更新于：2024-11-01

FZD4

更新于：2024-11-01

基本信息

别名

CD344、EVR1、exudative vitreoretinopathy 1

+ [10]

简介

Receptor for Wnt proteins (PubMed:30135577). Most frizzled receptors are coupled to the beta-catenin (CTNNB1) canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin (CTNNB1) and activation of Wnt target genes (PubMed:30135577). Plays a critical role in retinal vascularization by acting as a receptor for Wnt proteins and norrin (NDP) (By similarity). In retina, it can be activated by Wnt protein-binding and also by Wnt-independent signaling via binding of norrin (NDP), promoting in both cases beta-catenin (CTNNB1) accumulation and stimulation of LEF/TCF-mediated transcriptional programs (By similarity). A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues.

关联

项与 FZD4 相关的药物

ANT-39

靶点

FZD4

作用机制

FZD4激动剂

在研机构

AntlerA Therapeutics, Inc.初创企业 [+1]

原研机构

AntlerA Therapeutics, Inc.初创企业

在研适应症

视网膜疾患

非在研适应症-

最高研发阶段临床申请

首次获批国家/地区-

首次获批日期1800-01-20

SZN-413

靶点

FZD4 x LRP5

作用机制

FZD4激动剂 [+1]

在研机构

Surrozen, Inc.

原研机构

Surrozen, Inc.

在研适应症

糖尿病性视网膜病变 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

ANT-638

靶点

FZD4 x LRP6

作用机制

FZD4激动剂 [+1]

在研机构

AntlerA Therapeutics, Inc.初创企业

原研机构

AntlerA Therapeutics, Inc.初创企业

在研适应症

青光眼 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 FZD4 相关的临床结果

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100 项与 FZD4 相关的转化医学

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0 项与 FZD4 相关的专利（医药）

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507

项与 FZD4 相关的文献（医药）

2024-10-01·Journal of Molecular Medicine

WNT2B high‑expressed fibroblasts induce the fibrosis of IBD by promoting NK cells secreting IL-33

Article

作者: Xiao, Shuzhe ; Ren, Lu ; Chen, Xirong ; Chen, Peiyu ; Zhu, Yun ; Gong, Sitang ; Ma, Li ; Cheng, Yanling ; He, Zhihua ; Lan, Lin ; Geng, Lanlan ; Liu, Danqiong ; Gu, Jianbiao ; Cheng, Yang ; Tang, Rui ; Li, Huiwen

Fibrosis is an important pathological change in inflammatory bowel disease (IBD), but the mechanism has yet to be elucidated. WNT2B high‑expressed fibroblasts are enriched in IBD intestinal tissues, although the precise function of this group of fibroblasts remains unclear. This study investigated whether WNT2B high‑expressed fibroblasts aggravated intestinal tissue damage and fibrosis. Our study provides evidence that WNT2B high‑expressed fibroblasts and NK cells were enriched in colitis tissue of patients with IBD. WNT2B high‑expressed fibroblasts secreted wnt2b, which bound to FZD4 on NK cells and activated the NF-κB and STAT3 pathways to enhance IL-33 expression. TCF4, a downstream component of the WNT/β-catenin pathway, bound to p65 and promoted binding to IL-33 promoter. Furthermore, Salinomycin, an inhibitor of the WNT/β-catenin pathway, inhibited IL-33 secretion in colitis, thereby reducing intestinal inflammation.Knocking down WNT2B reduces NK cell infiltration and IL-33 secretion in colitis, and reduce intestinal inflammation and fibrosis. In conclusion, WNT2B high‑expressed fibroblasts activate NK cells by secreting wnt2b, which activates the WNT/β-catenin and NF-κB pathways to promote IL-33 expression and secretion, potentially culminating in the induction of colonic fibrosis in IBD. KEY MESSAGES: WNT2B high-expressed fibroblasts and NK cells are enriched in colitis tissue, promoting NK cells secreting IL-33. Wnt2b activates NF-κB and STAT3 pathways promotes IL-33 expression by activating p65 and not STAT3. syndrome TCF4 binds to p65 and upregulates the NF- κB pathway. Salinomycin reduces NK cell infiltration and IL-33 secretion in colitis. Knocking down WNT2B mitigates inflammation and fibrosis in chronic colitis.

2024-09-01·Bone Reports

Activation of Wnt signaling in human fracture callus and nonunion tissues

Article

作者: Lauzier, Dominique ; Hadjiargyrou, Michael ; Kotsiopriftis, Maria ; Hamdy, Reggie C ; Kloen, Peter

The Wnt signaling pathway is a key molecular process during fracture repair. Although much of what we now know about the role of this pathway in bone is derived from in vitro and animal studies, the same cannot be said about humans. As such, we hypothesized that Wnt signaling will also be a key process in humans during physiological fracture healing as well as in the development of a nonunion (hypertrophic and oligotrophic). We further hypothesized that the expression of Wnt-signaling pathway genes/proteins would exhibit a differential expression pattern between physiological fracture callus and the pathological nonunion tissues. We tested these two hypotheses by examining the mRNA levels of key Wnt-signaling related genes: ligands (WNT4, WNT10a), receptors (FZD4, LRP5, LRP6), inhibitors (DKK1, SOST) and modulators (CTNNB1 and PORCN). RNA sequencing from calluses as well as from the two nonunion tissue types, revealed that all of these genes were expressed at about the same level in these three tissue types. Further, spatial expression experiments identified the cells responsible of producing these proteins. Robust expression was detected in osteoblasts for the majority of these genes except SOST which displayed low expression, but in contrast, was mostly detected in osteocytes. Many of these genes were also expressed by callus chondrocytes as well. Taken together, these results confirm that Wnt signaling is indeed active during both human physiological fracture healing as well as in pathological nonunions.

2024-09-01·Ophthalmology Science

Familial Exudative Vitreoretinopathy With and Without Pathogenic Variants of Norrin/β-Catenin Signaling Genes

Article

作者: Kondo, Mineo ; Kondo, Hiroyuki ; Nagata, Tatsuo ; Nishina, Sachiko ; Higasa, Koichiro ; Matsushita, Itsuka ; Hayashi, Takaaki ; Sakamoto, Taiji ; Uchio, Eiichi ; Tsukahara-Kawamura, Tomoko ; Kusaka, Shunji

PurposeTo determine the clinical characteristics of familial exudative vitreoretinopathy (FEVR) associated with or without pathogenic variants of the Norrin/β-catenin genes.DesignThis was a multicenter, cross-sectional, observational, and genetic study.SubjectsTwo-hundred eighty-one probands with FEVR were studied.MethodsWhole-exome sequence and/or Sanger sequence was performed for the Norrin/β-catenin genes, the FZD4, LRP5, TSPAN12, and NDP genes on blood collected from the probands. The clinical symptoms of the probands with or without the pathogenic variants were assessed as well as differences in the inter Norrin/β-catenin genes.Main Outcome MeasuresThe phenotype associated with or without pathogenic variants of the Norrin/β-catenin genes.ResultsOne-hundred eight probands (38.4%) had 88 different pathogenic or likely pathogenic variants in the genes: 24 with the FZD4, 42 with the LRP5, 10 with the TSPAN12, and 12 with the NDP gene. Compared with the 173 probands without pathogenic variants, the 108 variant-positive probands had characteristics of familial predisposition (63.9% vs. 37.6%, P < 0.0001), progression during infancy (75.0% vs. 53.8%, P = 0.0004), asymmetrical severity between the 2 eyes (50.0% vs. 37.6%, P = 0.0472), and nonsyndromic characteristics (10.2% vs. 17.3%, P = 0.1185). The most frequent stage at which the more severe eye conditions was present was at stage 4 in both groups (40.7% vs. 34.7%). However, the advanced stages of 3 to 5 in the more severe eye were found more frequently in probands with variants than in those without variants (83.3% vs. 58.4%, P < 0.0001). Patients with rhegmatogenous retinal detachments progressed from stage 1 or 2 were found less frequently in the variant-positive probands (8.3% vs. 17.3%, P = 0.0346). Nine probands with NDP variants had features different from probands with typical Norrin/β-catenin gene variants including the sporadic, symmetrical, and systemic characteristics consistent with Norrie disease.ConclusionsThe results showed that the clinical characteristics of FEVR of patients with variants in the Norrin/β-catenin genes are different from those with other etiologies. We recommend that clinicians who diagnose a child with FEVR perform genetic testing so that the parents can be informed on the prognosis of the vision and general health in the child.Financial DisclosuresProprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

项与 FZD4 相关的新闻（医药）

2024-09-26

·GlobeNewswire-Health Care

Surrozen Earns $10 Million Milestone Payment in Retinal Diseases Collaboration

Boehringer is advancing the development of SZN-413 to prepare it for potential future clinical testing SZN-413 is a bi-specific antibody targeting Frizzled Class Receptor 4 (Fzd4) mediated Wingless/Integrated (Wnt) signaling, designed using Surrozen’s SWAP™ technology SZN-413 offers the possibility of restoring retinal function in patients living with retinal vascular diseases Sept. 24, 2024 -- Surrozen, Inc. (“Surrozen” or the “Company”) (Nasdaq: SRZN) announced that Boehringer Ingelheim will further develop SZN-413 to advance the compound and prepare it for clinical testing. Surrozen is pioneering targeted therapeutics that selectively activate the Wnt pathway for tissue repair and regeneration. The milestone achievement triggers a $10 million payment to Surrozen as part of the agreement. Retinal vascular diseases are responsible for a large proportion of global severe and moderate vision loss affecting close to 150 million people. Preclinical data have shown that SZN-413 could potentially stimulate Wnt signaling in the eye, induce normal retinal vessel regrowth, suppress pathological vessel growth and reduce vascular leakage (CLICK HERE). It could potentially reverse the effects of retinal vascular diseases by repairing damaged tissue and restoring retinal function. “We are excited that Boehringer has decided to move forward with the development of SZN-413 based on the completion of the initial period of joint research,” said Craig Parker, President and Chief Executive Officer of Surrozen. “With the strong genetic, experimental and clinical evidence of the role for Fzd-4 specific Wnt signaling in the retinal vasculature, we look forward to the further evaluation of this novel therapeutic approach to address one of the most urgent medical needs for people with retinal disease.” In the fourth quarter of 2022, Surrozen entered a strategic partnership with Boehringer Ingelheim for the research and development of SZN-413 for the treatment of retinal diseases. Under the terms of the agreement, Boehringer Ingelheim received an exclusive, worldwide license to develop SZN-413 and other Fzd4-specific Wnt-modulating molecules for all purposes, including as a treatment for retinal diseases, in exchange for an upfront payment to Surrozen of $12.5 million and up to $586.5 million in success-based development, regulatory, and commercial milestone payments, in addition to mid-single digit to low-double digit royalties on sales. Wnt signaling plays key roles in the control of development, homeostasis, and regeneration of many essential organs and tissues, including liver, intestine, lung, kidney, retina, central nervous system, cochlea, bone, and others. Modulation of Wnt signaling pathways has potential for treatment of degenerative diseases and tissue injuries. Surrozen’s platform and proprietary technologies have the potential to overcome the limitations in pursuing the Wnt pathway as a therapeutic strategy. Surrozen is a clinical stage biotechnology company discovering and developing drug candidates to selectively modulate the Wnt pathway. Surrozen is developing tissue-specific antibodies designed to engage the body’s existing biological repair mechanisms with a current focus on severe liver and eye diseases. For more information, please visit www.surrozen.com. The content above comes from the network. if any infringement, please contact us to modify.

引进/卖出

2024-09-23

·GBIHealth

全球医药企业主要管线进度更新（上） -2024H1

在GLP-1横扫一切的强势驱动下，无论是业绩和市值，还是各自的产品布局，全球大药企都在经历深刻的变局，甚至可以说进行了颠覆性的重排，仅是下面这张摘要图与半年前相比就有不小的差异。本文追踪了2024H1全球医药企业的主要管线进度，涵盖礼来、诺和诺德、强生、默沙东等11家全球医药企业。注：因篇幅原因上篇包含1-5家药企，下篇将继续为念呈现：罗氏ROG、阿斯利康AZN、诺华NVS、辉瑞PFE、赛诺菲SNY、百时美施贵宝BMY。礼来LLY LLY的业绩确实逆天，尤其2024年第二季度的收入肉眼可见跳了一大格、两年时间内几乎翻倍；而市值的成长却远不止翻倍，仅今年就从$500b飚到最高$850b，虽然近期略有回落，但自季报出炉两个交易日又怒涨了$100b，目前哪怕按公司全年业绩指引的上限也是66x市盈率…… Tirzepatide这个季度的极致爆发已经基本上奠定了与Semaglutide对决的后续基调，攻守之势异也。Mounjaro和Zepbound分别环比增长71%和140%，单季度销售额总共达到$4.3b；与之相比，S药已经连续两个季度走平，目前单季度T药已经追到S药的65%水平。在这个超级引擎的驱动下，公司业绩一路打破预期，几乎每个季度都在调高全年指引。管线的攻城略地仍在发力：在万众瞩目的代谢板块，Tirzepatide先后公布了OSA三期临床、HFpEF三期临床、MASH二期临床等结果，长效胰岛素也公布了两个三期临床结果，Amylin激动剂启动二期临床，Lp(a) siRNA药物Lepodisiran启动三期临床，但Empagliflozin的心衰三期临床也未能达到终点；阿尔茨海默药物Donanemab终于获得FDA批准；自免板块，以$3.2b 购Morphic获得小分子α4β7抑制剂，IL-13单抗Lebrikizumab在FDA给出CRL后重新提交上市申请，IL23p19单抗Mirikizumab在提交CD适应症上市申请后公布完整三期临床数据；肿瘤板块，去年收购Emergence得到的Nectin-4 ADC管线ETx-22进入临床，CDK4/6抑制剂Abemaciclib连续在mCRPC和HSPC等适应症的三期临床中失败。诺和诺德NVO NVO自从Semaglutide打开减重之门以来，连续两年多的股价连升势头终于被中断，从最高点$650b左右显著回调到$550b以下，特别是在中报公布当天大跌8%，业绩增长的步伐放缓恰恰与此前星辰大海的预期形成较大落差。近期正是两大减肥神药Semaglutide和Tirzepatide对决的天王山之战，面对T药的冲击和逼近，S药自身开始走平，连续两个季度环比增长几乎停滞，而对手T药这个季度简直是要疯、环比近乎要翻倍，二者之间的差距在急速缩小。最重要的研发进展当然还是围绕着Semaglutide，近期公布CKD的三期临床结果并提交该适应症的上市申请，口服25mg剂型的三期临床也公布积极结果，然而 HFpEF的上市申请被撤回、可能被隔壁LLY反超进度；Icodec虽然在欧洲、中国、日本陆续获批，但美国FDA却给了CRL拒绝批准；IcoSema复方公布了两个T2D三期临床结果；血友病双抗Mim8终于公布了三期临床结果；以€1.025b收购Cardior，获得一款靶向miR-132的ASO药物CDR-132L，目前正在开展治疗心衰的二期临床。强生JNJ JNJ在持续两年多不温不火的业绩之后，医药部分的季度收入首次有了比较可观的增长、到了$14.5b，但市值依然回不到$400b大关，与GLP-1双雄LLY和NOVO的距离仍在越拉越大。强生医药板块的业绩在大药企中还是相当稳健，其中Ustekinumab和Daratumumab上市十多年还迭创新高，Guselkumab和Macitentan+Selexipag也在高位维持稳步增长，CAR-T药物Cilta-cel在产能瓶颈缓解后开始重拾增长，但Ibrutinib、Infliximab、Abiraterone、Paliperidone等曾经的超重磅品种确实老态渐显。研发方面也有多项重磅突破：Cilta-cel凭借CARTITUDE-4三期临床的惊艳结果获批2-4LMM适应症，EGFR/cMET双抗Amivantamab获批治疗EGFRExon20插入突变的1L NSCLC，FcRn单抗Nipocalimab公布重症肌无力三期临床达到主要临床终点，靶向IL-23R的口服多肽JNJ-2113公布了52周治疗斑块状银屑病的二期试验结果，OX2R拮抗剂Seltorexant公布了伴随失眠症状的重度抑郁症三期临床结果，Macitentan与Tadalafil每日一次口服复方制剂获批治疗PAH；此外，公司近期连续完成自免领域的资产收购，包括从Numab以$1.25b收购将进入二期的IL4Rα/IL31双抗NM26，以及以$850m收购Proteologix获得将进入一期的IL13/TSLP双抗PX128和尚在临床前的IL13/IL22双抗PX130。当然，近期最有想象空间的大事件，就属传奇生物的收购传闻，潜在收购方（也应该是最顺理成章的人选）便是JNJ本尊。默沙东MRK MRK在新冠药回撤后经历过一小段业绩和股价的波动，但凭借K药坐稳药王且持续增长，市值原本稳稳站在$300b以上，然而就在中报公布当天大跌10%，主要是HPV疫苗在中国因反腐等原因大幅不及预期。研发进展除了围绕K药的各种扩适应症和联用方案以外，已经展现出更多的未来增长来源：PAH药物Sotatercept和21价肺炎疫苗V116（Capvaxive）先后获得 FDA批准，RSV抗体Clesrovimab公布了针对婴儿的Ph2b/3期临床达到主要和次要临床终点，新一代HIV药物Islatravir公布了联用Lenacapavir的二期临床结果，靶向B7H3的DS-7300启动SCLC三期临床，靶向CDH6的DS-6000启动了PROC 的2/3期临床；以$1.3b首付款+$1.7b里程碑收购EyeBio，获得一款靶向LRP5 两个表位和FZD4的三抗；坏消息包括，HER3 ADC管线U3-1402的上市申请被 FDA因生产原因拒绝，Olaparib的NSCLC三期临床和TIGIT单抗Vibostolimab联用K药治疗黑色素瘤的三期临床都遭遇失败。艾伯维ABBV 艾伯维虽然遭遇Adalimumab和Ibrutinib两大超重磅品种的下滑，所幸Risankizuma、Upadacitinib、Venetoclax、Cariprazine几个新生代贡献一定的增量，整体业绩才算没有太崩坏，外加通过收购获得ADC和精神疾病领域等重要管线，因此市值近期成功突破到$300b以上。自免板块主要仍以现有重磅的适应症扩展为主，包括Risankizumab获批UC适应症，Upadacitinib公布与Dupilumab头对头的特应性皮炎3/4期临床试验结果、公布治疗巨细胞动脉炎的三期临床结果并提交上市申请，另外还以$210m收购了Landos获得一款治疗IBD的NLRX1激动剂NX-13；此外，偏头痛药物Atogepant公布预防适应症的长期临床结果，CD20/CD3双抗Epcoritamab获批3L+ FL适应症。注：因篇幅原因上篇包含1-5家药企，下篇将继续为念呈现：罗氏ROG、阿斯利康AZN、诺华NVS、辉瑞PFE、赛诺菲SNY、百时美施贵宝BMY。

临床3期siRNA并购临床2期

2024-09-03

·研发客

预付款减少，投到哪的钱多了？| 投资观察

// • MNC资金更精准地流向细分领域，如蛋白降解剂中的分子胶技术等；AI领域交易增幅尤其显著。 • 合作开发交易的预付款呈下降趋势。 • 大额并购减少，小额收购的数量增加。部分MNC如辉瑞、强生公开宣布暂时不会有大额并购发生。近期中国同润生物以7亿美元的超高首付款达成与默沙东的合作交易，这在今年跨国药企（MNC）的预付款数额中颇为显眼。总结今年以来MNC的交易项目，预付款仅占交易总额的6.1%，预付款低于1亿美元的交易占比超过三分之二。如，和铂医药授权阿斯利康的交易，首付款仅1900万美元。预付款的减少让我们开始关注MNC资金流向的变化。小额预付款、高额里程碑 J.P. Morgan对2024上半年所有生物制药领域的BD交易总结发现，合作开发（partnership）类型占据了更大的交易份额，且还出现小额预付款、高额里程碑趋势。这与研发客对MNC的交易总结不谋而合。截至2024年8月31日，跨国药企共产生81笔交易项目，其中有52项是合作开发的交易。合作开发的模式在海外常见。雅法资本基金合伙人张艺林表示，这对MNC来说是一种更有效的策略，可以通过小公司灵活的平台定制开发一些创新产品，并且能全程参与临床试验开发，避免了Biotech临床能力不足的问题。以诺和诺德为例，通过各种技术领域的合作来增强代谢产品的管线。1月初与Omega Therapeutics合作开发可编程表观基因组学mRNA药物治疗肥胖症；AI方面，5月与Metaphore Biotechnologies达成合作，利用仿生学和人工智能开发针对肥胖相关治疗靶点；6月与Biosplice Therapeutics合作，开发糖尿病药物DYRK抑制剂。另一项值得关注的趋势是，交易的预付款趋于小数额化。81项交易中，有48项披露了预付款金额，其中有近半数（22项）低于5000万美元，33项少于1亿美元，预付款仅占交易总额的6.1%。其中，预付款最高额的交易是默沙东以7亿美元的预付款获得同润生物的CD3xCD19双抗CN201，最小数额的交易是罗氏旗下基因泰克与GenEdit合作开发治疗自身免疫病的核酸药物，基因泰克的预付款仅1500万美元。 2023年同期也呈现同样趋势，预付款占交易总额的比例只有4.7%。J.P. Morgan统计结果如是，生物制药行业交易的预付款份额自2020年来呈下降趋势，其中2024年上半年的预付款比例是6%。来源|J.P. Morgan 新药研发是高风险高投入的行业，小额的预付款降低了交易的经济风险，里程碑金额能不能最终实现，还需要看产品的进一步研发进展，也反映了MNC在BD交易时的谨慎态度。从Biotech角度看，面对当下整体融资困难现状，当然希望通过越高的首付款推进管线，张艺林表示，尤其中国Biotech对首付款的关注是常见现象，也出现在大量谈判之中，除同润生物的7亿美元预付款外，上半年中国企业出海的较高预付款还有舶望生物与诺华的1.85亿美元（拓展阅读舶望如何与诺华谈成交易|遇见舒东旭）、明济生物与艾伯维的1.5亿美元。精准投向细分领域 ADC、CGT疗法的交易在2024年迎来退潮期，双抗、小核酸、小分子药物等领域开始慢慢起势，放射性药物自2023下半年至今持续获得关注。而且，我们观察到，MNC的收购或交易指向了更加细分的创新技术或适应症。多家MNC纷纷布局细分领域，如蛋白降解剂中的分子胶技术、自免疾病中的炎症性肠病（IBD）以及核药中的大环肽技术。尤其在AI领域，交易增幅较为显著。例如IBD。自2023年起IBD就热度不减，默沙东斥资108亿美元收购Promethues获得一款治疗IBD的TL1A抗体，罗氏收购Telavant公司也获得一款TL1A抗体。礼来通过收购Morphic Therapeutics获得一款IBD治疗药物整合素α4β7抑制剂MORF-057。 2024年在IBD中出手最多的是艾伯维。从明济生物引进TL1A抗体FG-M701，收购Landos Biopharma获得NLRX1激动剂NX-13，收购Celsius Therapeutics获得TREM1抗体，且与Parvus Therapeutics合作，利用其Navacim调节性T细胞（Treg）免疫耐受平台技术，开发IBD的新型疗法。自免领域一直是艾伯维的核心领域，而曾经的药王修美乐2024年上半年销量下滑约32%，在老一代靶点IL23、TNF-α后，急需为其自免管线补充新鲜血液。TL1A成为艾伯维、默沙东、罗氏同时看中的新靶点。早在2011年，就有Nature文章发现TL1A在IBD和哮喘的临床前模型中显示出疗效，能够同时抑制炎症和纤维化。创新技术方面，蛋白降解领域中的分子胶技术获得众多MNC青睐。诺和诺德与Neomorph、武田与达歌生物、BMS与VantAI、默克与C4 Therapeutics，以及8月卫材与SEED Therapeutics的战略合作，皆围绕分子胶技术展开。拓展阅读武田选择创新伙伴有哪些标准？ “分子胶与PROTAC的交叉，既具有传统蛋白降解功能，也保留分子胶的‘粘合剂’特点，拓展了经典蛋白降解药物的适应症。”国内开发分子胶双机制降解剂的标新生物创始人杨小宝曾这样解释分子胶的技术优势。拓展阅读当PROTAC遇上分子胶此外，在一直热度未减的核药领域，诺华与PeptiDream的合作以及收购Mariana Oncology，持续加码大环肽技术。默沙东对抗体的兴趣已延伸到三抗，分别收购Harpoon Therapeutics获得一款DLL3/CD3/albumin三抗、以及收购EyeBio获得一个治疗眼科疾病的LRP5/Fzd4三特异性抗体。从靶点角度看，MNC的兴趣呈现多样化和创新性。以自免领域举例，除了上述的TL1A，还有α4β7、TREM1、ChemR23、NLRX1、STING等多款小分子和抗体。而阿斯利康对老靶点EGFR很感兴趣，分别于1月和7月从安锐生物和Pinetree Therapeutics引进了两款EGFR产品。观察两款产品可以发现，靶点虽老但技术分别具有创新性，分别是EGFR L858R变构抑制剂和EGFR降解剂。EGFR-TKI奥希替尼一直是阿斯利康王牌产品，继续深耕EGFR与管线形成互补，也反映出MNC在选择资产时并不盲目，存在一定的针对性和趋同性。 “小而美”并购潮来袭在并购交易方面，2024年至今的趋势是大额并购正在减少，小数额的生物技术公司收购正在增加。 2024年至8月底MNC共发生了27例收购，相比2023年同期的15项数量有所增加，且大多是处于早期临床阶段、小体量的生物技术公司。27例收购中，处于2期及以前临床阶段的公司达20家，占比近75%，且临床前和平台型公司就有6家（见下表）。最高额的并购，是诺和诺德以165亿美元收购CDMO企业Catalent，其他并购均低于50亿美元。 MNC在上半年都不约而同表示暂时不会有大额并购。辉瑞首席执行官Albert Bourla在6月公开宣布，将暂停大额并购，但会为小型并购敞开大门。同样，强生全球业务发展主管Nauman Shah在2024 BIO大会中公开表示，暂时没有大额收购的必要，而会关注体量较小的公司，与管线产品形成互补。张艺林表示，具体并购情况要视MNC的现金流而定，例如诺和诺德收购Catalent的原因之一是其本身现金充足，其次是满足司美格鲁肽的生产供应。谈及未来的大额并购案可能发生在哪些biotech，张艺林预测，Viking、Zymeworks、Agrenx等中型biotech都有被收购的概率。编辑 | 姚嘉 yao.jia@PharmaDJ.com 总第2192期访问研发客网站，深度报道和每日新闻抢鲜看 www.PharmaDJ.com

信使RNA并购引进/卖出寡核苷酸