編者按：多肽偶聯(lián)藥物（peptide-drug conjugates，PDCs）作為新一代極具潛力的靶向治療藥物類型，將肽類分子的高精確性與小分子藥物的強(qiáng)效活性進(jìn)行結(jié)合。通過提升靶向遞送能力并增強(qiáng)治療效果，PDCs在腫瘤、感染性疾病及代謝性疾病等多個(gè)領(lǐng)域展現(xiàn)治療潛力。然而，由于其結(jié)構(gòu)復(fù)雜，對穩(wěn)定性、可擴(kuò)展性及質(zhì)量控制提出了更高要求，也意味著PDCs的開發(fā)需要專業(yè)技術(shù)與先進(jìn)平臺的有力支撐。為應(yīng)對這些挑戰(zhàn)，藥明康德旗下WuXi TIDES一體化CRDMO平臺，憑借在多肽合成、小分子化學(xué)及偶聯(lián)技術(shù)領(lǐng)域的深厚積累，可為全球合作伙伴提供覆蓋從早期研究到商業(yè)化生產(chǎn)的全流程一站式解決方案。

多肽偶聯(lián)藥物是精準(zhǔn)腫瘤治療領(lǐng)域中極具前景的創(chuàng)新藥物類型之一。PDCs與抗體偶聯(lián)藥物（ADCs）基于相同原理，即通過靶向載體遞送細(xì)胞毒性藥物。不同之處在于，PDCs采用短小、可合成的肽鏈替代大型抗體。這些細(xì)胞靶向肽（CTPs）分子量僅為數(shù)千道爾頓，賦予PDCs卓越的組織穿透力、低免疫原性及高度設(shè)計(jì)靈活性。此外，PDCs通過腎臟途徑代謝清除，從而減輕系統(tǒng)性負(fù)擔(dān)。其小巧且具構(gòu)象可塑性的結(jié)構(gòu)還能引入非天然氨基酸、環(huán)狀結(jié)構(gòu)及多種化學(xué)修飾，進(jìn)一步提升穩(wěn)定性和靶向特異性。因此，PDCs正逐步成為靶向治療領(lǐng)域中發(fā)展迅速、潛力突出的新型治療模式。

每一個(gè)PDC的核心都由三個(gè)相互依存的關(guān)鍵部分組成，共同協(xié)作以擴(kuò)大藥物的治療窗口。首先是細(xì)胞靶向肽，可通過納摩爾級親和力識別疾病細(xì)胞上高表達(dá)的受體，常采用環(huán)狀或縛合（stapled）結(jié)構(gòu)，以維持二級結(jié)構(gòu)并增強(qiáng)結(jié)合力，如針對整合素的RGD基序及針對CD13的NGR序列。其次是連接子（linker），決定藥物釋放的時(shí)間與位置。連接子可設(shè)計(jì)為可裂解型（對pH、谷胱甘肽或腫瘤相關(guān)酶敏感）或不可裂解型（依賴載體的胞內(nèi)降解釋放藥物-連接子復(fù)合物）。最后是細(xì)胞毒性有效載荷，如多柔比星（doxorubicin）、紫杉醇（paclitaxel）或mertansine等。這些藥物通過偶聯(lián)可改善藥代動(dòng)力學(xué)、循環(huán)穩(wěn)定性與腫瘤選擇性，同時(shí)保持強(qiáng)效活性。PDCs的模塊化結(jié)構(gòu)從分子識別、可控釋放到精準(zhǔn)殺傷，形成了高效且清晰的藥物遞送路徑。

目前，已有數(shù)款治療用PDC療法獲全球監(jiān)管機(jī)構(gòu)批準(zhǔn)。Lutathera（Lutetium Lu-177 Dotatate）結(jié)合了生長抑素受體靶向肽與β射線放射性核素Lu-177，用于治療生長抑素受體陽性的胃腸胰神經(jīng)內(nèi)分泌腫瘤（GEP-NETs），可實(shí)現(xiàn)局部放射治療，并在安全可控的前提下維持持久療效。Pepaxto（melphalan flufenamide）是一種肽偶聯(lián)烷化劑，旨在靶向復(fù)發(fā)/難治性多發(fā)性骨髓瘤中升高的氨基肽酶活性。進(jìn)入細(xì)胞后，經(jīng)酶切反應(yīng)釋放melphalan，在惡性漿細(xì)胞內(nèi)發(fā)揮殺傷作用。這些療法的成功上市，驗(yàn)證了PDCs作為臨床可行新型藥物形式的潛力。

隨著研究的不斷深入和合成技術(shù)的日趨成熟，PDCs有望在腫瘤、代謝性疾病及感染性疾病等多個(gè)領(lǐng)域拓展其臨床應(yīng)用。由于PDCs兼具肽與小分子藥物的雙重特性，其復(fù)雜的結(jié)構(gòu)對藥物研發(fā)生產(chǎn)能力提出了更高要求。依托全面的多肽技術(shù)平臺與小分子化學(xué)能力，藥明康德的WuXi TIDES平臺可為多肽偶聯(lián)藥物的項(xiàng)目提供一站式解決方案，涵蓋從發(fā)現(xiàn)合成、工藝開發(fā)到生產(chǎn)的一體化支持。

展望未來，作為值得信賴的合作伙伴，藥明康德將持續(xù)賦能全球肽類藥物創(chuàng)新，助力客戶加速研發(fā)進(jìn)程，更快將高質(zhì)量的創(chuàng)新藥物帶給患者，早日實(shí)現(xiàn)“讓天下沒有難做的藥，難治的病”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.”

參考資料：

[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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