Belimumab

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. Mol Biol Rep. 2023;50(5):4653-4664. doi:10.1007/s11033-023-08380-x [3] França RKA, Studart IC, Bezerra MRL, et al. Progress on Phage Display Technology: Tailoring Antibodies for Cancer Immunotherapy. Viruses. 2023;15(9):1903. Published 2023 Sep 9. doi:10.3390/v15091903 [4] Jahandar-Lashaki S, Farajnia S, Faraji-Barhagh A, Hosseini Z, Bakhtiyari N, Rahbarnia L. Phage Display as a Medium for Target Therapy Based Drug Discovery, Review and Update. Mol Biotechnol. 2025;67(6):2161-2184. doi:10.1007/s12033-024-01195-6 [5] Cappuyns S, Corbett V, Yarchoan M, Finn RS, Llovet JM. Critical Appraisal of Guideline Recommendations on Systemic Therapies for Advanced Hepatocellular Carcinoma: A Review. JAMA Oncol. 2024;10(3):395-404. doi:10.1001/jamaoncol.2023.2677 [6] Poole RM, Vaidya A. Ramucirumab: first global approval. Drugs. (2014) 74:1047–58. doi: 10.1007/s40265-014-0244-2 [7] Fala L. Portrazza (Necitumumab), an IgG1 monoclonal antibody, FDA approved for advanced squamous non-small-cell lung cancer. Am Health Drug Benefits. (2016) 9:119–22. [8] Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. (2016) 387:1837–46. doi: 10.1016/S0140-6736(16)00587-0 [9] Boyerinas B, Jochems C, Fantini M, Heery CR, Gulley JL, Tsang KY, et al. Antibody-dependent cellular cytotoxicity activity of a novel anti–PD-L1 antibody avelumab (MSB0010718C) on human tumor cells. Cancer Immunol Res. (2015) 3:1148–57. doi: 10.1158/2326-6066.CIR-15-0059 [10] Nobre CF, Newman MJ, DeLisa A, Newman P. Moxetumomab pasudotox-tdfk for relapsed/refractory hairy cell leukemia: a review of clinical considerations. Cancer Chemother Pharmacol. (2019) 84:255–63. doi: 10.1007/s00280-019-03875-6 [11] Jespers LS, Roberts A, Mahler SM, Winter G, Hoogenboom HR. Guiding the selection of human antibodies from phage display repertoires to a single epitope of an antigen. Biotechnology. (1994) 12:899–903. doi: 10.1038/nbt0994-899 [12] Blair HA, Duggan ST. Belimumab: a review in systemic lupus erythematosus. Drugs. (2018) 78:355–66. doi: 10.1007/s40265-018-0872-z [13] Nogueira M, Torres T. Guselkumab for the treatment of psoriasis–evidence to date. Drugs Context. (2019) 8:212594. doi: 10.7573/dic.212594 [14] Liu L, Lu J, Allan BW, Tang Y, Tetreault J, Chow CK, et al. Generation and characterization of ixekizumab, a humanized monoclonal antibody that neutralizes interleukin-17A. J Inflamm Res. (2016) 9:39–50. doi: 10.2147/JIR.S100940 [15] Shen P, Zhang T, Hao L, et al. Efficacy and safety of serplulimab in solid tumors: a meta-analysis[J]. Frontiers in Pharmacology, 2025, 16: 1604874. [16] Kummerfeldt CE. Raxibacumab: potential role in the treatment of inhalational anthrax. Infect Drug Resist. (2014) 7:101–9. doi: 10.2147/IDR.S47305 [17] Papadopoulos N, Martin J, Ruan Q, Rafique A, Rosconi MP, Shi E, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis. (2012) 15:171–85. doi: 10.1007/s10456-011-9249-6 [18] Ulrichts H, Silence K, Schoolmeester A, de Jaegere P, Rossenu S, Roodt J, et al. Antithrombotic drug candidate ALX-0081 shows superior preclinical efficacy and safety compared with currently marketed antiplatelet drugs. Blood. (2011) 118:757. doi: 10.1182/blood-2010-11-317859 [19] Das R, Guan P, Sprague L, Verbist K, Tedrick P, An QA, et al. Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis. Blood. (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

点击“风与湿说”关注我们 “狼疮10年存活率超90%”——这个被国内外风湿免疫病指南证实的客观数据，却常常被网络上的“致命谣言”彻底淹没。 临床中，太多狼疮患者拿着手机走进诊室，眼神里满是惶恐：“主任，网上说这病会肾衰竭、会脑梗，是真的吗？”“长期吃激素，副作用会不会比病本身还可怕？” 网络上的碎片化信息杂乱无章，又多是放大风险的谣言，把原本可控的病情渲染得触目惊心，也让患者的焦虑越积越深。作为一名深耕风湿免疫领域多年的医生，我想先给大家吃颗“定心丸”：狼疮绝非不治之症，无需被谣言裹挟恐慌。 真正让人忧心的致命风险，并非来自疾病本身，而是藏在病情背后、易被忽视的六大“隐形杀手”，今天我们就从风险识别到科学避险层层拆解，帮大家把健康主动权牢牢握在手里。 头号杀手：感染（占狼疮死亡40%，首当其冲） 狼疮患者的免疫系统，会发生“识别错误”——它不抓外来的 “小偷”（细菌、病毒），反而攻击自身组织。再加上长期使用激素、免疫抑制剂压制免疫，身体如同大门敞开的房屋，病菌能轻易闯入，感染风险远超普通人。 据国内多中心临床研究数据显示，感染是导致狼疮患者死亡的首要原因，占比高达 40%。 高危场景 1.大剂量激素冲击治疗期间：免疫被强效压制，是感染 “高危窗口期”； 2.冬春流感季、换季肺炎高发期：病菌活跃，免疫力弱的人易中招； 3.术后伤口愈合阶段或皮肤黏膜破损时：伤口是病菌入侵的 “小缺口”。 保命指南 1.疫苗优先接种：病情稳定期打齐流感、肺炎疫苗，女性按需接种 HPV 疫苗，为身体 “加装防护网”； 2.主动避开病菌源：少去菜市场、医院输液室等密集场所，外出戴口罩、勤洗手； 3.警惕感染信号：体温超 38℃，伴随咳嗽、尿痛、腹泻等症状，立即联系医生查血排查，切勿硬扛。 4.机会性感染预防：大剂量激素联合环磷酰胺、吗替麦考酚酯等免疫抑制剂治疗的患者，需遵医嘱常规服用复方磺胺甲恶唑，预防卡氏肺孢子虫肺炎 —— 这是降低重症感染死亡率的关键。 二号杀手：肾衰竭（狼疮性肾炎，半数患者中招） 约 50% 的系统性红斑狼疮患者会并发狼疮性肾炎，这是狼疮攻击肾脏的直接体现。狼疮性肾炎，就是免疫复合物沉积在肾脏，导致过滤功能受损。若早期未干预，病情会逐步进展，最终 “过滤器” 彻底失灵，发展为尿毒症，只能靠透析或肾移植维持生命。 早期信号 1.尿液泡沫增多，呈啤酒沫状，静置 15 分钟不散：提示出现蛋白尿，肾脏过滤功能下降； 2.脚踝、眼睑莫名浮肿，按压后凹陷不易恢复：肾脏排水能力变差，水分潴留； 3.年轻人突发血压升高且无家族病史：肾脏受损影响血压调节，是肾炎的隐藏信号。 保命指南 1.定期复查不松懈：每月查尿常规（监测蛋白尿）、血肌酐（反映排毒功能），每 3~6 个月查 24 小时尿蛋白定量，早发现异常早处理； 2.严格控盐护肾：每日食盐摄入量控制在 5 克以内（约一啤酒瓶盖），减轻肾脏负担； 3.规范用药是关键：羟氯喹需长期服用，吗替麦考酚酯等免疫抑制剂遵医嘱调整剂量，不可擅自停药。 4.血压管理核心：狼疮性肾炎患者血压需严格控制在 130/80mmHg 以下，优先选用缬沙坦、贝那普利等 ACEI/ARB 类药物，既能降压又能减少尿蛋白、延缓肾损伤； 5.尿蛋白分级管理：24 小时尿蛋白＞1g 的患者需强化免疫抑制治疗，＜0.5g 则以维持治疗为主。 三号杀手：心脑血管事件（心梗/脑梗，沉默的加速器） 狼疮患者受慢性炎症和激素影响，动脉粥样硬化发生率是普通人群的 2~3 倍，且发病年龄提前 10~15 年。核心原因有两点：一是长期炎症像 “砂纸”，反复磨损血管内壁；二是激素治疗可能导致血脂、血糖升高，给血管 “添堵”。两者叠加加速动脉粥样硬化，进而诱发心梗、脑梗。 高危人群 1.长期使用激素超过5年者； 2.合并高血压、糖尿病、高血脂等基础病者； 3.吸烟、肥胖或缺乏运动的患者。 保命指南 血管保养三件套，缺一不可： 1.每年查一次颈动脉超声：颈动脉是全身血管的 “窗口”，排查斑块，早干预避免脱落引发心梗、脑梗；合并动脉粥样硬化的患者，低密度脂蛋白胆固醇需控制在 1.8mmol/L 以下； 2.坚持低油低糖低脂饮食：戒掉奶茶、炸鸡等高热量食物，减少血管 “垃圾” 堆积； 3.适度运动：每天快走 30 分钟，或选择太极、瑜伽，改善血液循环，比单纯吃药更有效。 4.抗血小板治疗：颈动脉斑块＞1.5mm 或有缺血症状的患者，需在医生评估后使用阿司匹林。 四号杀手：神经精神狼疮（大脑失控，危机四伏） 这种并发症，本质是免疫系统 “误攻” 大脑和神经，累及中枢或周围神经系统，症状复杂易混淆。一旦救治不及时，不仅可能留下永久性神经损伤，还会直接危及生命。 危险症状 1.重症表现：癫痫发作（突然抽搐、口吐白沫、意识丧失）；精神异常（出现幻觉、妄想、情绪极端，甚至有自杀倾向，易被误判为精神疾病）；脑血管病变（突发剧烈头痛、呕吐、半身麻木、视物模糊，可能是脑梗或脑出血信号）； 2.轻症预警信号：持续性头痛、记忆力下降、手脚麻木、注意力难以集中 —— 这些是早期干预的关键时机。 保命指南 出现以下情况，立即急诊就医： 1.剧烈头痛伴随喷射性呕吐：警惕脑炎或颅内高压； 2.短时间内性格大变、胡言乱语：排除精神因素后，优先考虑神经精神狼疮发作； 3.单侧手脚无力、言语不清、视物重影：可能是脑血管受累，拖延会加重神经损伤。 4.诊断核心依据：需结合脑脊液检查、头颅 MRI、抗神经元抗体检测，避免仅凭症状自行判断延误治疗。 五号杀手：疾病大爆发（炎症风暴，死亡率超50%） 狼疮 “炎症风暴”，就是免疫系统突然 “失控暴走”，不分敌我攻击全身多器官，导致肺、心、肝、肾等脏器同时受损衰竭。如果没及时启动强化治疗，这种情况的死亡率超 50%，且绝大多数由患者人为不当操作或外界诱因诱发。 诱发风暴行为 1.擅自停用或减用激素、免疫抑制剂：这些药物是控制免疫的 “关键武器”，擅自调整会让病情瞬间反弹； 2.轻信偏方、保健品 “排毒根治”：不仅无效，还会干扰规范治疗，加重脏器负担； 3.无计划怀孕且孕期不监测病情：孕期激素水平波动大，极易诱发炎症风暴，危及母婴安全。 4.临床常见诱因：感染（如 EB 病毒、流感病毒）、暴晒、过度劳累 —— 这三点是诱发病情爆发的 “头号元凶”，必须重点规避。 保命指南 1.坚守治疗底线：羟氯喹等对胎儿安全的药物，孕期不可停用，孕期擅自停药，病情复发率会飙升 70%； 2.计划性怀孕：抗 SSA/SSB 抗体阳性患者，需病情稳定半年以上，经风湿科与产科医生联合评估后再备孕，全程严格随访。 六号杀手：药物副作用（双刃剑，需要科学应对） 狼疮治疗需长期依靠药物维持，激素、免疫抑制剂是控制病情的核心，难免伴随一些副作用，这就像治疗的 “附加成本”。不过无需恐慌，只要科学应对、定期监测，就能把风险降到最低。如今贝利尤单抗、泰它西普等生物制剂已广泛用于临床，副作用更小、疗效更确切，为患者提供了新的治疗选择。 常见药物风险 1.激素：长期服用可能诱发胃出血、骨质疏松、股骨头坏死、血糖升高、眼压升高、电解质紊乱（低钾、低钙）； 2.免疫抑制剂：不同药物副作用不同 —— 环磷酰胺可能导致出血性膀胱炎，甲氨蝶呤可能引发口腔黏膜溃疡，吗替麦考酚酯可能损伤肝功能或引发血液毒性（如白细胞减少）。 保命指南 用药防护三件套，必备！ 1.搭配护胃药：服用激素期间，遵医嘱联用瑞巴派特、奥美拉唑等，给胃黏膜 “穿层防护衣”； 2.补充骨营养：每日服用钙片 + 维生素 D，定期查骨密度，预防骨质疏松； 3.定期监测指标：每 3 个月复查肝肾功能、血常规、尿常规及补体 C3、C4，根据指标调整用药方案。 4.针对性监测：使用环磷酰胺的患者需多喝水，定期查膀胱超声；使用甲氨蝶呤的患者需注意口腔护理，出现溃疡及时告知医生。 最后总结：狼疮可控，细节定成败 狼疮患者真正的敌人，从来不是疾病本身，而是不重视规范治疗、忽视细节管理的侥幸心态。从精准识别风险信号，到做好日常防护，再到坚守治疗底线，每一步都在为健康筑牢防线。 想要规避风险、长期安稳生活，记住这三点就够了： 1.医疗管理：锁定风湿免疫科专科医生，拒绝 “根治偏方”，规律复查调整方案； 2.生活管理：严格防晒，低油低盐饮食，适度运动，避免感染、劳累； 3.自我监测：牢记异常信号（泡沫尿、浮肿、头痛等），定期复查血常规、尿常规、补体 C3/C4 及抗 dsDNA 抗体 —— 这比美容打卡更重要。 狼疮从不是绝症，而是一场需要耐心与科学方法的 “健康持久战”。只要牢牢守住科学防护底线、做好日常细节管理，就能有效规避这些致命风险，正常生活、工作、生育，拥抱安稳未来。 如果您或家人朋友受到狼疮、干燥综合征、类风湿关节炎等其他风湿免疫疾病的问题，可长按下方二维码进行咨询。 风湿免疫指导 守护你的健康