Pretargeting of internalizing trastuzumab and cetuximab with a (18)F-tetrazine tracer in xenograft models.
Pretargeting of internalizing trastuzumab and cetuximab with a (18)F-tetrazine tracer in xenograft models.
复制标题
DOI：
10.1186/s13550-017-0344-6
复制
发表时间：
2017-12-02
期刊：
影响因子：
3.2
通讯作者：
Sarparanta M
中科院分区：
文献类型：
--
作者：
Keinänen O;Fung K;Pourat J;Jallinoja V;Vivier D;Pillarsetty NK;Airaksinen AJ;Lewis JS;Zeglis BM;Sarparanta M
正在研究基于预靶向的方法用于放射免疫成像和治疗应用，以减少患者的有效辐射负担。到目前为止，只有少数研究使用短寿命放射性同位素来预靶向抗体，而这样的内化抗体的例子更是罕见。在此，我们研究了使用逆电子需求狄尔斯-阿尔德（IEDDA）追踪两个临床相关的，内化的单克隆抗体，西妥昔单抗和曲妥珠单抗的预靶向方法。四嗪和反式-环辛烯（TCO）之间的生物正交反应用于在体内用氟-18（t1/2 = 109.8 min）标记的示踪剂示踪西妥昔单抗和曲妥珠单抗。在示踪剂注射至A431或BT-474荷瘤小鼠前24、48或72 h分别给予TCO-西妥昔单抗或TCO-曲妥珠单抗。对于西妥昔单抗，当抗体和示踪剂注射之间的滞后时间为72小时时，达到最高的肿瘤-血液比率。对于曲妥珠单抗，在不同滞后时间之间未观察到差异。对于两种抗体，肿瘤可以在PET图像中清楚地可视化，其中西妥昔单抗的最高肿瘤摄取为3.7 ± 0.1%ID/g，曲妥珠单抗的最高肿瘤摄取为1.5 ± 0.1%ID/g，如通过离体生物分布定量的。在血液中观察到两种抗体的体内IEDDA反应，但曲妥珠单抗的反应程度远低于西妥昔单抗。我们可以通过在预靶向PET成像中使用西妥昔单抗和曲妥珠单抗成功地可视化肿瘤，尽管抗体被内化并且仍然有一些未结合的抗体在血流中循环的挑战性情况。这清楚地表明了针对内化抗原的预靶向方法的潜力，并保证为此目的开发双正交反应物的药代动力学优化。本文的在线版本（10.1186/s13550-017-0344-6）包含补充材料，可供授权用户使用。
Pretargeting-based approaches are being investigated for radioimmunoimaging and therapy applications to reduce the effective radiation burden to the patient. To date, only a few studies have used short-lived radioisotopes for pretargeting of antibodies, and such examples with internalizing antibodies are even rarer. Herein, we have investigated pretargeting methodology using inverse electron-demand Diels-Alder (IEDDA) for tracing two clinically relevant, internalizing monoclonal antibodies, cetuximab and trastuzumab. Bioorthogonal reaction between tetrazine and trans-cyclooctene (TCO) was used for tracing cetuximab and trastuzumab in vivo with a fluorine-18 (t ½ = 109.8 min) labelled tracer. TCO-cetuximab or TCO-trastuzumab was administered 24, 48, or 72 h prior to the injection of tracer to A431 or BT-474 tumour-bearing mice, respectively. With cetuximab, the highest tumour-to-blood ratios were achieved when the lag time between antibody and tracer injections was 72 h. With trastuzumab, no difference was observed between different lag times. For both antibodies, the tumour could be clearly visualized in the PET images with the highest tumour uptake of 3.7 ± 0.1%ID/g for cetuximab and 1.5 ± 0.1%ID/g for trastuzumab as quantified by ex vivo biodistribution. In vivo IEDDA reaction was observed in the blood for both antibodies, but with trastuzumab, this was to a much lower degree than with cetuximab. We could successfully visualize the tumours by using cetuximab and trastuzumab in pretargeted PET imaging despite the challenging circumstances where the antibody is internalized and there is still some unbound antibody circulating in the blood flow. This clearly demonstrates the potential of a pretargeted approach for targeting internalizing antigens and warrants development of pharmacokinetic optimization of the biorthogonal reactants to this end. The online version of this article (10.1186/s13550-017-0344-6) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
4.7
作者：
Meyer JP;Houghton JL;Kozlowski P;Abdel-Atti D;Reiner T;Pillarsetty NV;Scholz WW;Zeglis BM;Lewis JS
通讯作者：
Lewis JS
DOI：
10.2967/jnumed.115.163824
发表时间：
2016-03
期刊：
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
影响因子：
--
作者：
Houghton JL;Zeglis BM;Abdel-Atti D;Sawada R;Scholz WW;Lewis JS
通讯作者：
Lewis JS
DOI：
10.1039/c0cc03078c
发表时间：
2010-11-14
期刊：
Chemical communications (Cambridge, England)
影响因子：
--
作者：
Li Z;Cai H;Hassink M;Blackman ML;Brown RC;Conti PS;Fox JM
通讯作者：
Fox JM
DOI：
10.1073/pnas.1113466109
发表时间：
2012-03-27
影响因子：
11.1
作者：
Devaraj, Neal K.;Thurber, Greg M.;Weissleder, Ralph
通讯作者：
Weissleder, Ralph
影响因子：
5.2
作者：
Gostring, Lovisa;Chew, Ming Tsuey;Frejd, Fredrik Y.
通讯作者：
Frejd, Fredrik Y.