Extending the use of biologics to mucous membranes by attachment of a binding domain.
Extending the use of biologics to mucous membranes by attachment of a binding domain.
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DOI：
10.1038/s42003-023-04801-6
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发表时间：
2023-05-02
影响因子：
5.9
通讯作者：
Klarlund, Jes K.
中科院分区：
文献类型：
--
作者：
Shanks, Robert M. Q.;Romanowski, Eric G.;Romanowski, John E.;Davoli, Katherine;McNamara, Nancy A.;Klarlund, Jes K.
生物制剂几乎完全是全身给药，但局部给药更可取，因为它最大限度地减少了脱靶暴露，并允许更积极的治疗。生物制剂对上皮的局部应用通常是无效的，因为大多数被液体覆盖，并且生物制剂被冲洗得太快而不能具有显著的治疗效果。在这里，我们探讨了这样的想法，即连接一个结合结构域可以作为一个“锚”，以延长湿上皮细胞上的生物制剂的停留时间，使他们的有效使用，即使在不频繁的应用。我们使用眼表局部应用作为挑战性测试，因为异物通过泪液流动和眨眼特别有效地被冲洗掉。我们的研究结果表明，抗体与麦胚凝集素结合，其结合组织中普遍存在的GlcNAc和唾液酸，在干眼小鼠模型中应用于眼表面时，其半衰期增加350倍，干眼是人类常见且繁重的疾病。重要的是，与凝集素缀合的IL-17 A、IL-23和IL-1β抗体减少了干眼的表现，即使每天仅施用一次。相反，未缀合的抗体是无效的。将锚固定到生物制品上是克服洗脱并扩展其治疗用途的简单方法。抗细胞因子抗体与锚麦胚凝集素的偶联被证明是一种有效的方法，用于增加生物制剂的保留并允许其在干眼病动物模型中对湿上皮的治疗用途。
Biologics are almost exclusively administered systemically, but localized delivery is preferable as it minimizes off-target exposure and allows more aggressive treatments. Topical application of biologics to epithelia is generally ineffective because most are covered with fluids and biologics are washed out too quickly to have significant therapeutic effects. Here we explore the idea that attaching a binding domain can serve as an “anchor” to extend the residency time of biologics on wet epithelia, allowing their effective use even with infrequent applications. We use topical application to the ocular surface as a challenging test since foreign substances are washed out especially efficiently by tear flow and blinking. Our results demonstrate that conjugation of antibodies to wheat germ agglutinin, which binds GlcNAc and sialic acid that are ubiquitously present in tissues, increases their half-life 350-fold upon application to the ocular surface in a mouse model of dry eye, a common and onerous disease in humans. Importantly, antibodies to IL-17A, IL-23, and IL-1β conjugated to the agglutinin reduces manifestations of dry eye, even when applied just once daily. In contrast, unconjugated antibodies are ineffective. Attaching an anchor to biologics is a simple means to overcome washout and to extend their therapeutic use. Conjugation of anti-cytokine antibodies to an anchor, wheat germ agglutinin, is demonstrated to be an effective method for increasing retention of biologics and allowing their therapeutic use on wet epithelia in an animal model of dry eye disease.
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影响因子：
16.1
作者：
Argüeso P
通讯作者：
Argüeso P
DOI：
10.1016/j.jtos.2020.05.009
发表时间：
2021-01
期刊：
The ocular surface
影响因子：
--
作者：
Fan NW;Dohlman TH;Foulsham W;McSoley M;Singh RB;Chen Y;Dana R
通讯作者：
Dana R
影响因子：
4.4
作者：
Kimura, Kazuhiro;Teranishi, Shinichiro;Nishida, Teruo
通讯作者：
Nishida, Teruo
DOI：
10.1038/labinvest.2011.189
发表时间：
2012-04
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.7
作者：
Alavi M;Asare-Addo K;Nokhodchi A
通讯作者：
Nokhodchi A