IMAB-027

Claudin 蛋白简介 目前，在人类基因组中已注释了至少 26 个编码 Claudin 蛋白（CLDNs 1-26）的基因，Claudin在上皮稳态、组织通透性和信号传导中的多种作用；除了在紧密连接形成中的经典作用外，Claudin 蛋白被发现是信号转导、细胞增殖、干细胞特性以及上皮 - 间质转化过程的关键参与者 (Furuse et al., 1998; Gunzel & Yu, 2013)。 图1. Claudin 蛋白结构：Claudin 具有四个跨膜结构。ECL1 和 ECL2 是单克隆抗体和 CPE 的结合位点。CPE，产气荚膜梭菌肠毒素（Clostridium perfringens enterotoxin）；ECL，胞外环。 (Sugiyama & Chau, 2025). Claudin 蛋白（CLDNs）是四跨膜蛋白，由跨膜分支结构域（TM 1-4）、细胞内 N 端和 C 端以及细胞外环（ECL 1-2）组成 （图1） (Furuse et al., 1998)。Claudin 蛋白（CLDNs）具有器官特异性表达模式，在恶性细胞中存在表达异常（包括过表达、异常表达或表达缺失）(Singh et al., 2010; Tao et al., 2023)；随着 Claudin 蛋白的生理及病理生理功能逐步被揭示，其已作为肿瘤学重要治疗靶点和诊断标志物被药研企业与科学家们重点关注；基于CLDN靶点研究也已从之前的单纯治疗，转向为诊疗一体 (Li, 2021)。 Claudin 靶点管线 由于 Claudin 蛋白具有细胞外可及性、组织表达受限、在恶性肿瘤中上调时具有独特的定位模式，且参与肿瘤发生过程，因此它们代表了一类极具潜力的癌症治疗靶点 (Hagen, 2017; Offner et al., 2005)。 Claudin 18.2 截至2025年8月，全球Claudin 蛋白相关药物管线合计199个，其中创新化药3款，生物药149款，细胞疗法55款，疫苗 1款；生物药149个管线中，Claudin 18.2以110个管线居首：自2016年ASCO会议上，德国生物技术公司Ganymed的Claudin 18.2抗体IMAB362惊艳亮相，相比单独化疗，将胃癌患者总生存期从8.4个月延长到13.2个月，死亡的风险下降了49%。很快，安斯泰来即以14亿美元收购Ganymed；由于胃癌是中国仅次于肺癌的第二大癌种，IMAB362的成功吸引了国内众多药企加入该靶点药物的研发竞争。值得注意的是，国内药企在Claudin 18.2靶点的研发竞争中，涌现了许多新尝试，包括双抗、CAR-T、ADC等。 图2. Claudin 靶点相关生物药管线分布 （药渡数据） 在Claudin 18.2火热竞争的背后，Claudin 6也成为密蛋白家族备受关注的新靶点。在一些癌种如NSCLC中，Claudin 18.2和Claudin 6都存在高表达的现象，Claudin 6高表达的患者其生存期显著短于Claudin 6低表达的患者，在这种背景下，头部生物技术公司如BioNtech，Daiichi Sankyo Inc等纷纷研发靶向Claudin 6的抗体或者CAR-T疗法等。 Claudin 6 截至2025年8月，全球Claudin 6相关管线34个，其中多抗16个占比接近50% ，抗体偶联药物（ADC） 10个，其余为细胞疗法（含NK, T细胞），疫苗（药渡数据）；CLDN6在健康成人组织中呈低表达，仅在胎盘和睾丸组织中有表达(图3)，而在多种实体瘤中呈现异常高表达。这种表达模式使其成为极具吸引力的治疗靶点，因为针对它的治疗理论上可以实现“精准打击”肿瘤细胞，同时避免对正常组织的损伤。CLDN6在卵巢癌（14%-55%）、睾丸癌（近80%）、子宫内膜癌（17%-21%）、胃癌（10%-52%）和非小细胞肺癌（6%-11%）等多种实体瘤中频繁过表达 (Katoh & Katoh, 2024; Sugiyama & Chau, 2025)。尤其是在铂类耐药卵巢癌中，CLDN6的高表达率使其成为解决这一临床未满足需求的重要突破口。 图3. CLDN6 expression profile of HPA RNA-seq normal tissues (NCBI) 与其他成员类似，CLDN6蛋白包含两个暴露于细胞外的结构域（ECL1和ECL2），这为抗体类药物和细胞治疗提供了可及的结合位点。特别是ECL1区域，其构象相对稳定且具有较好的抗原性，已成为大多数CLDN6靶向药物的结合区域。然而，CLDN家族成员（尤其是CLDN3、4、9）之间存在高度同源性，其中CLDN6与CLDN9的胞外区仅有3个氨基酸差异，这给药物开发带来了特异性设计的重大挑战 (图4)。早期开发的一些CLDN6单抗（如ASP1650）因难以区分CLDN6和CLDN9而终止开发，促使新一代药物必须解决交叉反应性问题。 图4. CLDN6& CLDN9 蛋白序列比对结果；蓝框为胞外区（ECL1&2）红色箭头所示序列差异  CLDN6作为具有高度肿瘤选择性的靶点，已成为实体瘤靶向治疗的新兴焦点。全球研发管线呈现多元化技术路线并行的格局，其中ADC类药物（TORL-1-23、DS-9606a、QLS5132等）进展最快，已在重度经治的卵巢癌、睾丸癌患者中显示出40-45%的客观缓解率；CLDN6相关双抗药物开发数量最多: 截至2025年8月激活状态临床项目7个代表药物BGB-B455、CTIM-76等，该策略通过T细胞重定向机制，在临床前模型中显示出高效肿瘤杀伤；细胞治疗领域则以BioNTech的CAR-T+CARVac联合策略为代表，在早期试验中达到80%的缓解率，为解决实体瘤CAR-T的持久性问题提供了创新方案。 当前研发的核心挑战包括靶点选择性优化、耐药机制克服和生物标志物开发等，而解决这些挑战需要依托结构生物学、抗体工程和药物设计技术的持续创新。 擎 科 产 品 当前主流的膜蛋白研究依赖去污剂，但其会破坏膜蛋白所处的天然膜环境（这一环境对膜蛋白的结构、功能及相互作用至关重要），导致无法准确解析局部分子环境对膜蛋白的影响。 擎科开发的合成纳米盘提取方案，无需经过复杂的中间处理步骤，可从膜蛋白天然存在的生理环境（如细胞膜中）直接提取目标分子；提取过程中不破坏膜蛋白周围的 “天然膜环境”（包括脂质组成、邻近分子互作等），可以解决传统方法因环境破坏而导致的研究偏差问题，膜蛋白领域的精准研究提供了重要工具。 基于改性合成 (styrene–maleic acid copolymers)聚合物直接组装细胞膜的策略成功制备多次跨膜蛋白纳米盘，相关蛋白全长表达，除末端标签外无额外修饰。组装纯化过程不使用去污剂、人工磷脂和包裹蛋白，最大程度接近蛋白质在细胞膜上的天然状态，避免引入无关蛋白的干扰，为解析膜蛋白的结构、功能及相互作用提供了更可靠的模型。 核心特性（Features） 高纯度：满足多样化的实验需求，既适用于抗体免疫，又可用于抗体库的高通量筛选，例如生物淘选（bio panning）和荧光激活细胞分选（FACS）等关键实验流程; 高生物活性：酶联免疫吸附测定（ELISA）检测方法确认具备高生物活性，确保了在各类实验中的可靠性; 适配性强：能够很好地适应抗体展示技术，为抗体相关研究提供了便利条件。 突出优势（Advantages） 基于全合成聚合物制备的合成纳米盘多次跨膜蛋白同时具备下列特点，使得研究结果更具可信度和参考价值，同时灵活匹配各种应用场景。 精准保留蛋白质天然状态； 纯度高，无异源蛋白质干扰； 适配药物研发中的靶点验证需求，提高候选药物筛选准确性，降低研发风险； 实际效益 (Benefits) 高纯度与高生物活性的双重保障，为药物研发过程的顺利推进提供了坚实支撑。在抗体筛选等关键环节，其优异性能能够显著提升筛选效率，缩短研发周期，降低研发成本，这不仅加速了潜在药物从实验室到临床应用的转化进程，也为生物医药领域的创新发展注入了强大动力。 产品列表 A．重组蛋白（现货） B．蛋白定制 除现货型多次跨膜蛋白，擎科还提供专业的蛋白定制与表达服务，从基因合成到功能验证，加速您的基础研究与药物开发。 联系我们： 官网：www.tsingke.com.cn 电话：400-668-3730 邮箱：market@tsingke.com.cn 数据展示 01 CLDN6  Human Claudin-6 Protein-(Nanodisc) (His Tag & Twin strepII tag) 电泳（SDS-PAGE） 图5. Human Claudin-6 Protein-(Nanodisc) (His Tag & Twin strepII tag) (Cat. No. DL30001) on SDS-PAGE. The purity of the protein is greater than 90%. 活性（Bioactivity）-ELISA 图6. ELISA plates were pre-coated with anti-His antibody, followed by Human Claudin-6 Protein-(Nanodisc) (His Tag & Twin strepII tag) (Cat. No. DL30001) (0.2μg/per well). Serial diluted anti-CLDN6 monoclonal antibody solutions were added, washed, and incubated with secondary antibody before reading. 活性（Bioactivity）-FACS 图7. 2×106 of yeast displaying anti-CLDN6 (DS-9606a) and and negative control strain were stained with 50 μL of 2 μg/mL  Human Claudin-6 Protein-(Nanodisc) (His Tag & Twin strepII tag) (Cat. No. DL30001) respectively, washed and then analyzed with FACS. Human Claudin-6 Protein-(Nanodisc) (EGFP & His Tag & Twin strepII tag) (Fluorescent) 电泳（SDS-PAGE） 图8. Human Claudin-6 Protein-(Nanodisc) (EGFP & His Tag & Twin strepII tag) (Fluorescent) (Cat. No. DL30002) on SDS-PAGE. The purity of the protein is greater than 90%. 活性（Bioactivity）-ELISA 图9. ELISA plates were pre-coated with anti-His antibody, followed by Human Claudin-6 Protein-(Nanodisc) (EGFP & His Tag & Twin strepII tag) (Fluorescent)  (Cat. No. DL30002) (0.2μg/per well). Serial diluted anti-CLDN6 monoclonal antibody solutions were added, washed, and incubated with secondary antibody before reading. 活性（Bioactivity）-FACS 图10. 2×106 of yeast displaying anti-CLDN6 (DS-9606a) and and negative control strain were stained with 50 μL of 2 μg/mL  Human Claudin-6 Protein-(Nanodisc) (EGFP & His Tag & Twin strepII tag) (Fluorescent) (Cat. No. DL30002) respectively, washed and then analyzed with FACS. 02 CLDN9 Human Claudin-9 Protein-(Nanodisc) (His Tag & Twin strepII tag) 电泳（SDS-PAGE） 图11. Human Claudin-9 Protein-(Nanodisc) (His Tag & Twin strepII tag) (Cat. No. DL30004) on SDS-PAGE. The purity of the protein is greater than 90%. 活性（Bioactivity）-ELISA 图12. ELISA plates were pre-coated with anti-His antibody, followed by Human Claudin-9 Protein-(Nanodisc) (His Tag & Twin strepII tag) (Cat. No. DL30004) (0.2μg/per well). Serial diluted anti-CLDN9 monoclonal antibody solutions were added, washed, and incubated with secondary antibody before reading. Human Claudin-9 Protein-(Nanodisc) (EGFP & His Tag & Twin strepII tag) (Fluorescent) 电泳（SDS-PAGE） 图13. Human Claudin-9 Protein-(Nanodisc) (EGFP & His Tag & Twin strepII tag) (Fluorescent) (Cat. No. DL30005) on SDS-PAGE. The purity of the protein is greater than 90%. 活性（Bioactivity）-ELISA 图14. ELISA plates were pre-coated with anti-His antibody, followed by H Human Claudin-9 Protein-(Nanodisc) (EGFP & His Tag & Twin strepII tag) (Fluorescent) (Cat. No. DL30005) (0.2μg/per well). Serial diluted anti-CLDN9 monoclonal antibody solutions were added, washed, and incubated with secondary antibody before reading. 03 CLDN 18.2 Human Claudin-18.2 Protein-(Nanodisc) (His Tag & Twin strepII tag) 电泳（SDS-PAGE） 图15. Human Claudin-18.2 Protein-(Nanodisc) (His Tag & Twin strepII tag) (Cat. No. DL30010) on SDS-PAGE. The purity of the protein is greater than 90%. 活性（Bioactivity）-ELISA 图16. ELISA plates were pre-coated with anti-His antibody, followed by Human Claudin-18.2 Protein-(Nanodisc) (His Tag & Twin strepII tag) (Cat. No. DL30010) (0.2μg/per well). Serial diluted anti-CLDN18.2 monoclonal antibody solutions were added, washed, and incubated with secondary antibody before reading. 活性（Bioactivity）-FACS 图17. 2×106 of yeast displaying anti-CLDN18.2 (Osemitamab) and negative control strain were stained respectively with 50 μL of 2 μg/mL Human Claudin-18.2 Protein-(Nanodisc) (His Tag & Twin strepII tag) (Cat. No. DL30010), washed and then analyzed with FACS. Human Claudin-18.2 Protein-(Nanodisc) (EGFP & Twin strep II &His Tag & FLAG tag) (Fluorescent) 电泳（SDS-PAGE） 图18. Human Claudin-18.2 Protein-(Nanodisc) (EGFP & Twin strep II &His Tag & FLAG tag) (Fluorescent) (Cat. No. DL30011) on SDS-PAGE. The purity of the protein is greater than 90%. 活性（Bioactivity）-ELISA 图19. ELISA plates were pre-coated with anti-His antibody, followed by Human Claudin-18.2 Protein-(Nanodisc) (EGFP & Twin strep II &His Tag & FLAG tag) (Fluorescent) (Cat. No. DL30011) (0.2μg/per well). Serial diluted anti-CLDN18.2 monoclonal antibody solutions were added, washed, and incubated with secondary antibody before reading. 活性（Bioactivity）-FACS 图20. 2×106 of yeast displaying anti-CLDN18.2 (Osemitamab) and negative control strain were stained respectively with 50 μL of 2 μg/mL Human Claudin-18.2 Protein-(Nanodisc) (EGFP & Twin strep II &His Tag & FLAG tag) (Fluorescent) (Cat. No. DL30011), washed and then analyzed with FACS. 04 CLDN 18.1 Human Claudin-18.1 Protein-(Nanodisc) (His Tag & Twin strepII tag) 电泳（SDS-PAGE） 图21. Human Claudin-18.1 Protein-(Nanodisc) (His Tag & Twin strep II tag) (Cat. No. DL30007) on SDS-PAGE. The purity of the protein is greater than 90%.  活性（Bioactivity）-ELISA 图22. ELISA plates were pre-coated with anti-His antibody, followed by Human Claudin-18.1 Protein-(Nanodisc) (His Tag & Twin strepII tag) (Cat. No. DL30007) (0.2μg/per well). Serial diluted anti-CLDN18.1 monoclonal antibody solutions were added, washed, and incubated with secondary antibody before reading. Human Claudin-18.1 Protein-(Nanodisc) (EGFP & His Tag & Twin strep II tag) (Fluorescent) 电泳（SDS-PAGE） 图23. Human Claudin-18.1 Protein-(Nanodisc) (EGFP & His Tag & Twin strep II tag) (Fluorescent) (Cat. No. DL30008) on SDS-PAGE. The purity of the protein is greater than 90%. 活性（Bioactivity）-ELISA 图24. ELISA plates were pre-coated with anti-His antibody, followed by Human Claudin-18.1 Protein-(Nanodisc) (EGFP & His Tag & Twin strep II tag) (Fluorescent) (Cat. No. DL30008) (0.2μg/per well). Serial diluted anti-CLDN18.1 monoclonal antibody solutions were added, washed, and incubated with secondary antibody before reading. 参考文献： [1]Furuse, M., Fujita, K., Hiiragi, T., Fujimoto, K., & Tsukita, S. (1998). Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol, 141(7), 1539-1550. https://doi.org/10.1083/jcb.141.7.1539  [2]Gunzel, D., & Yu, A. S. (2013). Claudins and the modulation of tight junction permeability. Physiol Rev, 93(2), 525-569. https://doi.org/10.1152/physrev.00019.2012  [3]Hagen, S. J. (2017). Non-canonical functions of claudin proteins: Beyond the regulation of cell-cell adhesions. Tissue Barriers, 5(2), e1327839. https://doi.org/10.1080/21688370.2017.1327839  [4]Katoh, M., & Katoh, M. (2024). Claudin 1, 4, 6 and 18 isoform 2 as targets for the treatment of cancer (Review). Int J Mol Med, 54(5). https://doi.org/10.3892/ijmm.2024.5424  [5]Li, J. (2021). Targeting claudins in cancer: diagnosis, prognosis and therapy. Am J Cancer Res, 11(7), 3406-3424. https://www.ncbi.nlm.nih.gov/pubmed/34354852  [6]Offner, S., Hekele, A., Teichmann, U., Weinberger, S., Gross, S., Kufer, P., Itin, C., Baeuerle, P. A., & Kohleisen, B. (2005). Epithelial tight junction proteins as potential antibody targets for pancarcinoma therapy. Cancer Immunol Immunother, 54(5), 431-445. https://doi.org/10.1007/s00262-004-0613-x  [7]Singh, A. B., Sharma, A., & Dhawan, P. (2010). Claudin family of proteins and cancer: an overview. J Oncol, 2010, 541957. https://doi.org/10.1155/2010/541957  [8]Sugiyama, K., & Chau, I. (2025). Claudins as diagnostic tools and therapeutic targets-Glimpse of the horizon.Cancer Treat Rev, 133, 102888. https://doi.org/10.1016/j.ctrv.2025.102888  [9]Tao, D., Guan, B., Li, H., & Zhou, C. (2023). Expression patterns of claudins in cancer. Heliyon, 9(11), e21338. https://doi.org/10.1016/j.heliyon.2023.e21338  更多有料内容请关注擎科生物媒体矩阵!