Site-Specifically Labeled Antibody-Drug Conjugate for Simultaneous Therapy and ImmunoPET.
Site-Specifically Labeled Antibody-Drug Conjugate for Simultaneous Therapy and ImmunoPET.
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DOI：
10.1021/acs.molpharmaceut.7b00802
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发表时间：
2018-03-05
影响因子：
4.9
通讯作者：
Zeglis BM
中科院分区：
文献类型：
--
作者：
Adumeau P;Vivier D;Sharma SK;Wang J;Zhang T;Chen A;Agnew BJ;Zeglis BM
抗体与细胞毒性药物结合可改变其体内药代动力学。因此，仔细评估抗体-药物偶联物的体内行为，特别是肿瘤靶向特性，是它们发展的关键一步。为了促进这一过程，我们创造了一种方法，促进了正电子发射断层扫描（PET）的毒素和放射性核素抗体的双重标记。为了最大限度地减少这些修饰的影响，这种化学酶方法利用菌株促进的叠氮化物-炔点击化学将这两种货物接枝到免疫球蛋白Fc结构域的重链聚糖上。作为概念验证，一种靶向her2的曲珠单抗免疫偶联物被创建，该偶联物既含有单甲基auristatin E （MMAE）毒素，也含有长寿命的正电子放射金属89Zr （t1/2 ~ 3.3天）。利用表达her2的乳腺癌小鼠模型，验证了89zr -曲妥珠单抗- mmae免疫偶联物的肿瘤靶向性和治疗效果。特异位点双标记结构使肿瘤组织通过PET成像清晰可见，产生约70% ID/g的肿瘤摄取。此外，一项纵向治疗研究显示，免疫偶联物具有显著的抗肿瘤活性，在20天的治疗过程中，肿瘤体积减少了约90%。
The conjugation of antibodies with cytotoxic drugs can alter their in vivo pharmacokinetics. As a result, the careful assessment of the in vivo behavior — and specifically the tumor-targeting properties — of antibody-drug conjugates represents a crucial step in their development. In order to facilitate this process, we have created a methodology that facilitates the dual labeling of an antibody with both a toxin and a radionuclide for positron emission tomography (PET). To minimize the impact of these modifications, this chemoenzymatic approach leverages strain-promoted azide-alkyne click chemistry to graft both cargoes to the heavy chain glycans of the immuoglobulin’s Fc domain. As a proof-of-concept, a HER2-targeting trastuzumab immunoconjugate was created bearing both a monomethyl auristatin E (MMAE) toxin as well as the long-lived positron-emitting radiometal 89Zr (t1/2 ~ 3.3 days). Both the tumor targeting and therapeutic efficacy of the 89Zr-trastuzumab-MMAE immunoconjugate were validated in vivo using a murine model of HER2-expressing breast cancer. The site-specifically dual-labeled construct enabled the clear visualization of tumor tissue via PET imaging, producing tumoral uptake of ~70 %ID/g. Furthermore, a longitudinal therapy study revealed that the immunoconjugate exerts significant anti-tumor activity, leading to a >90% reduction in tumor volume over the course of 20 days.
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基于无催化剂点击化学的酶介导抗体位点特异性放射性标记方法。
影响因子：
4.7
作者：
Zeglis, Brian M.;Davis, Charles B.;Aggeler, Robert;Kang, Hee Chol;Chen, Aimei;Agnew, Brian J.;Lewis, Jason S.
通讯作者：
Lewis, Jason S.
影响因子：
5.6
作者：
Jauw YW;Menke-van der Houven van Oordt CW;Hoekstra OS;Hendrikse NH;Vugts DJ;Zijlstra JM;Huisman MC;van Dongen GA
通讯作者：
van Dongen GA
影响因子：
3.1
作者：
Adumeau P;Sharma SK;Brent C;Zeglis BM
通讯作者：
Zeglis BM
影响因子：
3.9
作者：
Pinto, Ana Catarina;Ades, Felipe;Piccart-Gebhart, Martine
通讯作者：
Piccart-Gebhart, Martine
影响因子：
4.7
作者：
Zeglis, Brian M.;Davis, Charles B.;Abdel-Atti, Dalya;Carlin, Sean D.;Chen, Aimei;Aggeler, Robert;Agnew, Brian J.;Lewis, Jason S.
通讯作者：
Lewis, Jason S.