Mereo BioPharma Group Plc

NOVATO, Calif., Sept. 26, 2024 (GLOBE NEWSWIRE) -- Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE) today announced that it will present seven abstracts related to its ongoing late-stage program evaluating setrusumab (UX143) and osteogenesis imperfecta (OI), including a late-breaker oral presentation of the 14-month data from the Phase 2/3 Orbit study, at the American Society for Bone and Mineral Research (ASBMR) 2024 Annual Meeting. The meeting is being held September 27-30, 2024, in Toronto, Canada. “Presentations at this year’s ASBMR meeting add to our growing knowledge of the real-world impact and burden of OI and underscore the urgent need for an innovative therapy for these patients,” stated Eric Crombez, M.D., chief medical officer at Ultragenyx. “We will also present the phase 2 Orbit study results that we previously announced in June, which demonstrate a rapid and clinically meaningful increase in bone mineral density and a corresponding decrease in annualized fracture rate through month 14.” Details of the setrusumab presentations: Title: Integrated Bone Biomarker Analyses to Define Setrusumab Mechanism of Action in Pediatric and Young Adult Subjects with Osteogenesis Imperfecta and to Inform Dose Selection in the Orbit StudySession: Welcome Reception and Plenary Poster SessionPresentation Number: Plenary Poster (#Fri-423)Session Date / Time: Friday, September 27, 5:30 p.m. - 7:30 p.m. ETWill also be presented during the Clinical Career Spotlight Rapid Fire session (#Sun-423) and during Poster Session I (#Sun-423) Title: Burden of Illness of Osteogenesis Imperfecta in Ontario, CanadaSession: Late Breaking Poster Session IPresentation Number: #Sat-LB 592Session Date / Time: Saturday, September 28, 2:15 p.m.- 3:45 p.m. ET Title: Manifestations and Comorbid Conditions Among Patients with Osteogenesis Imperfecta (OI): A US Retrospective Claims Database AnalysisSession: Poster Session IPresentation Number: #Sat-447Session Date / Time: Saturday, September 28, 2:15 p.m.- 3:45 p.m. ET Title: Fracture Rates for Patients Living with Osteogenesis Imperfecta (OI): Real-world Results from US Retrospective ClaimsSession: Poster Session I Presentation Number: #Sat-446Session Date / Time: Saturday, September 28, 2:15 p.m. - 3:45 p.m. ET Title: Population Pharmacokinetics (PK) and PK/Pharmacodynamics Analyses to Select the Phase 3 Dose of Setrusumab in Pediatric Patients with Osteogenesis Imperfecta: Results from Phase 2 of the Orbit Study Session: Oral Presentations: Pregnancy Associated Bone Loss and Other Rare Bone DiseasesPresentation Number: #1063Presentation Date / Time: Sunday, September 29, 11:45 a.m. - 12:00 p.m. ET Title: Healthcare Resource Use (HRU) and Costs for Patients Living with Osteogenesis Imperfecta (OI): Results from US Retrospective ClaimsSession: Poster Session IIPresentation Number: #Sun-446Session Date / Time: Sunday, September 29, 2:15 p.m. - 3:45 p.m. ET Title: Sustained Reduction in Fracture Rate in Patients with OI Treated with Setrusumab: Fourteen Month Data from Phase 2 of the Phase 2/3 Orbit StudySession: Late-Breaking Oral Presentations: Clinical SciencePresentation Number: #1125Presentation Date / Time: Monday, September 30, 12:00 p.m. - 12:15 p.m. ET About Osteogenesis Imperfecta (OI)Osteogenesis Imperfecta (OI) includes a group of genetic disorders impacting bone metabolism. Approximately 85% to 90% of OI cases are caused by genetic variants in the COL1A1 or COL1A2 genes, leading to either reduced or abnormal collagen and changes in bone metabolism. The collagen mutations in OI can result in increased bone brittleness, which contributes to a high rate of fractures. Patients with OI also exhibit inadequate production of new bone and excess bone resorption, resulting in decreased bone mineral density, bone fragility and weakness. OI can also lead to bone deformities, abnormal spine curvature, pain, decreased mobility, and short stature. No treatments are globally approved for OI, which affects approximately 60,000 people in commercially accessible geographies. About Setrusumab (UX143)Setrusumab is a fully human monoclonal antibody that inhibits sclerostin, a negative regulator of bone formation. Blocking sclerostin is expected to increase new bone formation, bone mineral density and bone strength in OI. In mouse models of OI, the use of anti-sclerostin antibodies was shown to increase bone formation, improve bone mass to normal levels, and increase bone strength against fracture force testing to normal levels. In 2019, Mereo BioPharma completed the Phase 2b dose-finding study (ASTEROID) for setrusumab in 112 adults with OI. The ASTEROID study demonstrated treatment with setrusumab resulted in a clear, dose-dependent and statistically significant effect on bone formation and bone density at multiple anatomical sites among adult participants with OI. Ultragenyx and Mereo BioPharma are collaborating on the development of setrusumab globally based on the collaboration and license agreement between the parties. The companies have developed a comprehensive late-stage program to continue development of setrusumab in pediatric and young adult patients across OI sub-types I, III and IV. About UltragenyxUltragenyx is a biopharmaceutical company committed to bringing novel therapies to patients for the treatment of serious rare and ultrarare genetic diseases. The company has built a diverse portfolio of approved medicines and treatment candidates aimed at addressing diseases with high unmet medical need and clear biology, for which there are typically no approved therapies treating the underlying disease. The company is led by a management team experienced in the development and commercialization of rare disease therapeutics. Ultragenyx’s strategy is predicated upon time- and cost-efficient drug development, with the goal of delivering safe and effective therapies to patients with the utmost urgency. For more information on Ultragenyx, please visit the company's website at: www.ultragenyx.com. Forward-Looking Statements and Use of Digital MediaExcept for the historical information contained herein, the matters set forth in this press release, including statements related to Ultragenyx's expectations and projections regarding its future operating results and financial performance, business plans and objectives for UX143, expectations regarding the tolerability and safety of UX143, and future clinical and regulatory developments for UX143 are forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, collaboration with third parties, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainty of clinical drug development and unpredictability and lengthy process for obtaining regulatory approvals, the ability of the company and Mereo BioPharma to successfully develop UX143, the company’s ability to achieve its projected development goals in its expected timeframes, risks related to adverse side effects, risks related to reliance on third party partners to conduct certain activities on the company’s behalf, the potential for any license or collaboration agreement, including the company’s collaboration agreement with Mereo to be terminated, smaller than anticipated market opportunities for the company’s products and product candidates, manufacturing risks, competition from other therapies or products, and other matters that could affect sufficiency of existing cash, cash equivalents and short-term investments to fund operations, the company’s future operating results and financial performance, the timing of clinical trial activities and reporting results from same, and the availability or commercial potential of Ultragenyx’s products and drug candidates. Ultragenyx undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the business of Ultragenyx in general, see Ultragenyx's Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on August 2, 2024, and its subsequent periodic reports filed with the SEC. In addition to its SEC filings, press releases and public conference calls, Ultragenyx uses its investor relations website and social media outlets to publish important information about the company, including information that may be deemed material to investors, and to comply with its disclosure obligations under Regulation FD. Financial and other information about Ultragenyx is routinely posted and is accessible on Ultragenyx’s Investor Relations website (https://ir.ultragenyx.com/) and LinkedIn website (https://www.linkedin.com/company/ultragenyx-pharmaceutical-inc-/mycompany/). Contacts InvestorsJoshua Higa+1-415-475-6370ir@ultragenyx.com MediaCarolyn Wang+1-415-225-5050media@ultragenyx.com

LONDON, Sept. 12, 2024 (GLOBE NEWSWIRE) -- Mereo BioPharma Group plc (NASDAQ: MREO) (“Mereo” or the “Company”), a clinical-stage biopharmaceutical company focused on rare diseases, today announced that Dr. Denise Scots-Knight, Chief Executive Officer, will participate in a Fireside Chat at the 2024 Cantor Global Healthcare Conference on Wednesday, September 18, 2024, at 10:55am ET / 03:55pm BST. A live audio webcast can be accessed through the Investors section of the Company’s website at . An archived replay of the webcast will be available on the Company’s website for two weeks following the live event. About Mereo BioPharma Mereo BioPharma is a biopharmaceutical company focused on the development of innovative therapeutics for rare diseases. The Company has two rare disease product candidates, setrusumab for the treatment of osteogenesis imperfecta (OI) and alvelestat primarily for the treatment of severe alpha-1 antitrypsin deficiency-associated lung disease (AATD-LD). The Company’s partner, Ultragenyx Pharmaceutical, Inc., has completed enrollment in the Phase 3 portion of a pivotal Phase 2/3 pediatric study in young adults (5 to 25 years old) for setrusumab in OI and in the Phase 3 study in pediatric patients (2 to <7 years old) in the first half of 2024. The partnership with Ultragenyx includes potential additional milestone payments of up to $245 million and royalties to Mereo on commercial sales in Ultragenyx territories. Mereo has retained EU and UK commercial rights and will pay Ultragenyx royalties on commercial sales in those territories. Setrusumab has received orphan designation for osteogenesis imperfecta from the EMA and FDA, PRIME designation from the EMA and has pediatric disease designation from the FDA. Alvelestat has received U.S. Orphan Drug Designation for the treatment of AATD and Fast Track designation from the FDA. Following results from ASTRAEUS and ATALANTa in AATD-lung disease, the Company has aligned with the FDA and the EMA on the primary endpoints for a Phase 3 pivotal study which if successful could enable full approval in both the U.S. and Europe. In addition to the rare disease programs, Mereo has two oncology product candidates in clinical development. Etigilimab (anti-TIGIT) has completed a Phase 1b/2 basket study evaluating its safety and efficacy in combination with an anti-PD-1 in a range of tumor types including three rare tumors and three gynecological carcinomas – cervical, ovarian, and endometrial and is an ongoing Phase 1b/2 investigator led study at the MD Anderson Cancer Center in clear cell ovarian cancer; Navicixizumab, for the treatment of late line ovarian cancer, has completed a Phase 1 study and has been partnered with Feng Biosciences Inc. in a global licensing agreement that includes milestone payments and royalties. Mereo has entered into an exclusive global license agreement with ReproNovo SA for the development and commercialization of leflutrozole, a non-steroidal aromatase inhibitor. Under the terms of the agreement, ReproNovo, a reproductive medicine company, is responsible for all future development and commercialization of leflutrozole. For more information on Mereo BioPharma, please visit . Forward-Looking Statements This press release contains “forward-looking statements” that involve substantial risks and uncertainties. All statements other than statements of historical fact contained herein are forward-looking statements within the meaning of Section 27A of the United States Securities Act of 1933, as amended, and Section 21E of the United States Securities Exchange Act of 1934, as amended. Forward-looking statements usually relate to future events and anticipated revenues, earnings, cash flows or other aspects of our operations or operating results. Forward-looking statements are often identified by the words “believe,” “expect,” “anticipate,” “plan,” “intend,” “foresee,” “should,” “would,” “could,” “may,” “estimate,” “outlook” and similar expressions, including the negative thereof. The absence of these words, however, does not mean that the statements are not forward-looking. These forward-looking statements are based on the Company’s current expectations, beliefs and assumptions concerning future developments and business conditions and their potential effect on the Company. While management believes that these forward-looking statements are reasonable as and when made, there can be no assurance that future developments affecting the Company will be those that it anticipates. All of the Company’s forward-looking statements involve known and unknown risks and uncertainties some of which are significant or beyond its control and assumptions that could cause actual results to differ materially from the Company’s historical experience and its present expectations or projections. Such risks and uncertainties include, among others, the uncertainties inherent in the clinical development process; the Company’s reliance on third parties to conduct and provide funding for its clinical trials; the Company’s dependence on enrollment of patients in its clinical trials; and the Company’s dependence on its key executives. You should carefully consider the foregoing factors and the other risks and uncertainties that affect the Company’s business, including those described in the “Risk Factors” section of its Annual Report on Form 10-K, as well as discussions of potential risks, uncertainties, and other important factors in the Company’s subsequent filings with the Securities and Exchange Commission. The Company wishes to caution you not to place undue reliance on any forward-looking statements, which speak only as of the date hereof. The Company undertakes no obligation to publicly update or revise any of our forward-looking statements after the date they are made, whether as a result of new information, future events or otherwise, except to the extent required by law. Mereo BioPharma Contacts: Mereo Denise Scots-Knight, Chief Executive Officer Christine Fox, Chief Financial Officer +44 (0)333 023 7300 Burns McClellan (Investor Relations Adviser to Mereo) Lee Roth Investors +01 646 930 4406 investors@mereobiopharma.com

已批准药物的靶标的三分之一是G 蛋白偶联受体 (GPCR，)；然而，这些药物仅针对人类 GPCR 库的大约八分之一。GPCR 调节多种关键生理过程，包括器官发育、心血管功能、情绪、认知、多细胞性、细胞运动、免疫反应以及光感、味觉和气味。然而，许多GPCR表达较低，并且很大一部分具有未知的配体和不清楚的信号通路。由于小分子发现面临诸如成药性、选择性和分布等挑战，GPCR 可能更适合单克隆抗体 (mAb) 的靶向。单克隆抗体在这些方面具有更好的类似药物的特性。在此，回顾了之前发现的针对临床和/或开发中的 GPCR 的单克隆抗体，同时回顾了生物物理学方面的考虑因素，这些因素使得 GPCR 的使用极具挑战性，但也为生物成药性提供了机会。 1、背景介绍 人类基因组包含超过 800 个 GPCR，其中近 400 个是嗅觉受体。虽然嗅觉受体的表达主要限于嗅觉上皮，但一些嗅觉受体在其他组织中表达，针对它们可能具有治疗益处。GPCR 根据其序列同源性和进化的系统发育分析进行分类。A 类或视紫红质样家族包含所有嗅觉受体和许多临床靶向受体，包括趋化因子、胺和肽受体。B1 类受体共享一个大的细胞外 N 末端（ 图1 ) 和 B2 类属于粘附 GPCR 家族。粘附 GPCR 因其独特的延伸胞外结构域而成为特别令人感兴趣的抗体靶点。C 类 GPCR 被认为以二聚体的形式发挥作用，T 类味觉受体也是如此。最后，F 类受体包含 Frizzled 和 Smoothened两个调节生物体发育的 GPCR。 图 1. G 蛋白偶联受体胞外拓扑和配体结合模式。 生物制剂具有许多小分子药物无法实现的独特特性。许多生物制剂利用抗体的特性，特别是可以对 Fc（可结晶片段）区域进行改造，以延长药物半衰期并诱导抗体依赖性细胞毒性（或完全避免细胞毒性）。通常，抗体通过血液、组织间隙和淋巴系统扩散，并被排除在中枢神经系统之外。与小分子不同，抗体不会被肾脏清除，而是通过 Fc 受体介导的内吞作用降解。正如我们将在本次综述中详细介绍的那样，生物制剂的另一个优点是抗体可以融合在一起以创建针对两种不同受体的双特异性分子，或针对同一受体上的两个表位的双互补位分子。最后，由于其生物学性质，可以应用合成生物学方法（例如定向进化）来设计具有所需药物样特性的抗体、抗体片段和肽。 尽管 GPCR 具有新型治疗方式的潜力，但对于生物制剂药物的开发仍然难以捉摸。部分原因在于质膜中 GPCR 的结构。GPCR 的细胞外表面遵循常见的拓扑结构（ 图1A)：一个胞外 N 端结构域和三个胞外环。GPCR 的胞外环往往非常短，但大小变化很大，从 5 个氨基酸到超过 170 个氨基酸不等。正位结合口袋是配体结合的地方，位于跨膜结构域内。大多数细胞外环参与配体结合，尽管对于小分子来说，这些相互作用对配体结合的贡献微弱。视紫质是一种对激活状态进行了高度详细研究的 GPCR，其正位结合袋完全被细胞外环封闭，并且配体（视网膜）通过质膜横向扩散。 通常，GPCR 具有较短的 N 端结构域，但许多 GPCR 也具有具有多种功能的扩展 N 端结构域（ 图1B），包括形成双位和变构配体的第二个结合位点。GPCR 的 N 末端通常很容易生产为可溶性肽，并且这些肽经常被用作抗体发现活动的抗原。然而，此类抗体无法结合细胞外环。基于抗体的 GPCR 生物制剂面临的最大挑战之一是生成能够真正与埋藏在跨膜结构域深处的正位结合袋结合的抗体。 表 1. G 蛋白偶联受体靶向的生物类药物。包括激活剂（激动剂和正变构调节剂）、阻断剂（拮抗剂、反向激动剂和负变构调节剂）以及靶向 GPCR 的下一代分子。只有三种分子获得批准（dulaglutide、erenumab 和 mogamulizumab），只有一个分子在 3 期临床阶段（talquetamab）。 2. 针对G蛋白偶联受体的生物制剂的功能活性2.1. 激活 G 蛋白偶联受体的生物制剂 B1 类GPCR 的促胰液素家族已成为治疗糖尿病和肥胖症的激动剂抗体的靶标。临床批准的胰高血糖素样肽 1 受体 (GLP-1 R) 激动剂度拉鲁肽 (Trulicity) 由礼来公司设计，作为 GLP-1 肽与 IgG4 Fc（片段可结晶区）的融合体。已知 IgG4 与 FcRn 受体结合，通过回收延长抗体半衰期，事实上，度拉鲁肽在人体中的血清半衰期超过 12 小时，而艾塞那肽和其他 GLP-1 肽模拟物 的血清半衰期不到 2-5 小时。重要的是，IgG4 不会激活补体级联，从而导致抗体依赖性补体依赖性细胞毒性 (ADCC)。此外，F234A 和 L235A 突变被引入度拉鲁肽的 IgG4 Fc 区，以减少 ADCC 的可能性。总之，度拉鲁肽是一种独特的肽激动剂，与惰性 Fc 区融合以激活 GLP-1 R。此外，Gmax Biopharm 还开发了 glutazumab，一种 GLP-1 肽与抗 GLP-1R 抗体 轻链的融合物。Glutazumab 目前正在进行治疗糖尿病的临床试验。另一种与 GLP-1 肽融合以产生激动作用的抗 GLP-1 R 抗体 Everestmab 已被描述。Everestmab 是一种介于白蛋白结合域和突变 GLP-1 肽之间的双特异性纳米抗体。 同样，最近描述了 GLP-1 肽与GLP-1 R 抗体轻链的融合，称为 TB-059-002。安进 (Amgen) 最近报道了与葡萄糖依赖性促胰岛素多肽受体 (GIPR) 抗体 AMG-133融合的 GLP-1 肽的阳性数据，该抗体可作为双重 GLP-1 R 激动剂/GIPR 拮抗剂。将 GLP-1 肽与抗 GIPR 抗体连接具有延长 GLP-1 肽半衰期的优点，并且被证明可以增强该分子在胰腺中的定位。AMG-133 作为 GLP-1 R 激动剂/GIPR 拮抗剂，最近有报道显示在肥胖方面显示出有效的 1 期临床数据。 与 GLP-1 R、GIPR 和 PTHR1 一样，许多 GPCR 可以具有大的、扩展的细胞外结构域，通常位于其 N 末端（图1）。一种称为促甲状腺素受体或促甲状腺激素受体 (TSHR)的GPCR，具有大量富含亮氨酸的重复细胞外 N 末端结构域，并且已发现自身抗体可通过与该细胞外结构域结合来激活 TSHR，从而导致格雷夫斯病(又名毒性弥漫性甲状腺肿，是一种自身免疫性疾病)。与 TSHR 一样，C 类代谢型谷氨酸受体 (mGluR) 具有较大的 N 末端结构域，远端具有捕蝇草结构，并且已开发出骆驼单域抗体（纳米抗体）DN10 和 DN13 来激活 mGluR。mGluR 受体家族需要胞外域二聚化，DN10 和 DN13 均识别桥接两个二聚化胞外域的独特表位。有趣的是，DN10 识别 mGluR2 同二聚体，而 DN13 与 mGluR2 同二聚体和 mGluR2/mGluR4 异二聚体发生交叉反应。这种独特的药理学被证明可以有效增强 mGluR2 激动剂对神经元和 DN13 小鼠恐惧调节受损的抑制作用。最近，DN10 和 DN13 还被用于使用标记纳米抗体的时间分辨 FRET 传感器在体内检测 mGluR2 同二聚体和 mGluR2/mGluR4 异二聚体。 虽然这些是通过大的 N 末端胞外结构域激活受体的变构调节抗体的例子，但许多 GPCR 的胞外表面积有限，尤其是 A 类视紫红质样 GPCR 家族(图1A）。一些抗体已被证明可以通过直接结合短胞外环并且有时进入正位配体结合袋来激活 GPCR。安进 (Amgen) 最近报道了一种新型 apelin 受体 (APJR，apelin receptor ) 激动剂纳米抗体的设计。抗体 JN241 被发现可以阻断 APJR 激活，并且 CDR3 延伸到正构结合袋中。作者利用结构分析和构效关系信息设计成激动型抗体，通过在 CDR3 区域引入突变，将 JN241 转化为激动剂。此外，β1-肾上腺素能受体 (β1AR) 抗体被证明是偏向激动剂，可激活 G 蛋白，但不激活作为变构调节剂的 β-arrestin 信号传导。 2.2. 阻断 G 蛋白偶联受体的生物制剂 许多抗体已被描述为 G 蛋白偶联受体拮抗剂。促胰液素家族(B1 亚类)受体具有一个大的 N 末端结构域，可与形成 α 螺旋杆的激动剂结合（图1B）。 最近描述了一种针对 GLP-1 R 的竞争性拮抗抗体TB-001-003，GLP-1 R 是 B1 类或促胰液素家族 GPCR。TB-001-003 能够以与肽拮抗剂 avexitide (exendin-(9-39)) 类似的方式从 GLP-1R 中取代 GLP-1。相比之下，GLP-1 R 拮抗剂抗体 Fab 3F52 是针对 GLP-1R 大 N 末端产生的，X 射线晶体学显示可通过变构抑制机制抑制 GLP-1 结合。与 TB-001-003 类似，一种名为 Gipg013 的 GIPR 拮抗剂抗体被证明可以取代 GIPR N 末端结构域的 α 螺旋 GIP 肽。Regeneron 将 crotedumab （另一种称为胰高血糖素受体 (GCGR) 的促胰液素家族 GPCR 拮抗剂抗体）推进到了针对心脏代谢疾病的 1 期临床试验，但进一步的开发已停止。Crotedumab 是使用 GCGR 的人源化小鼠免疫产生的。 REMD Biotherapeutics 已将另一种 GCGR 拮抗剂抗体 volagidemab 推进到治疗糖尿病的 2 期试验。最后，还开发了针对 GCGR 的纳米抗体拮抗剂。一款称为erenumab，用于治疗偏头痛。Erenumab 与降钙素基因相关肽 1 型受体 (CALRL) 结合，并与受体活性修饰蛋白 1 (RAMP1) 接合。CALRL 和 RAMP1 的复合物称为降钙素基因相关肽受体 (CGRPR)，erenumab 是针对 RAMP1 和 CALRL 胞外结构域的不对称 Fc 融合而产生的。 其他具有大 N 末端结构域的受体已成为抗体拮抗剂的靶标。OncoMed报道 vantictumab可阻断 Frizzled 受体家族 (FZD)，该受体具有 FZD1、FZD2、FZD5、FZD7 和 FZD8 的交叉反应拮抗剂活性，并阻断 Wnt 信号传导以发挥抗肿瘤活性。FZD 受体拥有一个大的 N 末端，其远端含有富含半胱氨酸的结构域。富含亮氨酸的重复 GPCR (LGR) 家族通过 FZD 增强 Wnt 信号传导，具有较大的 N 末端，LGR5 是 Kyowa Kirin 开发的名为 KM4056的拮抗剂抗体的目标。 已经描述了许多针对 A 类视紫红质 GPCR 家族的拮抗剂抗体。FDA 批准了 getagozumab的 IND 许可，getagozumab 是一种内皮素受体 A (ETA) 拮抗剂抗体，另一种名为 AG8的 ETA 拮抗剂抗体最近也得到了表征。MedImmune 描述了 Fpro0165的发现和优化，Fpro0165 是一种甲酰基肽受体 1 (FPR1) 拮抗剂抗体，通过将抗体与受体的结构对接，该抗体被证明可以与受体的细胞外环 2 结合。此外，一系列合成纳米抗体，包括称为 AT118i4 的优化抗体，已被描述为血管紧张素 II 1 型受体 (AT1R) 的拮抗剂。使用胆囊收缩素 B 受体 (CCK-BR) 胞外结构域片段免疫的小鼠文库中的核糖体展示来发现一种有效的拮抗抗体，称为 scFv 77-2。scFv 77-2 在神经性疼痛的临床前模型中有效。 GPCR 拮抗剂抗体已针对趋化因子受体（称为 CCR 和 CXCR）大量开发，以便在不同疾病状态下调节免疫系统。趋化因子受体属于 A 类视紫红质受体家族，具有有限的细胞外表面积。Mogamulizumab 是一种临床批准用于治疗白血病的 CCR4 抗体，但其作用机制是诱导抗原依赖性细胞毒性 (ADCC) 杀死肿瘤细胞，而不是直接拮抗 CCR4。另一种 CCR4 拮抗剂抗体已被描述为阻断 CCR4 功能，随后通过腺相关病毒介导的抗体表达递送至肿瘤。针对 CXC 趋化因子受体 4 (CXCR4) 的抗体拮抗剂已被大力开发用于治疗癌症，其中包括 LY2624587，一种有效的拮抗剂。此外，ulocuplumab 已被开发并被证明是 CXCR4 内源配体 CXCL12 的竞争性拮抗剂。其他 CXCR4 抗体已在正构结合袋和细胞外环 中靶向并显示可竞争 CXCL12。CXCL12 与 CXCR4 以及 CXCR7 结合，已描述了针对 CXCR4 和 CXCR7 的抑制性纳米抗体。CXCR2 是另一种重要的趋化因子受体，在癌症中失调。一种新型双互补位抗体被描述为将两种效力较弱的纳米抗体结合在一起，从而产生一种强反向激动剂分子。此外，已经使用噬菌体展示合成抗体库描述了针对 CXCR2 的单克隆抗体。CCR5 是一种经过充分验证的 HIV-1 侵入共受体，并且已经开发出大量抗体来阻断 CCR5 信号传导和 HIV-1 结合。最后，已经描述了 CCR2、CCR7 和 CCR9的抗体拮抗剂。病毒性 GPCR 也已成为人们感兴趣的治疗靶点，例如由巨细胞病毒编码的病毒趋化因子受体 US28。US28 的过度表达与胶质母细胞瘤有关，并且已经描述了 US28 的拮抗剂抗体可用于胶质母细胞瘤的潜在治疗。 2.3. 靶向 G 蛋白偶联受体的下一代生物制剂 Mogamulizumab 是一种临床批准的治疗白血病的 CCR4 抗体。Kyowa Kirin 首先开发了 mogamulizumab，其作用机制是诱导 ADCC，从而消耗 CCR4 表达细胞。Mogamulizumab 被设计为减少岩藻糖基化，从而增强 ADCC。与 CCR4 类似，CCR8 是 ADCC 耗竭的目标，因为 CCR8 特异性表达于肿瘤微环境中的免疫抑制调节性 T 细胞 (Treg)。一种名为 Nb-Fc1b 的新型四价纳米抗体靶向表达 CCR8 的 Tregs 并抑制肿瘤生长。吉利德已将 GS-1811 推进到实体瘤的 1 期试验，以在表达 CCR8 的 Tregs 中触发 ADCC。同样，百时美施贵宝 (Bristol-Myers Squibb) 有一种名为 BMS-986340 的抗 CCR8 抗体，处于实体瘤的 1 期试验中。然而，正如 CCR8 敲除小鼠中所证明的那样，CCR8 的靶向需要 ADCC 来消除 Tregs，因为阻断 CCR8 信号传导对 Treg 介导的免疫抑制没有影响。 许多分子利用双特异性结合，其中抗体的每个臂结合不同的抗原。最近通过筛选源自患者的类器官中的双特异性抗体库，发现了一种名为 MCLA-158 的 LGR5 和 EGFR 双特异性抗体。BsNb PX4 是一种双特异性抗体，由两种纳米抗体组成，一种靶向 CXCR4，另一种靶向 PD-L1。在对 PD-L1 抑制具有抗性的肿瘤类型中，BsNb PX4 比单独使用每个纳米抗体治疗小鼠模型更有效。Talquetamab 是一种双特异性抗体，处于多发性骨髓瘤 3 期临床试验中，靶向 CD3 和 GPRC5D，该靶点在多发性骨髓瘤细胞上高度表达。此外，还描述了 CXCR5 和 CD3 双特异性抗体。 抗体药物偶联物 (ADC) 已针对许多 GPCR 靶标开发。对于 CXCR4，使用非天然氨基酸掺入将表面残基引入抗 CXCR4 抗体中，从而可以与 auristatin（一种用于治疗癌症的抗有丝分裂剂）结合。后来，针对称为 ADC 713 的抗体，通过增加药物与抗体比率 (DAR) 改进了该策略，从而降低了毒性。此外，一种名为达沙替尼的 Lck 抑制剂与 CXCR4 抗体偶联，以抑制自身免疫性疾病中的 T 细胞功能（因为 Lck 表达仅限于 T 细胞）。最后，描述了一种名为 4M5.3X4 的分子，它是一种针对 HIV 蛋白的小干扰 RNA，与 CXCR4 纳米抗体缀合，可抑制 CXCR4 阳性 T 淋巴细胞中的 HIV 复制。 CAR T 细胞疗法是细胞重编程的一种高级形式，可将免疫细胞靶向肿瘤以治疗癌症。孤儿 GPRC5D 已被证明在骨髓瘤癌细胞中过度表达，并已成为称为 MCARH109 的嵌合抗原 T (CAR-T) 细胞疗法的靶标。溶瘤疱疹病毒 (oHSV) 被设计为通过将病毒与称为 oHSV/Nb-gD 的 CXCR4 纳米抗体融合来靶向 CXCR4+ 胶质母细胞瘤细胞。oHSV/Nb-gD 还可以诱导 TRAIL 的表达，TRAIL 是一种 TNF 家族配体，可诱导 CXCR4 阳性胶质母细胞瘤细胞凋亡，从而减少肿瘤生长。 3. G蛋白偶联受体生物制剂发现的机遇与挑战3.1. 许多 G 蛋白偶联受体都是孤儿 约 400 个非嗅觉 GPCR 中大约有 30% 是孤儿，没有已知的配体，信号转导特性知之甚少。如上所述，许多针对 GPCR 的抗体起到变构或正构激活剂的作用。因此，抗体配体可用于去孤儿化 GPCR 信号通路，使用诸如 TRUPATH、APEX或 PRESTO-TANGO等技术。例如，许多分子针对 CAR T 细胞的 GPRC5D，因为 GPRC5D 在骨髓瘤癌细胞中高表达。然而，目前对 GPRC5D 的配体或信号转导机制知之甚少。因此，GPRC5D 抗体可用于通过 APEX 标记来分析信号传导，从而为内源配体的去孤儿化提供筛选平台。3.2. 如何实现 G 蛋白偶联受体偏向性的激动 GPCR 能够通过各种 G 蛋白家族成员和 β-arrestins 传递多效性信号，在这种情况下，有可能使用所谓的偏向激动剂来靶向有益途径。正如 APJR 抗体 JN241-9 所证明的那样，可以通过进行点突变来改变抗体配体的功能特征（在这种情况下拮抗剂转变为激动剂）。因此，诱变可以用作生物制剂基于结构的药物发现的平台。此外，通过对每个 GPCR 信号通路进行并行测试，有可能捕获通过治疗有益的通路发出信号的偏向抗体配体，并避免副作用。DNA 的快速且可扩展的合成使得强大且多样化的抗体库的开发成为可能，这使得能够发现能够与 GPCR 中的神秘位点结合的抗体，例如正构配体结合口袋（ 图2A）。DNA 合成还允许对正配体结合抗体进行大规模诱变，这将是设计针对 GPCR 的偏向激动剂抗体的策略。此外，与受体胞内侧结合的纳米抗体可用于稳定不同的受体构象，从而加速药物发现策略。 图 2. G 蛋白偶联受体生物制剂发现的机遇和挑战。A. 抗体可以靶向配体结合（正构）位点或 GPCR 的其他变构区域。 B. 抗体可以稳定 GPCR 构象，从而实现复杂的药理学（正负调节剂、反向激动剂等） C. 抗体可以激活 GPCR 下游的多种信号，并被设计为选择性激活某些途径。 D. 抗体可以破坏同一细胞（反式）或顺式（不同细胞中）的蛋白质相互作用，包括阻止更高级 GPCR 寡聚物的形成。 这里详细介绍了一些抗体影响 GPCR 信号传导的分子机制，并将它们分为两大类：正构或变构结合剂（图2A）。此外，这些抗体能够稳定 GPCR 构象（图2B），这是驱动受体下游功能选择性的一种方法（图2C)。3.3. G 蛋白偶联受体的细胞类型特异性表达 作为药物，抗体具有细胞类型特异性靶向的独特特性。抗体不是全身作用并立即代谢，而是倾向于在具有高浓度抗原的组织中积累。GPCR 通常在特定组织类型中以非常低的水平表达。大规模数据集，例如人类蛋白质图谱 和人类细胞图谱正在阐明受体特异性表达谱。最近一个特别令人兴奋的例子是趋化因子受体 CCR8，它在肿瘤微环境中的 Tregs 中表达受限。因此，利用高亲和力抗体，可以特异性地消除肿瘤微环境中的免疫抑制性 CCR8 阳性 Tregs。这是将 GPCR 独特的表达谱与抗体疗法的特性相结合的一个例子。3.4. 细胞外 G 蛋白偶联受体相互作用 最后，由于其高亲和力、通过亲合力结合和大尺寸，抗体疗法特别适合破坏蛋白质/蛋白质相互作用。最近，人类基因组中的一些细胞外蛋白质的细胞外蛋白质/蛋白质相互作用图谱（相互作用组学）受到关注。检查点抑制剂疗法会破坏细胞外蛋白质/蛋白质相互作用，而 GPCR 的细胞外相互作用才刚刚开始被绘制出来。调节细胞外与抗体的相互作用将为进一步了解 GPCR 的生物学及其广泛的 N 末端结构域和其他蛋白质之间涉及的各种相互作用提供信息。 10.1080/17460441.2023.2193389 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！ 长按关注本公众号  粉丝群/投稿/授权/广告等 请联系公众号助手 觉得本文好看，请点这里↓