封面解读

周  凌  /徐沪济

Ankylosing spondylitis (AS) is a chronic inflammatory disease affecting the sacroiliac joints and spine, causing pain, stiffness, and long-term functional impairment. Despite advances in biologic therapy, many patients still suffer from inadequate disease control. XKH004, China’s first domestically developed humanized IgG1 monoclonal antibody targeting IL-17A/F, and only the second worldwide against this target to reach the Biologics License Application (BLA) stage, presents a promising therapeutic advance. In a 52-week phase 3 trial, XKH004 demonstrated rapid and durable efficacy. The primary endpoint, an ASAS40 response at week 16, was achieved by 45.4% of patients receiving XKH004 compared to 19.4% on placebo. Efficacy sustained and deepened over time, reaching 66.2% by week 52. Robust improvements in disease activity, physical function, and quality of life were maintained throughout the trial, including among patients with prior TNF inhibitor failure. Through potent dual IL-17A/F blockade, XKH004 overcomes persistent inflammation to help restore mobility, function, and hope.

All Papers

1. Pseudomonas aeruginosa: From acute virulence to chronic persistence—mechanisms and therapeutic implications

通信作者：周西坤

Pseudomonas aeruginosa frequently causes nosocomial infections. Its capacity to evolve from an acute infection characterized by rapid tissue damage to a persistent chronic infection that is difficult to eradicate leads to reduced antibiotic efficacy, disease deterioration, and poor prognosis. This review dissect two major driving forces—intrinsic regulatory networks and adaptive evolution—define the central role of biofilms, and explore therapeutic implications. Future studies should further elucidate the dynamic crosstalk among the core regulatory systems within the host microenvironment and develop intervention strategies targeting key nodes in the acute-to-chronic transition.

引用：

Zhu H, Zhao H, Li J, et al. Pseudomonas aeruginosa: From acute virulence to chronic persistence—mechanisms and therapeutic implications. hLife 2026; 4: 601–632.

2. Why do promising preclinical drugs fail in clinical trials? From a trade-off framework to higher-fidelity models

通信作者：张亚平

Drug development is a high-risk marathon measured in decades. The principal bottleneck in pharmaceutical research and development has thus shifted from molecular discovery to clinical validation. The reasons are complex, spanning target selection, trial design, patient stratification, and commercial factors, but a key contributor is the limited ability of current preclinical systems to predict a drug's ultimate clinical value. This perspective propose that breaking this deadlock depends not on blindly raising screening throughput, but on developing evaluation systems that test safety, efficacy, and generalizability together. By prioritizing generalizability and human-relevant physiology and by cross-validating findings across complementary models, the catastrophic costs of failure can be shifted from thousands of trial participants to a controllable preclinical stage.

引用：

Zhou BW, Jin DJ, Zhang YP, Why do promising preclinical drugs fail in clinical trials? From a trade-off framework to higher-fidelity models. hLife 2026; 4: 633–636.

3. Integrating new approach methodologies into human-relevant preclinical research

通信作者：刘海鹰、司龙龙

Animal models have long underpinned preclinical research, yet their limited ability to predict human outcomes remains a persistent bottleneck in drug development. Recent advances in organoids and organ-on-chip systems offer new opportunities to model human physiology with improved fidelity to human physiology. This paper note that the field is undergoing a conceptual shift, from attempts to replace animal models toward strategies that integrate multiple model systems within context-of-use-driven translational frameworks. Rather than competing alternatives, animal models, organoids, organ-on-chip systems, and emerging computational approaches capture complementary dimensions of biological complexity, human relevance, and experimental control.

引用：

Tong L, Zhao H, Baldran-Groves L, et al. Integrating new approach methodologies into human-relevant preclinical research. hLife 2026; 4: 637–641.

4. Efficacy and safety of XKH004, a novel dual interleukin-17A/F inhibitory monoclonal antibody, in active ankylosing spondylitis: A 52-week phase 3 randomized study

hLife | 强直性脊柱炎治疗迎来“双靶点”时代？上海长征医院徐沪济团队证实国产IL-17A/F双靶点抗体XKH004，长期疗效与安全性双达标

通信作者：徐沪济

强直性脊柱炎是一种慢性免疫介导的炎症性疾病，主要侵犯骶髂关节和脊柱，常导致患者出现顽固性炎性腰背痛、脊柱僵硬及活动受限，严重影响生活质量。目前，以肿瘤坏死因子抑制剂为代表的生物制剂虽已大幅改善患者预后，但临床中仍有部分患者应答不佳或无法耐受，治疗缺口依然显著。针对这一现状，研发机制更新、疗效更优的靶向药物成为迫切需求。IL-17A与IL-17F作为关键的协同促炎因子，是极具潜力的治疗靶点。通过双靶点抑制策略，有望实现对炎症通路的更全面阻断，但其长期获益与安全性尚待高质量临床研究进一步证实。本研究系统评价了我国自主研发的人源化抗IL-17A/F IgG1单克隆抗体XKH004治疗活动性AS患者的长期疗效和安全性，为探索通过双靶点IL-17A/F抑制破解临床难治性AS治疗难题提供了关键依据。

引用：

Zhou L, Yan R, Ye S, et al. Efficacy and safety of XKH004, a novel dual interleukin-17A/F inhibitory monoclonal antibody, in active ankylosing spondylitis: A 52-week phase 3 randomized study. hLife 2026; 4: 642–657.

5. LARGE: A large language model-based tool that unveils high-resolution temporal dynamics of the antibiotic resistome during human aging

hLife | AI新工具LARGE：高分辨率看清肠道耐药基因随衰老的动态变化

通信作者：陈裕明、李子青、郑钜圣

抗生素耐药是当今全球公共卫生面临的重大挑战之一。人体肠道中定植着数以万亿计的细菌，其中许多携带抗生素耐药基因，这些基因共同构成了“肠道耐药组”。耐药基因可以在细菌之间转移，增加感染治疗的难度，也可能影响宿主的长期健康。然而，以往的研究工具多依赖已知耐药序列数据库，既难以识别全新的耐药基因，也难以在菌种水平上追踪其变化。人类衰老过程中，肠道耐药组究竟如何动态演变，一直是悬而未决的问题。本研究开发了LARGE（language model-based antibiotic resistance gene explorer），一种基于大语言模型的耐药基因检测工具，并首次将其运用于衰老人群队列，揭示了衰老人群的肠道耐药图谱。本研究首次在大样本人群层面揭示了人类衰老过程中肠道耐药组的动态变化规律，为理解“肠道菌群—耐药组—衰老相关疾病”之间的联系提供了新视角。LARGE的在线平台、注释数据与源代码均已公开，研究者无需编程或高性能计算背景，即可直接上传微生物数据完成耐药组分析。LARGE提供免费的在线平台（https://large.lab.westlake.edu.cn），无需本地安装即可在线运行，所有注释数据公开，源代码开源（https://github.com/hehang0618/LARGE），大幅降低了耐药组监测的技术门槛。未来，研究将进一步扩展至更多环境与更大规模、更多样化的人群，并探索饮食、益生菌等干预措施能否重塑肠道耐药组，从而促进健康衰老。

引用：

He H, Duan C, Deng K, et al. LARGE: A large language model-based tool that unveils high-resolution temporal dynamics of the antibiotic resistome during human aging. hLife 2026; 4: 658–677.

6. Rationally designed common-light-chain anti-EGFR/c-MET bispecific antibody ALK101 demonstrates potent, broad-spectrum antitumor activity

hLife | 理性设计“一轻链双靶”：新型双特异性抗体展现广谱抗肿瘤活性

通信作者：冯辉、严景华、李理

表皮生长因子受体酪氨酸激酶抑制剂（TKI）已成为携带EGFR激活突变的非小细胞肺癌（NSCLC）的标准治疗方案，第三代药物（如奥希替尼）进一步改善了临床疗效。然而，获得性耐药几乎不可避免，其中MET基因扩增是最主要的旁路耐药机制，可重新激活下游PI3K/AKT和MAPK信号通路，使EGFR抑制失效。临床前研究证实，同时靶向EGFR和c-MET的双特异性抗体（BsAb）优于两种单抗联用；全球首个获批的EGFR×c-MET双抗Amivantamab在多项临床试验中验证了这一治疗范式。不过，双抗的人工构建长期受制于轻链错配等制造难题，共享轻链（CLC）策略虽能显著简化生产，但其开发仍主要依赖大规模噬菌体展示库筛选或转基因小鼠平台，周期长、投入大。本研究建立了一套基于结构指导的理性设计方法，可在轻链直接参与抗原识别的普遍情况下，直接从已有单克隆抗体快速构建共享轻链双特异性抗体，并由此获得候选分子ALK101。本研究建立了无需大规模经验性筛选、具有普适性的共享轻链双抗理性设计框架，可显著加速双特异性抗体的开发进程；由此获得的ALK101具备与已获批标杆药物相当的体内外活性与良好的初步成药性，为克服EGFR-TKI耐药的肺癌患者提供了新的候选治疗方案。需要指出的是，ALK101的疗效与安全性目前仅在异种移植瘤模型和临床前研究中得到评估，其临床治疗潜力仍有待人体试验验证。

引用：

Jiang L, Han X, He H, et al. Rationally designed common-light-chain anti-EGFR/c-MET bispecific antibody ALK101 demonstrates potent, broad-spectrum antitumor activity. hLife 2026 ; 4: 678–682.

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