Avelumab

作者：周予西 美工：何国红 罗真真 排版：马超 ▶ 01 引言 噬菌体展示技术自1985年问世以来，彻底改变了抗体药物的研发路径。2018年诺贝尔化学奖的颁发，让这项“让噬菌体为人类打工”的技术从实验室走向聚光灯下。 如今，这项技术已催生出一个庞大的治疗性抗体家族，它们被用于治疗从类风湿关节炎到癌症等多种疾病。从第一个基于该技术开发的“药王”修美乐，到最新获批的国产创新药赛立奇单抗，噬菌体展示技术正在重塑全球抗体药物研发格局。 ▶ 02 抗体文库：多样性的源泉与技术的演进 噬菌体展示技术的强大能力，源于其使用的核心工具——抗体文库。根据序列来源与构建方式，主要分为四种类型，以应对不同研发需求。 ◑ 天然库由未经免疫的健康人B细胞构建，旨在模拟人体天然的抗体多样性，其优势是“广谱性”，可针对几乎所有抗原进行筛选，但初始抗体亲和力通常较低。 ◐ 免疫库采用经过特定抗原免疫的人或动物B细胞构建，优势在于“精准性”，文库富含靶向该抗原的序列，能高效筛选出高亲和力抗体，但应用范围仅限于其免疫的抗原。 ◑ 半合成库通过基因工程，将人工合成的随机序列（主要针对关键互补决定区CDR）与天然的抗体框架区组合而成，在天然库基础上引入了可控的多样性。 ◐ 合成库的序列则完全通过人工设计与化学合成，是工程化程度最高的文库，可从头优化骨架、系统引入多样性，并能规避天然序列的专利或免疫原性问题。 ▲ 图 1 三优生物噬菌体展示库概览 三优生物已构建了国际领先的“智能超万亿分子发现平台”，噬菌体抗体库种类多样，可以覆盖几乎所有的抗体产生需求。 同时，三优生物的AI-STAL噬菌体抗体库在行业内也具备显著优势。 ▲ 图2 三优生物与其他行业内企业抗体噬菌体展示库对比 ▶ 03 药物盘点与典型案例 噬菌体展示技术自实现产业化以来，已催生出一个覆盖多种疾病领域的治疗性抗体家族，噬菌体来源的抗体约占比20%，适应症涵盖了从自身免疫病到癌症的广泛适应症，并不断向双特异性抗体等创新形式拓展。 01 肿瘤治疗领域 肿瘤治疗长期面临精准性不足、耐药性频发等难题，而噬菌体展示技术凭借其强大的靶向筛选能力与多样化抗体构建优势，在该领域大放异彩，催生了从裸抗体、免疫检查点抑制剂到抗体偶联药物（ADC）、双特异性抗体的多种创新疗法。这些药物不仅能精准识别肿瘤细胞特异性抗原，阻断关键增殖或血管生成通路，还能通过激活机体自身免疫反应或直接递送毒性分子杀伤癌细胞，为不同阶段、不同类型的肿瘤患者提供了多元化治疗选择。 雷莫芦单抗（Ramucirumab）：靶向血管内皮生长因子受体2 (VEGFR2) 的全人源单克隆抗体，通过噬菌体展示技术发现。它精确阻断VEGF与受体的结合，抑制肿瘤血管生成。2014年首次获批用于晚期胃癌，后适应症扩展至非小细胞肺癌、结直肠癌、肝细胞癌等多个癌种，成为抗血管生成治疗的中坚力量。 纳武利尤单抗（Necitumumab）：全人源IgG1-κ单克隆抗体，选择性结合表皮生长因子受体（EGFR），阻断配体结合及下游信号传导，抑制癌细胞增殖、血管生成等关键过程。2015年获批与吉西他滨、顺铂联合治疗转移性鳞状非小细胞肺癌，为EGFR过表达的癌症患者提供了新的治疗选择。 阿替利珠单抗（Atezolizumab）：人源化IgG1-κ免疫检查点抑制剂，靶向PD-L1，阻断其与PD-1结合，恢复肿瘤特异性T细胞免疫力。2016年起陆续获批尿路上皮癌、非小细胞肺癌、三阴性乳腺癌等多个适应症，是癌症免疫治疗领域的重要药物，目前仍有多项临床研究在推进。 阿维鲁单抗（Avelumab）：全人源IgG1-λ免疫检查点抑制剂，靶向PD-L1，同时可能通过抗体依赖的细胞毒性（ADCC）发挥作用。2017年获批转移性默克尔细胞癌，后扩展至泌尿系结石癌、肾细胞癌等适应症，为晚期肿瘤患者提供了多元化治疗方案。 莫塞妥莫单抗（Moxetumomab pasudotox-tdfk）：重组免疫毒素，由鼠源scFv与截短的假单胞菌外毒素融合而成，靶向CD22抗原，用于治疗复发/难治性毛细胞白血病。2018年获批，是噬菌体展示技术优化抗体亲和力的典型案例，为罕见白血病患者提供了新的治疗选择。 02 自身免疫与炎症性疾病 自身免疫与炎症性疾病常伴随免疫系统紊乱，传统治疗药物往往存在疗效有限、副作用明显等问题，而这是噬菌体展示技术最早取得辉煌战绩的领域。该技术通过筛选全人源抗体，从源头降低免疫原性风险，诞生了现代医药史上的“药王”，并推动了一系列精准靶向药物的研发，彻底改变了自身免疫病的治疗格局，让无数患者摆脱了长期依赖激素、疗效不佳的困境。 阿达木单抗（Adalimumab）：首个通过噬菌体展示技术上市的全人源抗体药物，2002年获批用于类风湿关节炎。靶向肿瘤坏死因子-α（TNF-α），无需后续人源化改造，疗效与安全性俱佳。上市后成为治疗类风湿关节炎、强直性脊柱炎、银屑病等多种自身免疫病的金标准，曾连续十余年蝉联全球药品销售额榜首，2023年全球销售额仍高达约144亿美元，充分验证了该技术的巨大商业价值。 贝利尤单抗（Belimumab）：2011年获批，是首个专门用于治疗系统性红斑狼疮的生物制剂。靶向B细胞刺激因子（BLyS），通过抑制异常活跃的B细胞控制病情，证明了噬菌体展示技术能够攻克复杂、难治的自身免疫病靶点。 古塞奇尤单抗（Guselkumab）：全人源IgG1-λ单克隆抗体，靶向IL-23的p19亚基，阻断IL-23/Th17通路，抑制炎症反应。2017年获批治疗中重度斑块状银屑病，后扩展至银屑病关节炎等适应症，为自身免疫性皮肤病和关节病提供了精准治疗方案。 依奇珠单抗（Ixekizumab）：人源化IgG4-κ单克隆抗体，靶向IL-17A，抑制炎症因子介导的病理反应。2016年起陆续获批银屑病、银屑病关节炎、强直性脊柱炎等适应症，是自身免疫性疾病领域的重要药物，尤其在银屑病治疗中疗效显著。 赛立奇单抗（Serplulimab）：2024年获批，国内首个通过噬菌体展示技术自主研发并上市的全人源抗IL-17A单克隆抗体，用于治疗中重度斑块状银屑病和强直性脊柱炎。从递交上市申请到获批仅用时约17个月，体现了国内在该技术平台上全链条能力的成熟，打破了外资垄断局面。 03 感染性疾病 面对突发传染病、耐药菌感染等公共卫生挑战，传统疫苗研发周期长、抗生素滥用导致耐药性等问题日益突出，而抗体作为“被动免疫”疗法的潜力，通过噬菌体展示技术得以充分实现。该技术能快速筛选出高亲和力中和抗体，无需依赖机体主动免疫，可直接用于感染预防或治疗，尤其适用于免疫功能低下人群、突发传染病应急响应等场景，为感染性疾病防控提供了全新的高效解决方案。 瑞西巴库单抗（Raxibacumab）：全人源IgG1-λ单克隆抗体，靶向炭疽芽孢杆菌的保护性抗原（PA），中和致命毒素。2012年获批用于吸入性炭疽的预防和治疗，是应对生物恐怖主义的重要药物，彰显了噬菌体展示技术在抗感染领域的应用价值。 04 眼科疾病 眼科疾病尤其是眼底病变，因发病部位特殊、药物穿透难度大，长期缺乏有效治疗手段，许多患者面临失明风险。而噬菌体展示技术催生的抗体药物在眼科领域取得了重要突破，通过优化抗体分子大小（如Fab片段），实现了对眼底病变部位的高效穿透与精准靶向，同时兼顾安全性，为湿性年龄相关性黄斑变性、糖尿病黄斑水肿等致盲性眼病提供了有效治疗手段，显著改善了患者的视力预后。 雷珠单抗（Ranibizumab）：Fab抗体片段，靶向VEGF-A，抑制眼底新生血管生成。2006年获批治疗湿性年龄相关性黄斑变性，后扩展至糖尿病黄斑水肿、视网膜静脉阻塞等适应症，是眼科抗VEGF治疗的标杆药物，极大改善了患者视力预后。 05 血液系统疾病及其他 除了常见疾病领域，噬菌体展示技术的应用持续向更多小众、难治性疾病领域拓展。对于罕见病、血液系统疾病等“缺医少药”的领域，该技术凭借灵活的抗体格式设计（如纳米抗体）、高效的靶点筛选能力，成功突破传统研发瓶颈，为这些疾病提供了创新解决方案，让小众患者群体也能获得针对性治疗，填补了临床治疗空白。 卡普拉珠单抗（Caplacizumab）：人源化双价单可变域抗体（VHH），靶向血管性血友病因子（vWF）的A1结构域，用于治疗获得性血栓性血小板减少性紫癜。2018年获批，是首个纳米抗体类药物，体现了噬菌体展示技术在开发新型抗体格式中的灵活性。 依玛珠单抗（Emapalumab）：全人源IgG1-λ单克隆抗体，靶向IFNγ，抑制其下游信号传导，用于治疗难治性噬血细胞性淋巴组织细胞增生症。2018年获批，为罕见免疫失调疾病提供了针对性治疗方案，目前还在探索用于COVID-19等疾病的治疗。 ▶ 04 技术创新与未来趋势 噬菌体展示技术正通过与前沿科技的融合持续进化。高通量自动化平台与人工智能的深度结合正在重塑抗体发现流程。自动化系统将筛选周期大幅缩短，而人工智能则通过分析海量数据实现了从“试错筛选”到“理性设计”的范式转变，能够预测性能甚至从头设计新序列，为攻克传统难题提供了全新路径。该技术的灵活性使其成为开发双特异性抗体、抗体偶联药物等复杂疗法不可或缺的核心工具。它能有效解决多重蛋白组装中的工程挑战，加速下一代精准药物的诞生。 与此同时，技术的应用疆域也在不断拓展。超越肿瘤与自身免疫病等传统领域，研究人员正积极探索其在抗病毒、神经退行性疾病乃至更前沿方向的新治疗可能性。通过与多种创新技术的协同，这一经典平台持续焕发新的活力，有望驱动未来出现更多突破性的治疗方案。 Sanyou 10th Anniversary: From Library to Drug- A Review of Therapeutic Antibodies Derived Phage Display Technology ▶ 01 Introduction Since its advent in 1985, phage display technology has revolutionized the research and development (R&D) landscape of antibody drugs. The awarding of the 2018 Nobel Prize in Chemistry brought this "technology that makes phages work for humans" from the laboratory into the spotlight. Today, this technology has spawned a large family of therapeutic antibodies used to treat a wide range of diseases, from rheumatoid arthritis to cancer. From Humira, the first "blockbuster drug" developed based on this technology, to Serplulimab, the latest approved domestic innovative drug, phage display technology is reshaping the global landscape of antibody drug R&D. ▶ 02 Antibody Libraries: The Source of Diversity and Technological Evolution The powerful capability of phage display technology stems from its core tool-the antibody library. Based on sequence sources and construction methods, it is mainly divided into four types to meet different R&D needs. Naive library: Constructed from B cells of non-immunized healthy humans, it aims to simulate the natural antibody diversity of the human body. Its advantage lies in "broad spectrum", as it can screen against almost all antigens, but the initial antibody affinity is usually low. Immune library: Built using B cells from humans or animals immunized with specific antigens. Its strength is "precision"-the library is enriched with sequences targeting the antigen, enabling efficient screening of high-affinity antibodies, but its application scope is limited to the immunized antigen. Semi-synthetic library: Formed by combining artificially synthesized random sequences (mainly targeting the key complementarity-determining regions, CDRs) with natural antibody framework regions through genetic engineering, introducing controllable diversity on the basis of naive libraries. Synthetic library: Sequences are completely designed and chemically synthesized artificially, making it the most engineered library. It can optimize the scaffold from scratch, systematically introduce diversity, and avoid patent or immunogenicity issues associated with natural sequences.   ▲ Fig.1 Overview of the Sanyou Bio Phage Display Library Sanyou Bio has built an internationally leading "Intelligent Trillion-Level Molecule Discovery Platform", offering a diverse range of phage antibody libraries that can cover almost all antibody generation needs. Meanwhile, Sanyou Bio's AI-STAL phage antibody library holds significant advantages in the industry. ▲ Fig.2 Comparison of Antibody Phage Display Libraries Between Sanyou Bio and Enterprises in Other Industries   ▶ 03 Drug Inventory and Typical Cases Since the industrialization of phage display technology, it has nurtured a family of therapeutic antibodies covering multiple disease areas. Antibodies derived from phages account for approximately 20%, with indications ranging from autoimmune diseases to cancer, and continue to expand into innovative forms such as bispecific antibodies. 01 Tumor Therapy Tumor therapy has long faced challenges such as insufficient precision and frequent drug resistance. Phage display technology, with its powerful targeted screening capabilities and diverse antibody construction advantages, has shone brightly in this field, spawning various innovative therapies from naked antibodies and immune checkpoint inhibitors to antibody-drug conjugates (ADCs) and bispecific antibodies. These drugs can not only accurately recognize tumor-specific antigens, block key proliferation or angiogenesis pathways, but also kill cancer cells by activating the body's own immune response or directly delivering toxic molecules, providing diversified treatment options for tumor patients at different stages and with different types. Ramucirumab: A fully human monoclonal antibody targeting vascular endothelial growth factor receptor 2 (VEGFR2), discovered through phage display technology. It precisely blocks the binding of VEGF to its receptor and inhibits tumor angiogenesis. First approved for advanced gastric cancer in 2014, its indications have since expanded to non-small cell lung cancer, colorectal cancer, hepatocellular carcinoma and other cancer types, becoming a backbone of anti-angiogenic therapy.   Necitumumab: A fully human IgG1-κ monoclonal antibody that selectively binds to epidermal growth factor receptor (EGFR), blocking ligand binding and downstream signaling, thereby inhibiting key processes such as cancer cell proliferation and angiogenesis. Approved in 2015 for the treatment of metastatic squamous non-small cell lung cancer in combination with gemcitabine and cisplatin, it provides a new treatment option for cancer patients with EGFR overexpression Atezolizumab: A humanized IgG1-κ immune checkpoint inhibitor targeting PD-L1, which blocks its binding to PD-1 and restores tumor-specific T cell immunity. Since 2016, it has been successively approved for multiple indications including urothelial carcinoma, non-small cell lung cancer, and triple-negative breast cancer. It is an important drug in the field of cancer immunotherapy, with multiple clinical studies still ongoing. Avelumab: A fully human IgG1-λ immune checkpoint inhibitor targeting PD-L1, which may also exert effects through antibody-dependent cellular cytotoxicity (ADCC) . Approved for metastatic Merkel cell carcinoma in 2017, its indications later expanded to urinary tract cancer, renal cell carcinoma, etc., providing diversified treatment plans for advanced tumor patients. Moxetumomab pasudotox-tdfk: A recombinant immunotoxin composed of a murine scFv fused with a truncated Pseudomonas exotoxin, targeting CD22 antigen for the treatment of relapsed/refractory hairy cell leukemia. Approved in 2018, it is a typical case of optimizing antibody affinity using phage display technology, offering a new treatment option for patients with rare leukemia. 02 Autoimmune and Inflammatory Diseases Autoimmune and inflammatory diseases are often accompanied by immune system disorders. Traditional therapeutic drugs often have limitations such as limited efficacy and obvious side effects. This is the field where phage display technology first achieved brilliant results. By screening fully human antibodies, the technology reduces immunogenicity risks from the source, giving birth to the "blockbuster drug" in modern medical history and promoting the R&D of a series of precision-targeted drugs, which has completely changed the treatment pattern of autoimmune diseases and freed countless patients from the predicament of long-term dependence on hormones and poor efficacy. Adalimumab: The first fully human monoclonal antibody drug marketed through phage display technology, approved for rheumatoid arthritis in 2002. Targeting tumor necrosis factor-α (TNF-α), it requires no subsequent humanization modification and has excellent efficacy and safety. After its launch, it has become the gold standard for the treatment of various autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, and psoriasis. It topped the global drug sales list for more than a decade consecutively, with global sales still as high as approximately 14.4 billion US dollars in 2023, fully verifying the enormous commercial value of this technology. Belimumab: Approved in 2011, it is the first biological agent specifically used for the treatment of systemic lupus erythematosus. Targeting B cell-activating factor (BLyS), it controls the disease by inhibiting abnormally active B cells, demonstrating that phage display technology can tackle complex and intractable autoimmune disease targets. Guselkumab: A fully human IgG1-λ monoclonal antibody targeting the p19 subunit of IL-23, blocking the IL-23/Th17 pathway and inhibiting inflammatory responses. Approved for the treatment of moderate-to-severe plaque psoriasis in 2017, its indications later expanded to psoriatic arthritis, providing a precision treatment plan for autoimmune skin diseases and joint diseases. Ixekizumab: A humanized IgG4-κ monoclonal antibody targeting IL-17A, inhibiting pathological reactions mediated by inflammatory factors. Since 2016, it has been successively approved for indications such as psoriasis, psoriatic arthritis, and ankylosing spondylitis. It is an important drug in the field of autoimmune diseases, especially with significant efficacy in psoriasis treatment. Serplulimab: Approved in 2024, it is the first domestically independently developed and marketed fully human anti-IL-17A monoclonal antibody through phage display technology, used for the treatment of moderate-to-severe plaque psoriasis and ankylosing spondylitis. It took only about 17 months from the submission of the marketing application to approval, reflecting the maturity of China's full-chain capabilities on this technology platform and breaking the monopoly of foreign capital. 03 Infectious Diseases Faced with public health challenges such as emerging infectious diseases and drug-resistant bacterial infections, problems such as the long R&D cycle of traditional vaccines and drug resistance caused by antibiotic abuse have become increasingly prominent. The potential of antibodies as a "passive immunization" therapy has been fully realized through phage display technology. This technology can quickly screen high-affinity neutralizing antibodies without relying on the body's active immunity, and can be directly used for infection prevention or treatment. It is particularly suitable for scenarios such as immunocompromised populations and emergency response to emerging infectious diseases, providing a new and efficient solution for the prevention and control of infectious diseases. Raxibacumab: A fully human IgG1-λ monoclonal antibody targeting the protective antigen (PA) of Bacillus anthracis, neutralizing lethal toxins. Approved for the prevention and treatment of inhalational anthrax in 2012, it is an important drug for responding to bioterrorism, demonstrating the application value of phage display technology in the field of anti-infection. 04 Ophthalmic Diseases Ophthalmic diseases, especially fundus lesions, have long lacked effective treatment methods due to their special location and difficulty in drug penetration, putting many patients at risk of blindness. Antibody drugs derived from phage display technology have made important breakthroughs in the field of ophthalmology. By optimizing the size of antibody molecules (such as Fab fragments), they achieve efficient penetration and precise targeting of fundus lesion sites while ensuring safety. They provide effective treatment methods for blinding eye diseases such as wet age-related macular degeneration and diabetic macular edema, significantly improving patients' visual prognosis. Ranibizumab: A Fab antibody fragment targeting VEGF-A, inhibiting fundus neovascularization. Approved for the treatment of wet age-related macular degeneration in 2006, its indications later expanded to diabetic macular edema, retinal vein occlusion, etc. It is a benchmark drug for anti-VEGF therapy in ophthalmology, greatly improving patients' visual prognosis. 05 Hematological Diseases and Others In addition to common disease areas, the application of phage display technology continues to expand into more niche and intractable disease areas. For fields with "lack of medical treatment" such as rare diseases and hematological diseases, this technology has successfully broken through traditional R&D bottlenecks through flexible antibody format design (such as nanobodies) and efficient target screening capabilities, providing innovative solutions for these diseases. It enables niche patient groups to receive targeted treatment and fills the gap in clinical treatment. Caplacizumab: A humanized bivalent single variable domain antibody (VHH) targeting the A1 domain of von Willebrand factor (vWF), used for the treatment of acquired thrombotic thrombocytopenic purpura. Approved in 2018, it is the first nanobody drug, demonstrating the flexibility of phage display technology in developing new antibody formats. Emapalumab: A fully human IgG1-λ monoclonal antibody targeting IFNγ, inhibiting its downstream signaling, used for the treatment of refractory hemophagocytic lymphohistiocytosis. Approved in 2018, it provides a targeted treatment plan for rare immune disorders and is currently being explored for the treatment of diseases such as COVID-19. ▶ 04 Technological Innovation and Future Trends Phage display technology is continuously evolving through integration with cutting-edge science and technology. The in-depth integration of high-throughput automated platforms and artificial intelligence is reshaping the antibody discovery process. Automated systems have significantly shortened the screening cycle, while artificial intelligence has achieved a paradigm shift from "trial-and-error screening" to "rational design" by analyzing massive amounts of data. It can predict performance and even design new sequences from scratch, providing a new path for overcoming traditional challenges. The flexibility of this technology makes it an indispensable core tool for developing complex therapies such as bispecific antibodies and antibody-drug conjugates. It can effectively solve engineering challenges in multi-protein assembly and accelerate the birth of next-generation precision drugs. At the same time, the application scope of the technology is constantly expanding. Beyond traditional fields such as tumors and autoimmune diseases, researchers are actively exploring new therapeutic possibilities in antiviral, neurodegenerative diseases and even more cutting-edge directions. Through synergy with various innovative technologies, this classic platform continues to radiate new vitality and is expected to drive more breakthrough treatment plans in the future. ▶ Reference [1] Zhang Y. Evolution of phage display libraries for therapeutic antibody discovery. MAbs. 2023;15(1):2213793. doi:10.1080/19420862.2023.2213793 [2] Pung HS, Tye GJ, Leow CH, Ng WK, Lai NS. Generation of peptides using phage display technology for cancer diagnosis and molecular imaging. 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(2016) 127:1666–75. doi: 10.1182/blood-2015-12-684399 关于三优生物 三优生物是一家以“让天下没有难做的创新生物药”为使命，以超万亿分子库和智能科技驱动的生物医药高科技企业。 公司致力于打造全球顶尖的原创新药创新工场。公司以智能超万亿分子库（AI-STAL）为核心；以干湿结合、国际领先的创新生物药智能化及一体化研发平台为依托；以多样化的业务模式推动全球创新药物的研发及产业化。 公司总部位于中国上海，在亚洲、北美洲、欧洲等多地建立了业务中心，形成了全球化的业务网络，现有投产及布局的研发及GMP场地20000多平方米。 公司已与全球2000多家药企、生技公司等建立了良好的合作关系，已赋能1200多个新药研发项目；已完成50多个合作研发项目，其中10多个协同研发项目已推至IND及临床研发阶段。 公司已申请130多项发明专利，其中30多项发明专利已获得授权，并获得了国家级高新技术企业、上海市专精特新、ISO9001、ISO27001等10余项资质及体系认证。 推荐阅读 三优十周年｜平台篇-抗体工程平台 三优十周年｜平台篇-体外药效平台 特应性皮炎：从免疫紊乱到精准靶向的治疗革命 三优十周年｜抗衰老-从长生神药到系统与精准干预 战略跃迁｜打造全球顶尖的原创新药创新工场 三优十周年｜恶病质的代谢紊乱与靶向药物的研发态势 三优十周年｜中国药企撬动千亿美元赛道 三优十周年｜平台篇-创新抗体产生平台 三优十周年｜眼科治疗前沿：用抗体药物精准点亮未来 三优十周年｜磁阵列全人源小鼠抗体发现平台 三优十周年｜新“药王”加冕：减重增肌 三优十周年｜抗体药物如何实现精准“狙击”炎症？ 三优十周年｜血液肿瘤治疗革命-精准分层治疗新时代 三优十周年｜抗体药免疫原性全方位解析 三优十周年｜肿瘤免疫2025及2018双诺奖解析 三优十周年｜TCE药物-重塑免疫治疗版图的新力量