAPY AND IMAGING
DOI:
https://doi.org/10.22159/ijpps.2017v9i1.11109Keywords:
Pretargeting, Radiometals, Polylysine, Radioimmunotherapy, Radioimmunoimaging, KidneyAbstract
Objective: The aim of this study was to synthesise and evaluate polylysine-based effectors for pretargeted radioimmunotherapy and imaging. These molecules can readily be size-modified and charge-modified to decrease the renal uptake of radioactivity, which is often a major problem for small radiolabeled molecules. Several chelators and biotin molecules (for antibody-streptavidin-binding in vivo) are also easily incorporated into one structure because of the polylysine.
Methods: The effectors were synthesised using poly-L-lysine, NHS-LC-biotin, CHX-A''-DTPA or p-SCN-Bn-DOTA and succinic anhydride. They were characterised, labelled with 213Bi for targeted α therapy, 68Ga for PET and 111In for SPECT, and evaluated in vitro. A kidney uptake study was performed as well with two different-sized 213Bi-labeled effectors, to evaluate how the difference in size affects the renal filtration.
Results: Radiochemical purities between 97.4±0.6 % and 99.6±0.1 % and decay-corrected yields of 80.2±2.4 % after purification were achieved with the radiolabeled molecules, as well as a specific activity of 7.6 × 103GBq/µmol. The avidin binding capacity was 94.4±1.9%. The kidney uptake study demonstrated a reduction of renal absorbed dose by 80% when modifying the molecular size and charge.
Conclusion: The synthesised polylysine-based effectors show potential for further in vivo evaluation in pretargeted radioimmunotherapy and imaging.
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Elgqvist J, Frost S, Pouget JP, Albertsson P. The potential and hurdles of targeted alpha therapy clinical trials and beyond. Front Oncol 2014;3:324.
Tomblyn MB, Katin MJ, Wallner PE. The new golden era for radioimmunotherapy: not just for lymphomas anymore. Cancer control 2013;20:60-71.
Barbet J, Bardies M, Bourgeois M, Chatal JF, Cherel M, Davodeau F, et al. Radiolabeled antibodies for cancer imaging and therapy. Methods Mol Biol 2012;907:681-97.
Frampas E, Rousseau C, Bodet-Milin C, Barbet J, Chatal JF, Kraeber-Bodere F. Improvement of radioimmunotherapy using pretargeting. Front Oncol 2013;3:159.
Sharkey RM, Chang CH, Rossi EA, McBride WJ, Goldenberg DM. Pretargeting: taking an alternate route for localizing radionuclides. Tumour Biol 2012;33:591-600.
Lindegren S, Frost SH. Pretargeted radioimmunotherapy with alpha-particle emitting radionuclides. Curr Radiopharm 2011;4:248-60.
Park SI, Shenoi J, Pagel JM, Hamlin DK, Wilbur DS, Orgun N, et al. Conventional and pretargeted radioimmunotherapy using bismuth-213 to target and treat non-Hodgkin lymphomas expressing CD20: a preclinical model toward optimal consolidation therapy to eradicate minimal residual disease. Blood 2010;116:4231-9.
Pagel JM, Kenoyer AL, Back T, Hamlin DK, Wilbur DS, Fisher DR, et al. Anti-CD45 pretargeted radioimmunotherapy using bismuth-213: high rates of complete remission and long-term survival in a mouse myeloid leukemia xenograft model. Blood 2011;118:703-11.
Zeglis BM, Sevak KK, Reiner T, Mohindra P, Carlin SD, Zanzonico P, et al. A pretargeted PET imaging strategy based on bioorthogonal diels-alder click chemistry. J Nucl Med 2013;54:1389-96.
Wilbur DS, Park SI, Chyan MK, Wan F, Hamlin DK, Shenoi J, et al. Design and synthesis of bis-biotin-containing reagents for applications utilising monoclonal antibody-based pretargeting systems with streptavidin mutants. Bioconjugate Chem 2010;21:1225-38.
Haraldsson B, Nystrom J, Deen WM. Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev 2008;88:451-87.
Lindegren S, Andersson H, Jacobsson L, Back T, Skarnemark G, Karlsson B. Synthesis and biodistribution of At-211-labeled, biotinylated, and charge-modified poly-L-lysine: Evaluation for use as an effector molecule in pretargeted intraperitoneal tumor therapy. Bioconjugate Chem 2002;13:502-9.
Torchilin VP, Trubetskoy VS, Narula J, Khaw BA, Klibanov AL, Slinkin MA. Chelating polymer-modified monoclonal antibodies for radio immunodiagnostics and radioimmunotherapy. J Controlled Release 1993:24:111-8.
Delrosario RB, Wahl RL. Biotinylated iodo-polylysine for pretargeted radiation delivery. J Nucl Med 1993;34:1147-51.
Khaw BA, Tekabe Y, Johnson LL. Imaging experimental atherosclerotic lesions in ApoE knockout mice: enhanced targeting with Z2D3-anti-DTPA bispecific antibody and 99mTc-labeled negatively charged polymers. J Nucl Med 2006;47:868-76.
Apostolidis C, Molinet R, Rasmussen G, Morgenstern A. Production of Ac-225 from Th-229 for targeted alpha therapy. Anal Chem 2005;77:6288-91.
Zielinska B, Apostolidis C, Bruchertseifer F, Morgenstern A. An improved method for the production of Ac-225/Bi-213 from Th-229 for targeted alpha therapy. Solvent Extr Ion Exch 2007;25:339-49.
Frost SH, Jensen H, Lindegren S. In vitro evaluation of avidin antibody pretargeting using At-labeled and biotinylated poly-L-lysine as effector molecule. Cancer 2010;116 Suppl 4:1101-10.
Habeeb AF. Determination of free amino groups in protein by trinitrobenzene sulfonic acid. Anal Biochem 1966;14:328.
Pippin CG, Parker TA, Mcmurry TJ, Brechbiel MW. Spectrophotometric method for the determination of a bifunctional DTPA ligand in DTPA monoclonal antibody conjugates. Bioconjugate Chem 1992;3:342-5.
McDevitt MR, Finn RD, Ma D, Larson SM, Scheinberg DA. Preparation of alpha-emitting Bi-labeled antibody constructs for clinical use. J Nucl Med 1999;40:1722-7.
Lindegren S, Karlsson B, Jacobsson L, Andersson H, Hultborn R, Skarnemark G. At-labeled and biotinylated effector molecules for pretargeted radioimmunotherapy using poly-L-and poly-D-lysine as multi-carriers. Clin Cancer Res 2003;9:3873-9.
Frost SH, Back T, Chouin N, Jensen H, Hultborn R, Jacobsson L, et al. In vivo distribution of avidin-conjugated MX35 and At-labeled, biotinylated poly-L-lysine for pretargeted intraperitoneal alpha-radio immunotherapy. Cancer Biother Radiopharm 2011;26:727-36.
Wilbur DS, Hamlin DK, Chyan MK, Brechbiel MW. Streptavidin in antibody pretargeting. 5. Chemical modification of recombinant streptavidin for labelling with the alpha-particle-emitting radionuclides Bi and At. Bioconjugate Chem 2008;19:158-70.
Wilbur DS, Hamlin DK, Buhler KR, Pathare PM, Vessella RL, Stayton PS, et al. Streptavidin in antibody pretargeting. 2. Evaluation of methods for decreasing localization of streptavidin to kidney while retaining its tumor binding capacity. Bioconjugate Chem 1998;9:322-30.
Wilbur DS, Hamlin DK, Meyer DL, Mallett RW, Quinn J, Vessella RL, et al. Streptavidin in antibody pretargeting. 3. Comparison of biotin binding and tissue localization of 1,2-cyclohexanedione and succinic anhydride modified recombinant streptavidin. Bioconjugate Chem 2002;13:611-20.
Graves S, Schultz J, Lin Y, Henry A, Sanderson J, Jackson J, et al. Reduced antibody response to streptavidin through site-directed mutagenesis. Faseb J 2000;14:A1135.
Rossin R, Lappchen T, Van den Bosch SM, Laforest R, Robillard MS. Diels-alder reaction for tumor pretargeting: in vivo chemistry can boost tumor radiation dose compared with the directly labeled antibody. J Nucl Med 2013;54:1989-95.
Seckute J, Devaraj NK. Expanding room for tetrazine ligations in the in-vivo chemistry toolbox. Curr Opin Chem Biol 2013;17:761-7.
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