Design and Characterization of Immune-Stimulating Imidazo[4,5-c]quinoline Antibody-Drug Conjugates.
Design and Characterization of Immune-Stimulating Imidazo[4,5-c]quinoline Antibody-Drug Conjugates.
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DOI：
10.1021/acs.molpharmaceut.2c00392
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发表时间：
2022-09-05
影响因子：
4.9
通讯作者：
Tumey, L. Nathan
中科院分区：
文献类型：
--
作者：
Fang, Siteng;Brems, Brittany M.;Olawode, Emmanuel O.;Miller, Jared T.;Brooks, Tracy A.;Tumey, L. Nathan
传统的抗体-药物结合物(ADC)技术利用肿瘤靶向抗体选择性地将超强细胞毒素输送到肿瘤组织。虽然这项技术非常成功，导致FDA批准了10多个ADC，但该领域仍在为适度的疗效和重大的非靶标毒性而苦苦挣扎。在ADC领域挣扎的同时，新一代免疫激活疗法已经出现，最明显的例子是PD-1/PD-L1抑制剂，它们现在是各种癌症标准治疗方案的一部分。这些免疫肿瘤治疗药物的成功促使了对各种新的免疫刺激方法的研究，包括Toll样受体(Toll-like Receptor，TLR)激活剂。在这里，我们描述了ADC技术的优化，以选择性地输送一系列有效的TLR7激动剂。一系列咪唑并[4，5-c]喹啉激动剂(以化合物1为例)在低纳摩尔浓度下选择性地激动人和小鼠的TLR7受体，导致人外周血单核细胞释放干扰素α并上调抗原提呈细胞表面CD86值。化合物1通过一个可切割的连接子连接到脱糖基化的(Fc-γ缺失)HER2靶向抗体上，得到一个ADC(抗HER2vc-1)，它通过“旁观者”机制有效和选择性地激活肿瘤相关巨噬细胞中的TLR7通路。我们证明，当与HER2+细胞孵育时，该ADC迅速将TLR7激动剂释放到培养液中。在与同型对照ADC孵育时没有观察到这种释放，而且联合注射裸露抗体可以抑制这种释放。在与HER2+HCC1954细胞的共培养实验中，该ADC可诱导小鼠巨噬细胞中NF-κB途径的激活和hPBMC释放干扰素α，而相应的同型对照ADC则不能。最后，在SCID米色小鼠的HCC1954异种移植研究中，我们证明了ip抗HER2_vc-1诱导肿瘤完全消退。与最近报道的相关ADC技术不同，我们的技术依赖于TLR7激动剂被动扩散到肿瘤相关巨噬细胞中，而不是FC-γ介导的摄取。基于这些观察，我们相信这种ADC技术在肿瘤学和传染病应用方面都具有巨大的潜力。
Traditional antibody-drug conjugate (ADC) technology has employed tumor-targeting antibodies to selectively deliver ultrapotent cytotoxins to tumor tissue. While this technology has been highly successful, resulting in the FDA approval of over 10 ADCs, the field continues to struggle with modest efficacy and significant off-target toxicity. Concurrent with the struggles of the ADC field, a new generation of immune-activating therapeutics has arisen, most clearly exemplified by the PD-1/PD-L1 inhibitors that are now part of standard-of-care treatment regimens for a variety of cancers. The success of these immuno-oncology therapeutic agents has prompted the investigation of a variety of new immuno-stimulant approaches, including toll-like receptor (TLR) activators. Herein, we describe the optimization of ADC technology for the selective delivery of a potent series of TLR7 agonists. A series of imidazole [4,5-c]quinoline agonists (as exemplified by compound 1) were shown to selectively agonize the human and mouse TLR7 receptor at low nanomolar concentrations, resulting in the release of IFNα from human peripheral blood mononuclear cells (hPBMCs) and the upregulation of CD86 on antigen-presenting cells. Compound 1 was attached to a deglycosylated (Fc-γ null) HER2-targeting antibody via a cleavable linker, resulting in an ADC (anti-HER2_vc-1) that potently and selectively activated the TLR7 pathway in tumor-associated macrophages via a “bystander” mechanism. We demonstrated that this ADC rapidly released the TLR7 agonist into the media when incubated with HER2+ cells. This release was not observed upon incubation with an isotype control ADC and furthermore was suppressed by co-administration of the naked antibody. In co-culture experiments with HER2+ HCC1954 cells, this ADC induced the activation of the NFκB pathway in mouse macrophages and the release of IFNα from hPBMCs, while a corresponding isotype control ADC did not. Finally, we demonstrated that IP administration of anti-HER2_vc-1 induced complete tumor regression in an HCC1954 xenograft study in SCID beige mice. Unlike related ADC technology that has been reported recently, our technology relies on the passive diffusion of the TLR7 agonist into tumor-associated macrophages rather than Fc-γ-mediated uptake. Based on these observations, we believe that this ADC technology holds significant potential for both oncology and infectious disease applications.
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DOI：
10.3390/ph3010146
发表时间：
2010-01-12
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
Abès R;Teillaud JL
通讯作者：
Teillaud JL
DOI：
10.1002/chem.201702942
发表时间：
2017-12-14
期刊：
Chemistry (Weinheim an der Bergstrasse, Germany)
影响因子：
--
作者：
Aichhorn S;Linhardt A;Halfmann A;Nadlinger M;Kirchberger S;Stadler M;Dillinger B;Distel M;Dohnal A;Teasdale I;Schöfberger W
通讯作者：
Schöfberger W
影响因子：
15
作者：
Kern, Jeffrey C.;Cancilla, Mark;Garbaccio, Robert M.
通讯作者：
Garbaccio, Robert M.
影响因子：
29.4
作者：
Nuhn, Lutz;De Koker, Stefaan;De Geest, Bruno G.
通讯作者：
De Geest, Bruno G.
影响因子：
4.9
作者：
Benjamin, Samantha R.;Jackson, Courtney P.;Tumey, L. Nathan
通讯作者：
Tumey, L. Nathan