同行致远 | 已有数款获批上市，这类新兴靶向疗法展现治疗潜力 | Bilingual

编者按：多肽偶联药物（peptide-drug conjugates，PDCs）作为新一代极具潜力的靶向治疗药物类型，将肽类分子的高精确性与小分子药物的强效活性进行结合。通过提升靶向递送能力并增强治疗效果，PDCs在肿瘤、感染性疾病及代谢性疾病等多个领域展现治疗潜力。然而，由于其结构复杂，对稳定性、可扩展性及质量控制提出了更高要求，也意味着PDCs的开发需要专业技术与先进平台的有力支撑。为应对这些挑战，药明康德旗下WuXi TIDES一体化CRDMO平台，凭借在多肽合成、小分子化学及偶联技术领域的深厚积累，可为全球合作伙伴提供覆盖从早期研究到商业化生产的全流程一站式解决方案。

多肽偶联药物是精准肿瘤治疗领域中极具前景的创新药物类型之一。PDCs与抗体偶联药物（ADCs）基于相同原理，即通过靶向载体递送细胞毒性药物。不同之处在于，PDCs采用短小、可合成的肽链替代大型抗体。这些细胞靶向肽（CTPs）分子量仅为数千道尔顿，赋予PDCs卓越的组织穿透力、低免疫原性及高度设计灵活性。此外，PDCs通过肾脏途径代谢清除，从而减轻系统性负担。其小巧且具构象可塑性的结构还能引入非天然氨基酸、环状结构及多种化学修饰，进一步提升稳定性和靶向特异性。因此，PDCs正逐步成为靶向治疗领域中发展迅速、潜力突出的新型治疗模式。

每一个PDC的核心都由三个相互依存的关键部分组成，共同协作以扩大药物的治疗窗口。首先是细胞靶向肽，可通过纳摩尔级亲和力识别疾病细胞上高表达的受体，常采用环状或缚合（stapled）结构，以维持二级结构并增强结合力，如针对整合素的RGD基序及针对CD13的NGR序列。其次是连接子（linker），决定药物释放的时间与位置。连接子可设计为可裂解型（对pH、谷胱甘肽或肿瘤相关酶敏感）或不可裂解型（依赖载体的胞内降解释放药物-连接子复合物）。最后是细胞毒性有效载荷，如多柔比星（doxorubicin）、紫杉醇（paclitaxel）或mertansine等。这些药物通过偶联可改善药代动力学、循环稳定性与肿瘤选择性，同时保持强效活性。PDCs的模块化结构从分子识别、可控释放到精准杀伤，形成了高效且清晰的药物递送路径。

目前，已有数款治疗用PDC疗法获全球监管机构批准。Lutathera（Lutetium Lu-177 Dotatate）结合了生长抑素受体靶向肽与β射线放射性核素Lu-177，用于治疗生长抑素受体阳性的胃肠胰神经内分泌肿瘤（GEP-NETs），可实现局部放射治疗，并在安全可控的前提下维持持久疗效。Pepaxto（melphalan flufenamide）是一种肽偶联烷化剂，旨在靶向复发/难治性多发性骨髓瘤中升高的氨基肽酶活性。进入细胞后，经酶切反应释放melphalan，在恶性浆细胞内发挥杀伤作用。这些疗法的成功上市，验证了PDCs作为临床可行新型药物形式的潜力。

随着研究的不断深入和合成技术的日趋成熟，PDCs有望在肿瘤、代谢性疾病及感染性疾病等多个领域拓展其临床应用。由于PDCs兼具肽与小分子药物的双重特性，其复杂的结构对药物研发生产能力提出了更高要求。依托全面的多肽技术平台与小分子化学能力，药明康德的WuXi TIDES平台可为多肽偶联药物的项目提供一站式解决方案，涵盖从发现合成、工艺开发到生产的一体化支持。

展望未来，作为值得信赖的合作伙伴，药明康德将持续赋能全球肽类药物创新，助力客户加速研发进程，更快将高质量的创新药物带给患者，早日实现“让天下没有难做的药，难治的病”的愿景。

Peptide-Drug Conjugates: A New Frontier in Targeted Therapy

Peptide-drug conjugates (PDCs) represent a promising new generation of targeted therapeutics that combine the precision of peptides with the potency of small molecules. By enhancing selective delivery and improving therapeutic efficacy, PDCs are showing strong promise across oncology, infectious diseases, and metabolic disorders. At the same time, their intricate architectures demand specialized expertise and advanced technology to ensure stability, scalability, and quality throughout development.

Addressing these needs, WuXi TIDES, part of WuXi AppTec, has established an integrated CRDMO platform dedicated to peptide therapeutics. Leveraging deep expertise in peptide synthesis, small-molecule chemistry, and conjugation technologies, the platform delivers comprehensive end-to-end solutions for peptide conjugate discovery, development, and manufacturing, supporting partners from early research to commercial production.

Peptide-drug conjugates are emerging as one of the most promising modalities in precision oncology. Built upon the same fundamental principle as antibody-drug conjugates (ADCs), PDCs distinguish themselves by using short, synthetically designed peptides in place of large antibodies.These cell-targeting peptides (CTPs), typically only a few kilodaltons in size, endow PDCs with remarkable tissue penetration, low immunogenicity, and high design flexibility.In addition, PDCs are cleared through renal pathways, minimizing systemic burden.Their small, conformationally adaptable structures also allow incorporation of non-natural amino acids, cyclic motifs, and chemical modifications that enhance stability and targeting selectivity.As a result, PDCs represent a fast-advancing platform in the landscape of targeted therapeutics.

At the core of every PDC are three interdependent parts that work together to widen the therapeutic windowversus the free drug:a cell-targeting peptidethat recognizes receptors enriched on diseased cells with nanomolar affinity, often in cyclic or stapled formats that preserve secondary structure and strengthen binding (e.g., RGD motifs for integrins, NGR for CD13);a linkerthat governs when and where the payload is released, using cleavable chemistries responsive to pH, glutathione, or tumor-associated enzymes, or non-cleavable designs that rely on intracellular degradation of the carrier to liberate an active drug-linker complex;and a cytotoxic payload—such as doxorubicin, paclitaxel, or mertansine—whose conjugation improves pharmacokinetics, circulation stability, and tumor selectivity without sacrificing potency. This modular architecture creates a clear progression from molecular recognition to controlled release and, ultimately, targeted cell killing.

To date, there are a few PDC therapeutics approved by global regulatory agencies.Lutathera (Lutetium Lu-177 Dotatate) couples a somatostatin-targeting peptide with the beta-emitting radionuclide Lu-177 to treat somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, delivering localized radiotherapy and achieving durable disease control with a manageable safety profile typical of radioligand approaches. Pepaxto (melphalan flufenamide) is a peptide-conjugated alkylator designed to target elevated aminopeptidase activity in relapsed/refractory multiple myeloma; once internalized, enzymatic cleavage releases melphalan and exerts cytotoxic effects inside malignant plasma cells. These approvals demonstrate the PDCs' potential as a feasible new modality to benefit patients in clinics.

As research advances and synthetic technologies mature, PDCs are poised to broaden their clinical applications across oncology, metabolic, and infectious diseases.Because PDCs integrate peptide targeting and cytotoxic payloads, their complex structures demand specialized development capabilities.Leveraging a comprehensive peptide platform integrated with small-molecule chemistry, WuXi TIDES provides a one-stop solution—spanning discovery synthesis, process development, and manufacturing—for peptide-conjugate discovery projects.

As a trusted global partner, WuXi AppTec continues to empower innovation across peptide therapeutics. By enabling partners worldwide to accelerate development and bring high-quality candidates to patients faster, the company advances the vision that “every drug can be made and every disease can be treated.”

参考资料：

[1] Xiao W, Jiang W, Chen Z, Huang Y, Mao J, Zheng W, Hu Y, Shi J. Advance in peptide-based drug development: delivery platforms, therapeutics and vaccines. Signal Transduct Target Ther. 2025 Mar 5;10(1):74. doi: 10.1038/s41392-024-02107-5. PMID: 40038239; PMCID: PMC11880366.

[2] Peptide-Drug Conjugate Services. Retrieved October 16, 2025 from https://labtesting.wuxiapptec.com/peptide-drug-conjugate-services/

[3] Peptide Conjugate Discovery. Retrieved October 18, 2025 from https://tides.wuxiapptec.com/services-solutions/peptide/discovery/peptide-conjugate/

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