针对 C3b 和血管内皮生长因子的新型双特异性融合蛋白在新生血管性和非渗出性老年性黄斑病变模型中的临床前研究。

IF 2.6 3区医学 Q2 OPHTHALMOLOGY Ophthalmology and Therapy Pub Date : 2024-08-01 Epub Date: 2024-06-21 DOI:10.1007/s40123-024-00982-3

Yeri Lee, Donggeon Kim, Philip E D Chung, Minkyeong Lee, Nahmju Kim, Jihoon Chang, Byoung Chul Lee

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引用次数: 0

摘要

简介KNP-301是一种双特异性片段可结晶区（Fc）融合蛋白，可同时抑制C3b和血管内皮生长因子（VEGF），用于晚期老年性黄斑变性（AMD）患者。本研究评估了 KNP-301 的体外效力、体内疗效、玻璃体内药代动力学（IVT PK）和可注射性：通过表面等离子体共振（SPR）、酶联免疫吸附试验（ELISA）和细胞生物测定评估了 KNP-301 的 C3b 和血管内皮生长因子结合情况。利用激光诱导的脉络膜新生血管（CNV）模型和碘酸钠诱导的非渗出性 AMD 模型来测试 KNP-301 小鼠替代物的体内疗效。利用荧光素血管造影（FA）和光谱域光学相干断层扫描（SD-OCT）扫描，分析了 CNV 小鼠模型中病变的减少情况。在非渗出性 AMD 小鼠模型中，通过免疫荧光染色评估了外核层（ONL）。最后，以新西兰白兔为实验对象，通过静脉注射 KNP-301 进行了玻璃体内药代动力学研究，并通过高浓度粘度测试检验了 KNP-301 的可注射性：结果：KNP-301 可选择性地结合 C3b，从而阻断替代途径，而不是经典途径。KNP-301 还能捕获血管内皮生长因子，阻碍血管内皮生长因子中介信号的传递。我们的双重阻断策略对新生血管性和非渗出性 AMD 模型均有效。此外，由于 KNP-301 在玻璃体腔内的半衰期较长，其优点是用药次数可能较少。我们的粘度评估证实，KNP-301符合IVT注射剂的标准：结论：与目前的疗法不同，KNP-301有望覆盖新生血管性和非渗出性AMD晚期患者，其在玻璃体内腔的长期PK曲线将为患者的用药间隔提供方便。

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Pre-Clinical Studies of a Novel Bispecific Fusion Protein Targeting C3b and VEGF in Neovascular and Nonexudative AMD Models.

Introduction: KNP-301 is a bi-specific fragment crystallizable region (Fc) fusion protein, which inhibits both C3b and vascular endothelial growth factor (VEGF) simultaneously for patients with late-stage age-related macular degeneration (AMD). The present study evaluated in vitro potency, in vivo efficacy, intravitreal pharmacokinetics (IVT PK), and injectability of KNP-301.

Methods: C3b and VEGF binding of KNP-301 were assessed by surface plasmon resonance (SPR) and enzyme-linked immunosorbent assay (ELISA), and cellular bioassays. A laser-induced choroidal neovascularization (CNV) model and a sodium iodate-induced nonexudative AMD model were used to test the in vivo efficacy of mouse surrogate of KNP-301. Utilizing fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD-OCT) scans, the reduction in disease lesions were analyzed in a CNV mouse model. In the nonexudative AMD mouse model, outer nuclear layer (ONL) was assessed by immunofluorescence staining. Lastly, intravitreal pharmacokinetic study was conducted with New Zealand white rabbits via IVT administration of KNP-301 and injectability of KNP-301 was examined by a viscosity test at high concentrations.

Results: KNP-301 bound C3b selectively, which resulted in a blockade of the alternative pathway, not the classical pathway. KNP-301 also acted as a VEGF trap, impeding VEGF-mediate signaling. Our dual-blockade strategy was effective in both neovascular and nonexudative AMD models. Moreover, KNP-301 had an advantage of potentially less frequent dosing due to the long half-life in the intravitreal chamber. Our viscosity assessment confirmed that KNP-301 meets the criteria of the IVT injection.

Conclusions: Unlike current therapies, KNP-301 is expected to cover patients with late-stage AMD of both neovascular and nonexudative AMD, and its long-term PK profile at the intravitreal chamber would allow convenience in the dosing interval of patients.

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来源期刊

Ophthalmology and Therapy OPHTHALMOLOGY-

CiteScore

4.20

自引率

3.00%

发文量

157

审稿时长

6 weeks

期刊介绍： Aims and Scope Ophthalmology and Therapy is an international, open access, peer-reviewed (single-blind), and rapid publication journal. The scope of the journal is broad and will consider all scientifically sound research from preclinical, clinical (all phases), observational, real-world, and health outcomes research around the use of ophthalmological therapies, devices, and surgical techniques. The journal is of interest to a broad audience of pharmaceutical and healthcare professionals and publishes original research, reviews, case reports/series, trial protocols and short communications such as commentaries and editorials. Ophthalmology and Therapy will consider all scientifically sound research be it positive, confirmatory or negative data. Submissions are welcomed whether they relate to an international and/or a country-specific audience, something that is crucially important when researchers are trying to target more specific patient populations. This inclusive approach allows the journal to assist in the dissemination of quality research, which may be considered of insufficient interest by other journals. Rapid Publication The journal’s publication timelines aim for a rapid peer review of 2 weeks. If an article is accepted it will be published 3–4 weeks from acceptance. The rapid timelines are achieved through the combination of a dedicated in-house editorial team, who manage article workflow, and an extensive Editorial and Advisory Board who assist with peer review. This allows the journal to support the rapid dissemination of research, whilst still providing robust peer review. Combined with the journal’s open access model this allows for the rapid, efficient communication of the latest research and reviews, fostering the advancement of ophthalmic therapies. Open Access All articles published by Ophthalmology and Therapy are open access. Personal Service The journal’s dedicated in-house editorial team offer a personal “concierge service” meaning authors will always have an editorial contact able to update them on the status of their manuscript. The editorial team check all manuscripts to ensure that articles conform to the most recent COPE, GPP and ICMJE publishing guidelines. This supports the publication of ethically sound and transparent research. Digital Features and Plain Language Summaries Ophthalmology and Therapy offers a range of additional features designed to increase the visibility, readership and educational value of the journal’s content. Each article is accompanied by key summary points, giving a time-efficient overview of the content to a wide readership. Articles may be accompanied by plain language summaries to assist readers who have some knowledge of, but not in-depth expertise in, the area to understand the scientific content and overall implications of the article. The journal also provides the option to include various types of digital features including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations. All additional features are peer reviewed to the same high standard as the article itself. If you consider that your paper would benefit from the inclusion of a digital feature, please let us know. Our editorial team are able to create high-quality slide decks and infographics in-house, and video abstracts through our partner Research Square, and would be happy to assist in any way we can. For further information about digital features, please contact the journal editor (see ‘Contact the Journal’ for email address), and see the ‘Guidelines for digital features and plain language summaries’ document under ‘Submission guidelines’. 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At least two extensive reviews are required to make the editorial decision, with the exception of some article types such as Commentaries, Editorials, and Letters which are generally reviewed by one member of the Editorial Board. Where reviewer recommendations are conflicted, the editorial board will be contacted for further advice and a presiding decision. Manuscripts are then either accepted, rejected or authors are required to make major or minor revisions (both reviewer comments and editorial comments may need to be addressed). Once a revised manuscript is re-submitted, it is assessed along with the responses to reviewer comments and if it has been adequately revised it will be accepted for publication. Accepted manuscripts are then copyedited and typeset by the production team before online publication. Appeals against decisions following peer review are considered on a case-by-case basis and should be sent to the journal editor. 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