Pamvatamig

摘要：肺癌作为全球癌症相关死亡的首要原因，始终是人类健康的重大威胁，其中非小细胞肺癌（NSCLC）占比近 85%。尽管免疫检查点抑制剂（ICIs）等免疫疗法显著提升了肺癌治疗效果，但仍有大量患者对免疫治疗不敏感，且初始响应患者易快速出现获得性耐药。双特异性抗体（bsAbs）能够同时结合两种不同抗原或表位，在增强抗肿瘤疗效的同时兼具良好安全性，成为新型抗肿瘤疗法的研究热点。目前，除已获批的阿米万他单抗（amivantamab）外，KN046、AK112、SHR-1701 三种新型双特异性抗体正处于 Ⅲ 期临床试验阶段，另有众多双特异性抗体处于Ⅰ/Ⅱ 期临床试验。本文将从双特异性抗体的结构、分类、作用机制入手，详细介绍其在非小细胞肺癌治疗中的相关临床试验，并探讨当前面临的挑战、潜在解决方案及未来展望，为临床医生和科研人员提供全面参考。 一、非小细胞肺癌治疗现状与双特异性抗体的崛起 肺癌是全球癌症死亡的 “头号杀手”，而非小细胞肺癌（NSCLC）作为肺癌最主要的亚型，约占所有肺癌病例的 85%。过去 decade，靶向治疗和免疫治疗的出现极大改善了非小细胞肺癌患者的预后，但临床中仍面临两大关键问题：一是治疗耐药，许多患者在接受酪氨酸激酶抑制剂（TKI）靶向治疗或免疫检查点抑制剂（ICIs）治疗后，会逐渐出现耐药现象，导致治疗失败；二是患者响应率低，仅有少数患者能从现有治疗中获得持久获益，大量患者对治疗无响应或响应时间短暂。 在此背景下，双特异性抗体（bsAbs）应运而生。早在 20 世纪 60 年代，Nisonoff 首次提出双特异性抗体的概念，将其定义为能同时结合两种不同抗原或表位的抗体。与传统单克隆抗体（mAb）相比，双特异性抗体凭借独特的 “双靶向” 能力，可精准作用于肿瘤微环境（TME）中的关键靶点，既能增强抗肿瘤效应，又能减少单一靶点治疗带来的耐药风险，为非小细胞肺癌治疗开辟了新路径。 2021 年 5 月 21 日，阿米万他单抗（amivantamab）在美国首次获批，用于治疗接受含铂化疗后进展的局部晚期或转移性 EGFR 外显子 20 插入突变的非小细胞肺癌成人患者。这一里程碑事件标志着双特异性抗体正式进入非小细胞肺癌临床治疗领域。根据 ClinicalTrials.gov 数据，目前已有数十种双特异性抗体处于非小细胞肺癌相关临床试验阶段，涵盖不同靶点组合与治疗策略，展现出广阔的应用前景。二、双特异性抗体的生产与分类（一）双特异性抗体的生产技术演进 双特异性抗体的生产技术历经数十年发展，主要经历了杂交瘤技术、化学重组技术和基因工程技术三个阶段，各阶段技术特点与局限性各异： 图 1 双特异性抗体的发展历史图谱 杂交瘤技术：早期双特异性抗体主要通过杂交瘤技术构建，该技术将产生两种不同单克隆抗体的杂交瘤细胞（杂交瘤 A 产生 mAb A，杂交瘤 B 产生 mAb B）进行体细胞融合，形成四源杂交瘤细胞（quadroma），进而分泌双特异性抗体。然而，这种方法存在明显缺陷：一方面，两种重链和轻链的随机配对会产生 10 种可能的分子构型，其中仅 1 种为功能性双特异性抗体，导致目标抗体产量极低；另一方面，重链与轻链的错误组装易引发免疫副作用，限制其临床应用（图 2A）。 化学重组技术：化学重组技术通过酶解将两种不同单克隆抗体拆解为片段，再利用化学交联剂（如双砜交联剂、双马来酰亚胺等）将片段重新连接，形成双特异性抗体。早期化学重组技术常导致抗体失活、解折叠或聚集，但随着生物偶联技术和点击化学技术的发展，该技术在双特异性抗体 - 药物偶联物（bsADCs）的构建中展现出优势，可实现更高产量、更稳定均一的双特异性抗体制备（图 2B）。 基因工程技术：随着基因工程技术的快速发展，其凭借能降低抗体免疫原性、提高耐受性、增强特异性活性（如改善抗原亲和力、调节药代动力学、优化效应功能）等优势，成为当前双特异性抗体制备的主流技术。基因重组和蛋白质工程是构建双特异性抗体的主要基因工程技术，通过对抗体基因进行改造和重组，可在不同平台上构建出多样化的双特异性抗体。目前，已获批或处于临床试验阶段的双特异性抗体，绝大多数通过基因工程技术构建（图 2C）。 图 2 双特异性抗体制备的三种策略（A）杂交瘤细胞融合构建双特异性抗体：产生 mAb A 的杂交瘤 A 与产生 mAb B 的杂交瘤 B 融合，形成分泌双特异性抗体的四源杂交瘤细胞；（B）化学偶联构建双特异性抗体：通过酶解获得两种单克隆抗体片段，再利用化学交联剂连接形成双特异性抗体；（C）基因工程构建双特异性抗体：通过基因重组和蛋白质工程技术，将两种单克隆抗体片段在不同平台重组，构建出对称 IgG 亚型、不对称 IgG 亚型和非 IgG 亚型双特异性抗体。（二）双特异性抗体的结构分类 根据是否含有 Fc 片段，双特异性抗体可分为IgG 样双特异性抗体和非 IgG 样双特异性抗体两大类，二者在结构、特性和功能上存在显著差异： IgG 样双特异性抗体：以完整 IgG 结构为基础，含有 Fc 片段，因此具有更好的溶解性、稳定性和更长的半衰期。同时，Fc 片段可介导抗体依赖的细胞毒性（ADCC）、补体依赖的细胞毒性（CDC）和抗体依赖的细胞吞噬作用（ADCP），进一步增强肿瘤杀伤效果。根据结构对称性，IgG 样双特异性抗体又可分为对称型和不对称型，其中不对称型占绝大多数。常见的 IgG 样双特异性抗体构建平台包括 CrossMab、Knobs-into-Holes（KiH，洞 - 入 - 栓）、Triomab 四源杂交瘤、DuoBody、双可变域免疫球蛋白（DVD-Ig）等（表 1）。 非 IgG 样双特异性抗体：以单链可变片段（scFv）为基础，不含 Fc 片段，具有分子量小、组织穿透性强的优势，但同时存在半衰期短、结构不稳定、表达量低的缺陷。常见的非 IgG 样双特异性抗体构建平台包括双亲和重定向蛋白（DART）、双特异性 T 细胞衔接器（BiTE）、串联双抗体（TandAbs）、双纳米抗体（bi-Nanobody）等（表 1）。 表 1 不同平台双特异性抗体的特性及相关临床抗体 三、双特异性抗体在非小细胞肺癌中的作用机制 双特异性抗体通过多样化的作用机制发挥抗肿瘤效应，根据治疗策略可分为免疫治疗型双特异性抗体和靶向治疗型双特异性抗体两大类，不同类型抗体的作用机制各有侧重（图 3）。 图 3 本文综述框架图免疫治疗型双特异性抗体包括结合双免疫调节分子（如 PD-(L) 1×CTLA-4、PD-(L) 1×TIM-3 等）、连接免疫细胞与肿瘤细胞（如 CD3×EpCAM、CD3×CEA 等）的抗体；靶向治疗型双特异性抗体包括阻断双信号通路（如 EGFR×c-MET、HER2×HER3 等）的抗体及双特异性抗体 - 药物偶联物（bsADCs）；此外，双特异性抗体还可与化疗、靶向治疗、免疫治疗联合应用（一）免疫治疗型双特异性抗体：重塑肿瘤免疫微环境 免疫治疗型双特异性抗体主要通过调节肿瘤免疫微环境、激活抗肿瘤免疫反应发挥作用，具体包括以下两种机制： 结合双免疫调节分子，恢复 T 细胞活性：肿瘤细胞可通过上调免疫检查点分子（如 PD-1/PD-L1、CTLA-4、TIM-3、LAG-3 等）逃避免疫系统攻击。免疫检查点抑制剂（ICIs）虽能阻断单一检查点通路，但响应率仅约 20%，且易引发耐药。双特异性抗体可同时结合两种免疫调节分子，一方面增强免疫抑制通路阻断效果，另一方面减少单一药物联合使用带来的毒性（图 4A）。 常见的靶点组合包括： PD-(L)1×CTLA-4：PD-1/PD-L1 通路可抑制 T 细胞活性，CTLA-4 通路可竞争性结合 CD80/CD86 分子抑制 T 细胞激活，二者在肿瘤浸润淋巴细胞（TILs）中常共表达。KN046（PD-L1×CTLA-4）、AK104（PD-1×CTLA-4）等双特异性抗体，可同时阻断两条通路，在增强抗肿瘤效应的同时，降低传统 ICIs 联合治疗的毒性。例如，AK104 治疗非小细胞肺癌的 Ⅲ 级及以上治疗相关不良事件（TRAEs）发生率仅 11.3%，远低于纳武利尤单抗（抗 PD-1）联合伊匹木单抗（抗 CTLA-4）的 34.0%。 PD-(L)1×TIM-3：TIM-3 是耗竭 CD8+T 细胞的标志物，在抗 PD-1 治疗耐药患者中表达上调。AZD7789（PD-1×TIM-3）可同时阻断 PD-1 和 TIM-3 通路，在临床前模型中实现肿瘤消退，为抗 PD-1 耐药患者提供新选择。 PD-(L)1×LAG-3：LAG-3 在 41.5% 的非小细胞肺癌患者 TILs 中表达，可增强调节性 T 细胞（Tregs）的抑制功能、抑制 CD8 + 效应 T 细胞功能。MGD013（PD-1×LAG-3）可恢复耗竭 T 细胞功能，其治疗非小细胞肺癌的 Ⅲ 级及以上 TRAEs 发生率为 18%，安全性良好。 此外，双特异性抗体还可结合免疫检查点与非检查点分子（如 PD-(L) 1×VEGF、PD-(L) 1×TGF-β）。例如，AK112（PD-1×VEGF）可同时阻断 PD-1 通路（激活免疫）和 VEGF 通路（抑制肿瘤血管生成），在 Ⅲ 期临床试验中，其治疗 PD-L1 阳性晚期非小细胞肺癌的客观缓解率（ORR）达 50%，中位无进展生存期（mPFS）达 11.14 个月，显著优于帕博利珠单抗（ORR 38.5%，mPFS 5.82 个月）。 连接免疫细胞与肿瘤细胞，定向杀伤肿瘤：此类双特异性抗体可同时结合 T 细胞表面的 CD3 分子和肿瘤细胞表面的肿瘤相关抗原（TAAs）/ 肿瘤特异性抗原（TSAs），将 T 细胞重定向至肿瘤细胞表面，激活 T 细胞并形成免疫突触，促使 T 细胞释放穿孔素和颗粒酶，最终实现肿瘤细胞裂解（图 4B，图表来源：原文 Figure 4）。由于其作用不依赖于 MHCⅠ 类分子表达，可克服肿瘤因 MHCⅠ 类分子丢失导致的免疫逃逸。 常见的靶点组合包括： CD3×EpCAM：EpCAM 在 86.5% 的非小细胞肺癌患者中表达，可促进肿瘤细胞增殖。卡妥索单抗（Catumaxomab，CD3×EpCAM）是首个获批的双特异性抗体，虽因商业原因退市，但为后续 CD3×TAAs 类双特异性抗体研发奠定基础。 CD3×CEA：CEA 是常见肿瘤标志物，在非小细胞肺癌中高表达，参与肿瘤细胞增殖、黏附与迁移。CEA TCB（CD3×CEA）通过单域结合 CD3ε 链，可在肿瘤内激活 T 细胞，将 “免疫冷肿瘤” 转化为 “免疫热肿瘤”，目前处于 Ⅰ/Ⅱ 期临床试验阶段（NCT03337698），为非小细胞肺癌治疗提供新方向。（二）靶向治疗型双特异性抗体：阻断肿瘤信号通路 靶向治疗型双特异性抗体主要通过阻断肿瘤细胞生长依赖的关键信号通路，或通过抗体 - 药物偶联形式精准递送细胞毒性药物，实现肿瘤杀伤，具体包括以下两种机制： 阻断双信号通路，克服治疗耐药：肿瘤细胞的存活与增殖常依赖多条信号通路，单一靶点抑制剂易导致肿瘤通过激活替代通路产生耐药。双特异性抗体可同时靶向两条关键信号通路，抑制下游信号传导，从而增强抗肿瘤效应并克服耐药（图 4C）。 常见的靶点组合包括： EGFR×c-MET：EGFR 是非小细胞肺癌重要驱动基因，约 15% 患者存在 EGFR 突变；c-MET 是 proto - 癌基因，其扩增或 exon 14 跳跃突变是 EGFR-TKI 耐药的重要原因。阿米万他单抗（amivantamab，EGFR×c-MET）通过同时结合 EGFR 和 c-MET，抑制下游信号通路，还可通过 Fc 片段介导 NK 细胞的 ADCC 效应增强杀伤。在 Ⅰ 期临床试验（NCT02609776）中，其治疗 EGFR exon 20 插入突变非小细胞肺癌的 ORR 达 40%，mPFS 为 8.3 个月，mOS 为 22.8 个月，成为首个获批用于该类患者的双特异性抗体。此外，MCLA-129（EGFR×c-MET）通过增强 ADCC 和 ADCP 效应，可克服 c-MET 信号非依赖性 EGFR-TKI 耐药，目前处于 Ⅰ/Ⅱ 期临床试验阶段。 HER2×HER3：HER3 虽酪氨酸激酶活性弱，但可与 HER2 形成异二聚体激活下游通路，在含 NRG1 融合的非小细胞肺癌中（尤其是浸润性黏液腺癌，发生率 10%-30%）发挥关键作用。Zenocutuzumab（MCLA-128，HER2×HER3）通过 “锚定 - 阻断” 机制，一方面通过 HER2 臂锚定肿瘤细胞提高 HER3 抗体浓度，另一方面通过 HER3 臂阻断 NRG1 结合，抑制信号通路激活。在 Ⅰ/Ⅱ 期临床试验（NCT02912949）中，其治疗 NRG1 融合非小细胞肺癌的 ORR 达 35%，为该类罕见突变患者提供有效治疗选择。 MET×MET：REGN5093 通过同时结合 MET 的两个不同表位，抑制 MET 驱动的肿瘤细胞生长。在 Ⅰ/Ⅱ 期临床试验（NCT04077099）中，2000mg 剂量组治疗 MET 异常非小细胞肺癌的部分缓解率为 16.7%，展现出一定抗肿瘤活性，但仍需更多临床试验验证其疗效。 双特异性抗体-药物偶联物（bsADCs）：精准递送细胞毒性药物：bsADCs 由双特异性抗体通过化学连接子与细胞毒性药物偶联而成，兼具双特异性抗体的精准靶向性和细胞毒性药物的强效杀伤性，可增强肿瘤细胞内药物递送效率，减少对正常细胞的毒性（图 4D）。 目前在非小细胞肺癌领域研究较多的 bsADCs 包括： BL-B01D1（EGFR×HER3 bsADC）：由 EGFR×HER3 双特异性抗体（SI-B001）与拓扑异构酶 Ⅰ 抑制剂（Ed-01）通过组织蛋白酶 B 可切割连接子偶联而成。在 Ⅰ 期临床试验（NCT05194982）中，其治疗 EGFR 突变非小细胞肺癌的 ORR 达 63.2%，DCR 达 89.5%；治疗 EGFR 野生型非小细胞肺癌的 ORR 达 44.0%，DCR 达 94.0%，展现出广谱且强效的抗肿瘤活性。 CBP-1008（FRα×TRPV6 bsADC）：FRα 和 TRPV6 在肺癌中高表达，CBP-1008 对 FRα 具有更高结合亲和力。在 Ⅰa/Ⅰb 期临床试验（NCT04740398）中，其治疗铂耐药卵巢癌的 ORR 达 25.6%，DCR 达 62.2%，安全性可控。鉴于 FRα 和 TRPV6 在非小细胞肺癌中的高表达，未来有望开展针对非小细胞肺癌的临床试验，为患者提供新选择。 图 4 双特异性抗体治疗非小细胞肺癌的作用机制（A）桥接双免疫调节分子恢复 T 细胞活性：双特异性抗体结合 T 细胞表面的两个免疫调节分子，恢复耗竭 T 细胞活性，启动抗肿瘤免疫反应；（B）重定向 T 细胞至肿瘤细胞：双特异性抗体结合 T 细胞表面 CD3 和肿瘤细胞表面 TAA，激活 T 细胞释放穿孔素和颗粒酶，裂解肿瘤细胞；（C）抑制双信号通路：双特异性抗体靶向肿瘤细胞表面两条信号通路的受体，抑制下游信号传导，诱导肿瘤细胞死亡；（D）双特异性抗体 - 药物偶联物（bsADC）递送细胞毒性药物：bsADC 结合肿瘤细胞后释放细胞毒性药物，实现肿瘤细胞精准杀伤四、双特异性抗体在非小细胞肺癌中的临床应用：从单药到联合治疗（一）双特异性抗体单药治疗：为耐药患者提供新选择 目前已有多款双特异性抗体在非小细胞肺癌单药治疗中展现出良好疗效，尤其为靶向治疗或免疫治疗耐药患者提供了新的治疗方向。根据已公布的临床试验数据，不同靶点双特异性抗体的单药疗效与安全性存在差异（表 2）。 表 2 双特异性抗体单药治疗非小细胞肺癌的已公布结果临床试验 从表中数据可见，阿米万他单抗在 EGFR exon 20 插入突变非小细胞肺癌中表现突出，ORR 达 40%，且 Ⅲ 级及以上 TRAEs 发生率仅 6.0%，安全性良好；SHR-1701在 PD-L1 阳性患者中 ORR 达 44.2%，展现出优异的免疫调节活性；BL-B01D1作为 bsADC，在 EGFR 突变和野生型患者中均有良好疗效，尤其 EGFR 突变患者 ORR 达 67.5%，为不同 EGFR 状态患者提供了新选择。（二）双特异性抗体联合治疗：进一步提升疗效 鉴于单药治疗仍存在响应率有限、部分患者耐药等问题，双特异性抗体联合化疗、靶向治疗或免疫治疗成为研究热点，通过协同作用进一步提升疗效（表 5）。 双特异性抗体 + 化疗：化疗可通过杀伤肿瘤细胞释放肿瘤抗原，增强免疫应答，与双特异性抗体形成协同效应。目前多款双特异性抗体联合化疗的方案已进入临床试验，部分已获得突破性进展。 AK112 + 化疗：AK112（PD-1×VEGF）联合培美曲塞和卡铂，于 2024 年 5 月首次获批用于 EGFR 突变且 TKI 治疗进展的局部晚期 / 转移性非鳞非小细胞肺癌。在 Ⅲ 期临床试验（HARMONi-A）中，AK112 联合化疗的 ORR 达 50.6%，DCR 达 93.1%，显著优于安慰剂联合化疗（ORR 35.4%，DCR 83.2%）；尽管 Ⅲ 级及以上 TRAEs 发生率为 54.0%，但低于阿替利珠单抗（抗 PD-L1）联合贝伐珠单抗（抗 VEGF）和化疗的 60.4%，安全性更优。 KN046 + 化疗：KN046（PD-L1×CTLA-4）联合铂类双药化疗作为一线治疗，在 Ⅱ 期临床试验（NCT04054531）中，ORR 达 50.6%，DCR 达 87.7%，2 年随访显示 mOS 超过 2 年，且 Ⅲ 级及以上 TRAEs 发生率仅 25.3%，安全性良好，为非小细胞肺癌一线治疗提供新方案。 阿米万他单抗 + 化疗：在 Ⅲ 期临床试验（NCT04538664）中，阿米万他单抗联合化疗治疗 EGFR exon 20 插入突变非小细胞肺癌的 ORR 达 73.0%，mPFS 达 12.9 个月，显著优于单纯化疗（ORR 43.0%，mPFS 6.9 个月）；在另一项 Ⅲ 期临床试验（NCT04988295）中，其联合化疗治疗奥希替尼耐药的 EGFR 突变非小细胞肺癌的 ORR 达 64.0%，mPFS 达 6.3 个月，同样优于单纯化疗（ORR 36.0%，mPFS 4.2 个月），但需注意其 Ⅲ 级及以上 TRAEs 发生率较高（72%-75%），临床应用中需加强不良反应管理。 双特异性抗体 + 靶向治疗：双特异性抗体与靶向药物联合，可从不同机制阻断肿瘤信号通路，增强抗肿瘤效应，尤其在克服靶向治疗耐药方面具有优势。 AK104 + 安罗替尼：AK104（PD-1×CTLA-4）联合安罗替尼（多靶点 TKI），在 Ⅰb/Ⅱ 期临床试验（NCT04646330）中，治疗 PD-L1 TPS≥1% 的非小细胞肺癌患者的 ORR 达 62.5%，DCR 达 100%，其中非鳞非小细胞肺癌患者 ORR 达 80.0%，且仅 1 例患者出现 Ⅲ 级 TRAEs（6.0%），安全性优异。 阿米万他单抗 + 拉泽替尼：拉泽替尼是第三代 EGFR-TKI，阿米万他单抗联合拉泽替尼治疗奥希替尼耐药的 EGFR 突变非小细胞肺癌，在 Ⅲ 期临床试验（NCT04487080）中，ORR 达 86.0%，mPFS 达 23.7 个月，显著优于传统治疗；在 CHRYSALIS-2 试验中，其治疗罕见 EGFR 突变非小细胞肺癌的 ORR 达 52.0%，mPFS 达 11.1 个月，为罕见突变患者提供了有效治疗选择。 双特异性抗体 + 免疫治疗：目前该领域研究较少，主要探索双特异性抗体与 PD-1/PD-L1 抑制剂的联合应用。例如，REGN7075（EGFR×CD28）联合西米普利单抗（抗 PD-1），在 Ⅰ/Ⅱ 期临床试验（NCT04626635）中，18 例患者的 TRAEs 发生率为 78.0%，未出现 Ⅲ 级及以上 TRAEs，安全性可控，但因入组人数较少， antitumor efficacy 仍需进一步验证。 表 5 双特异性抗体联合治疗非小细胞肺癌的已公布结果临床试验 五、双特异性抗体治疗非小细胞肺癌面临的挑战与解决方案 尽管双特异性抗体在非小细胞肺癌治疗中展现出显著优势，但临床应用中仍面临诸多挑战，需通过技术创新和策略优化逐步解决。（一）“靶向脱瘤” 毒性导致副作用增加 部分肿瘤相关抗原（TAAs）不仅表达于肿瘤细胞，在正常组织中也有低水平表达，双特异性抗体结合正常细胞上的抗原后，可能引发 “靶向脱瘤（on-target off-tumor）” 毒性，增加治疗相关副作用。例如，EpCAM 在正常上皮细胞中也有表达，CD3×EpCAM 双特异性抗体可能导致正常上皮细胞损伤，引发胃肠道反应等副作用。 针对这一问题，目前主要有两种解决方案：一是挖掘肿瘤特异性更高的靶点，例如受体酪氨酸激酶样孤儿受体（ROR1）、Notch 信号通路成员等，这些靶点在肿瘤细胞中高表达，正常组织中低表达或不表达，可减少对正常细胞的损伤；二是开发 “掩蔽技术（masking technology）”，通过在双特异性抗体上连接可被肿瘤微环境（TME）中蛋白酶切割的掩蔽片段（如 XTEN 掩蔽剂），使抗体在正常组织中处于 “失活” 状态，进入肿瘤微环境后，掩蔽片段被蛋白酶切割，抗体恢复活性并结合肿瘤抗原，实现精准杀伤。目前基于掩蔽技术的药物（如 CX-904、JANX008、TAK186 等）已进入 Ⅰ 期临床试验阶段，有望降低 “靶向脱瘤” 毒性。（二）肿瘤微环境抑制与 TILs 浸润不足限制疗效 非小细胞肺癌的肿瘤微环境（TME）常处于免疫抑制状态，且部分患者肿瘤组织中肿瘤浸润淋巴细胞（TILs）数量不足（即“免疫冷肿瘤”），导致双特异性抗体无法有效激活抗肿瘤免疫反应，限制疗效发挥。例如，抗 PD-(L) 1 双特异性抗体在 TILs 缺乏的患者中响应率显著降低。 为改善这一状况，可采取以下策略：一是联合放疗（RT），放疗可通过杀伤肿瘤细胞释放肿瘤抗原，促进 T 细胞浸润，将 “免疫冷肿瘤” 转化为 “免疫热肿瘤”。临床前研究显示，在 Lewis 肺癌小鼠模型中，双特异性抗体（BA）联合放疗的肿瘤抑制效果显著优于单药治疗，且能延长小鼠生存期；二是联合免疫调节剂，例如将双特异性抗体与抗 PD-(L) 1 抑制剂联合，可进一步逆转肿瘤微环境的免疫抑制状态，增强 T 细胞活性。目前已有多项双特异性抗体联合放疗或免疫调节剂的临床试验正在开展，有望为 TILs 浸润不足的患者提供新选择。（三）免疫原性增加导致 TRAEs 发生率上升 双特异性抗体的结构复杂性（如异源重链/轻链、突变位点等）可能导致其产生免疫原性，引发机体产生抗药物抗体（ADAs），不仅可能中和抗体活性，还可能激活免疫系统，增加治疗相关不良事件（TRAEs）的发生率。例如，阿米万他单抗静脉输注时，约 60% 患者出现输液相关反应（IRRs），部分患者因严重 IRRs 需调整治疗方案。 针对这一问题，可通过以下方式优化：一是优化给药方式与剂型，例如开发皮下注射剂型，减少药物与免疫系统的直接接触。研究显示，皮下注射阿米万他单抗的 IRRs 发生率降至 13.0%，且能维持与静脉输注相当的疗效；二是建立免疫原性风险评估体系，通过分析抗体结构、患者免疫状态等因素，提前预测免疫原性风险，指导临床用药选择，减少 TRAEs 发生。（四）生物标志物研究不足影响患者精准筛选 目前双特异性抗体相关生物标志物研究仍处于起步阶段，缺乏有效的生物标志物指导患者筛选，导致部分可能获益的患者未接受治疗，而不适合的患者接受治疗后不仅无效，还可能面临副作用风险。例如，PD-(L) 1 表达水平虽是免疫治疗常用生物标志物，但在双特异性抗体治疗中，其预测价值有限，部分 PD-L1 阴性患者仍能从治疗中获益。 为解决这一问题，需加强生物标志物探索：一是利用空间多组学技术，通过分析肿瘤微环境中细胞组成、分子表达等空间分布特征，挖掘与双特异性抗体疗效相关的生物标志物。例如，研究发现 CD74 高表达患者接受 AK104 治疗的 PFS 和 OS 更优，CD8 高表达患者接受 KN046 治疗的 mOS 更长，这些标志物有望用于患者筛选；二是监测外周血标志物，例如 EGFR 配体（如双调蛋白 AREG）表达水平与阿米万他单抗疗效相关，通过检测外周血中配体表达，可辅助预测治疗响应，实现精准治疗。（五）耐药问题未得到足够关注 与传统治疗类似，双特异性抗体治疗后也会出现耐药现象，但目前关于非小细胞肺癌患者双特异性抗体耐药的机制研究较少，缺乏有效的应对策略。双特异性抗体耐药可能与以下因素相关：一是T 细胞耗竭，长期使用双特异性抗体可能导致 T 细胞持续激活，逐渐进入耗竭状态，失去抗肿瘤能力；二是肿瘤微环境进一步恶化，治疗后肿瘤微环境中免疫抑制细胞（如 Tregs、M2 型巨噬细胞）增多，抑制 T 细胞活性；三是靶点突变或表达下调，例如 EGFR 突变、c-MET 表达下调等，导致双特异性抗体无法有效结合靶点。 针对耐药问题，未来需重点开展两方面工作：一是深入研究耐药机制，通过收集耐药患者的肿瘤组织和血液样本，利用基因组学、转录组学等技术分析耐药相关分子变化，明确耐药机制；二是开发新一代药物，例如三特异性抗体（tsAbs），可同时结合三个靶点，通过更复杂的作用机制克服双特异性抗体耐药，目前已有多款三特异性抗体进入临床前研究阶段，有望成为解决耐药的新方向。（六）缺乏头对头临床试验验证优越性 尽管双特异性抗体理论上比两种单克隆抗体联合治疗更具优势（如减少靶点竞争、降低毒性等），但目前缺乏头对头临床试验比较二者疗效与安全性，无法充分验证双特异性抗体的优越性。例如，AK104（PD-1×CTLA-4）的 Ⅲ 级及以上 TRAEs 发生率（11.3%）低于纳武利尤单抗联合伊匹木单抗（34.0%），但二者疗效对比仍需头对头试验验证。 未来需开展更多头对头临床试验，通过直接比较双特异性抗体与传统联合治疗的疗效、安全性及长期获益，为临床治疗方案选择提供更充分证据。同时，还需积累长期随访数据，分析双特异性抗体的长期疗效与安全性，为其在临床中的广泛应用奠定基础。六、双特异性抗体在非小细胞肺癌治疗中的未来展望 随着技术不断进步和临床研究深入，双特异性抗体在非小细胞肺癌治疗中的应用前景将更加广阔，未来可能在以下方向取得突破：（一）靶点组合多样化，覆盖更多治疗场景 目前双特异性抗体的靶点组合主要集中于 PD-(L) 1×CTLA-4、EGFR×c-MET 等经典组合，未来将进一步拓展靶点范围，开发更多新型靶点组合，覆盖不同分子分型、不同治疗阶段的非小细胞肺癌患者。例如，针对 KRAS 突变、ROS1 融合等罕见靶点的双特异性抗体，针对肿瘤微环境中免疫抑制分子（如 IDO、ARG1）的双特异性抗体，以及同时靶向免疫检查点和肿瘤代谢相关分子的双特异性抗体，有望为更多患者提供治疗选择。（二）联合治疗策略优化，提升疗效与安全性 未来将进一步优化双特异性抗体联合治疗策略，除已有的联合化疗、靶向治疗外，还将探索联合放疗、溶瘤病毒、CAR-T 细胞治疗等新型联合方案，通过多机制协同作用，进一步提升疗效。同时，将通过剂量调整、给药顺序优化等方式，减少联合治疗的副作用，提高患者耐受性。例如，双特异性抗体联合放疗的方案，有望在增强疗效的同时，通过精准放疗减少对正常组织的损伤，降低副作用发生率。（三）技术创新推动药物升级，解决现有痛点 随着基因工程、蛋白质工程等技术的发展，双特异性抗体的药物形式将不断升级，例如开发更稳定、半衰期更长的非 IgG 样双特异性抗体，通过糖基化修饰、Fc 片段改造等方式增强抗体效应功能，利用纳米技术提高抗体的肿瘤穿透性等。这些技术创新将有效解决当前双特异性抗体面临的 “靶向脱瘤” 毒性、免疫原性、肿瘤穿透性差等问题，推动药物性能提升。（四）精准治疗水平提升，实现个体化治疗 随着生物标志物研究深入，未来将建立完善的双特异性抗体疗效预测体系，通过检测患者肿瘤组织中靶点表达、免疫细胞组成、基因变异等多维度指标，实现患者精准分层，为不同患者制定个体化治疗方案。例如，CD74 高表达患者优先选择 AK104，CD8 高表达患者优先选择 KN046，EGFR 配体高表达患者优先选择阿米万他单抗，通过精准筛选提高治疗响应率，减少无效治疗。（五）拓展至早期治疗阶段，改善长期预后 目前双特异性抗体主要用于晚期非小细胞肺癌治疗，未来将逐步拓展至早期和局部晚期患者，例如用于新辅助治疗、辅助治疗，通过术前缩小肿瘤、术后清除微小残留病灶（MRD），降低复发风险，改善患者长期预后。例如，SHR-1701 联合化疗作为非小细胞肺癌新辅助治疗的 Ⅰ/Ⅱ 期临床试验（NCT04580498）已显示出良好前景，ORR 达 58.0%，未来有望成为新辅助治疗的重要选择。七、结论 肺癌作为全球癌症相关死亡的首要原因，非小细胞肺癌的治疗始终面临巨大挑战。双特异性抗体凭借其独特的 “双靶向” 能力，在克服治疗耐药、提升患者响应率、降低治疗毒性等方面展现出显著优势，已成为非小细胞肺癌治疗领域的重要研究方向。目前，阿米万他单抗已获批用于 EGFR exon 20 插入突变非小细胞肺癌，KN046、AK112、SHR-1701 等双特异性抗体处于 Ⅲ 期临床试验阶段，众多药物处于早期临床研究，为患者带来新的治疗希望。 然而，双特异性抗体在非小细胞肺癌治疗中仍面临 “靶向脱瘤” 毒性、肿瘤微环境抑制、免疫原性、生物标志物缺乏、耐药等挑战，需通过挖掘新型靶点、开发掩蔽技术、联合放疗、加强生物标志物研究、探索耐药机制等方式逐步解决。未来，随着技术创新、联合治疗策略优化和精准治疗水平提升，双特异性抗体将在非小细胞肺癌治疗中发挥更重要作用，不仅覆盖更多治疗场景，还将拓展至早期治疗阶段，为患者带来长期生存获益，推动非小细胞肺癌治疗进入新的时代。 识别微信二维码，添加生物制品圈小编，符合条件者即可加入 生物制品微信群！ 请注明：姓名+研究方向！ 版 权 声 明 本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观不本站。

- Petosemtamab in combination with pembrolizumab in 1L PD-L1+ r/m HNSCC phase 2 trial demonstrates 63% response rate observed among 43 evaluable patients and 79% overall survival rate at 12-months - Based on the Company’s current operating plan, existing cash, cash equivalents, including successful public offering raising $345M gross proceeds, and marketable securities expected to fund Merus’ operations at least into 2028 UTRECHT, The Netherlands and CAMBRIDGE, Mass. , Aug. 05, 2025 (GLOBE NEWSWIRE) -- Merus N.V. (Nasdaq: MRUS) (Merus, the Company, we, or our), an oncology company developing innovative, full-length multispecific antibodies and antibody drug conjugates (Biclonics®, Triclonics® and ADClonics®), today announced financial results for the second quarter and provided a business update. “We were excited to share the unprecedented efficacy of petosemtamab with pembrolizumab in first-line head and neck cancer at 2025 ASCO®, and were thrilled by the response from clinicians and KOLs, which we believe continues to drive strong phase 3 site activation and support our expectation that both phase 3 trials will be substantially enrolled by year end 2025,” said Bill Lundberg, M.D., President, Chief Executive Officer of Merus. “Additionally, I believe these data substantially enhance the likelihood of clinical success of petosemtamab. We are looking forward to providing initial clinical data on mCRC in the second half of 2025.” Petosemtamab (MCLA-158: EGFR x LGR5 Biclonics®): Solid TumorsLiGeR-HN1 phase 3 trial in 1L recurrent/metastatic (r/m) head and neck squamous cell carcinoma (HNSCC) and LiGeR-HN2 phase 3 trial in 2/3L r/m HNSCC enrolling – with both trials expected to be substantially enrolled by YE25 and potential top line interim readout for one or both trials in 2026; phase 2 trial in 1L, 2L and 3L+ metastatic colorectal cancer (mCRC) enrolling; mCRC initial clinical data planned for 2H25 Merus provided updated interim clinical data from the phase 2 trial of petosemtamab with pembrolizumab as 1L treatment for PD-L1+ (CPS≥1) r/m HNSCC at the 2025 American Society of Clinical Oncology® (ASCO®) Annual Meeting, demonstrating a 63% response rate among 43 evaluable patients and a 79% overall survival rate at 12 months. The presentation was detailed in our press release, Merus’ Petosemtamab with Pembrolizumab Interim Data Demonstrates Robust Efficacy and Durability in 1L PD-L1+ r/m HNSCC ( May 22 , 2025). LiGeR-HN1, a phase 3 trial evaluating the efficacy and safety of petosemtamab in combination with pembrolizumab in 1L PD-L1+ r/m HNSCC compared to pembrolizumab, and LiGeR-HN2, a phase 3 trial evaluating the efficacy and safety of petosemtamab in 2/3L HNSCC compared to standard of care, are enrolling and we expect both trials to be substantially enrolled by YE25. Merus believes a randomized registration trial in HNSCC with an overall response rate endpoint could potentially support accelerated approval and the overall survival results from the same study could potentially verify its clinical benefit to support regular approval for the Company’s phase 3 trial in 1L, and in phase 3 trial in 2/3L HNSCC. We expect to provide topline interim readout of one or both phase 3 registration trials in 2026. In February 2025 , the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation (BTD) to petosemtamab in combination with pembrolizumab for the first-line treatment of adult patients with recurrent or metastatic programmed death-ligand 1 (PD-L1) positive HNSCC with combined positive score (CPS) ≥ 1. This designation was detailed in our press release, Petosemtamab Granted Breakthrough Therapy Designation by the U.S. FDA for 1L PD-L1 Positive Head and Neck Squamous Cell Carcinoma ( February 18, 2025 ). BTD was also granted for petosemtamab monotherapy for the treatment of patients with recurrent or metastatic HNSCC whose disease has progressed following treatment with platinum based chemotherapy and an anti-programmed cell death receptor-1 (PD-1) or anti-programmed death ligand 1 (PD-L1) antibody, detailed in our press release, Petosemtamab granted Breakthrough Therapy Designation by the U.S. FDA ( May 13 , 2024). Merus provided updated interim clinical data on petosemtamab monotherapy in 2L+ r/m HNSCC at the European Society for Medical Oncology Asia Congress , demonstrating a 36% response rate among 75 evaluable patients. The oral presentation was detailed in our press release, Merus’ Petosemtamab Monotherapy Interim Data Continues to Demonstrate Clinically Meaningful Activity in 2L+ r/m HNSCC ( Dec. 7 , 2024). A phase 2 trial evaluating petosemtamab in combination with standard chemotherapy in 1L and 2L mCRC, and as monotherapy in heavily pretreated (3L+) mCRC, is enrolling. We expect to provide initial clinical data for petosemtamab in mCRC in 2H25. BIZENGRI® (zenocutuzumab-zbco: HER2 x HER3 Biclonics®)Approved by FDA for adults with pancreatic adenocarcinoma or non–small cell lung cancer (NSCLC) that are advanced unresectable or metastatic and harbor a neuregulin 1 (NRG1) gene fusion who have disease progression on or after prior systemic therapy Merus has exclusively licensed to Partner Therapeutics, Inc. (PTx) the right to commercialize BIZENGRI® for the treatment of NRG1+ cancer in the U.S. This was detailed in our press release, Merus and Partner Therapeutics Announce License Agreement for the U.S. Commercialization of Zenocutuzumab in NRG1 Fusion-Positive Cancer ( December 2 , 2024). MCLA-129 (EGFR x c-MET Biclonics®): Solid TumorsInvestigation of MCLA-129 is ongoing in METex14 NSCLC; phase 2 trial in combination with chemotherapy in 2L+ EGFR mutant (EGFRm) NSCLC enrolling MCLA-129 is subject to a collaboration and license agreement with Betta Pharmaceuticals Co. Ltd. (Betta), which permits Betta to develop MCLA-129, and potentially commercialize exclusively in China, while Merus retains global rights outside of China. Collaborations Incyte CorporationSince 2017, Merus has been working with Incyte Corporation (Incyte) under a global collaboration and license agreement focused on the research, discovery and development of bispecific antibodies utilizing Merus’ proprietary Biclonics® technology platform. For each program under the collaboration, Merus receives reimbursement for research activities and is eligible to receive potential development, regulatory and commercial milestones and sales royalties for any products, if approved. During the second quarter of 2025, Merus received the milestone payment of $1 million for the candidate nomination of a discovery program under the collaboration. Eli Lilly and CompanyIn January 2021, Merus and Eli Lilly and Company (Lilly) announced a research collaboration and exclusive license agreement to develop up to three CD3-engaging T-cell re-directing bispecific antibody therapies utilizing Merus’ Biclonics® platform and proprietary CD3 panel along with the scientific and rational drug design expertise of Lilly. The collaboration is progressing well with two programs advancing through preclinical development. Gilead SciencesIn March 2024, Merus and Gilead Sciences announced a collaboration to discover novel antibody based trispecific T-cell engagers using Merus’ patented Triclonics® platform. Under the terms of the agreement, Merus will lead early-stage research activities for two programs, with an option to pursue a third. Gilead will have the right to exclusively license programs developed under the collaboration after the completion of select research activities. If Gilead exercises its option to license any such program from the collaboration, Gilead will be responsible for additional research, development and commercialization activities for such program. The collaboration is progressing well with two programs advancing through preclinical development. Ono PharmaceuticalIn 2018, the Company granted Ono Pharmaceutical Co., Ltd. (Ono) an exclusive, worldwide, royalty-bearing license, with the right to sublicense, research, test, make, use and market a limited number of bispecific antibody candidates based on Merus’ Biclonics® technology platform directed to an undisclosed target combination. BiohavenIn January 2025 , Merus and Biohaven announced a research collaboration and license agreement to co-develop three novel bispecific antibody drug conjugates (ADCs), leveraging Merus’ leading Biclonics® technology platform, and Biohaven’s next-generation ADC conjugation and payload platform technologies. Under the terms of the agreement, Biohaven is responsible for the preclinical ADC generation of three Merus bispecific antibodies under mutually agreed research plans. The agreement includes two Merus bispecific programs generated using the Biclonics® platform, and one program under preclinical research by Merus. Each program is subject to mutual agreement for advancement to further development, with the parties then sharing subsequent external development costs and commercialization, if advanced. Corporate ActivitiesCompleted public offering raising $345M gross proceedsThis equity raise is detailed in a press release: Merus N.V. Announces Pricing of Public Offering of Common Shares ( June 4 , 2025). Cash Runway, existing cash, cash equivalents and marketable securities expected to fund Merus’ operations at least into 2028 As of June 30, 2025, Merus had $892 million cash, cash equivalents and marketable securities. Based on the Company’s current operating plan, the existing cash, cash equivalents and marketable securities are expected to fund Merus’ operations at least into 2028. Second Quarter 2025 Financial Results Total revenue for the three months ended June 30, 2025 increased by $1.5 million as compared to the three months ended June 30, 2024 , primarily as a result of increases in Incyte revenue of $1.5 million , PTx revenue of $0.5 million , and Gilead revenue of $0.1 million , partially offset by a decrease in Lilly revenue of $0.6 million . Research and development (R&D) expense for the three months ended June 30, 2025 increased by $44.8 million as compared to the three months ended June 30, 2024 . The increase in R&D expense is primarily driven by an increase of $37.9 million in clinical trial support provided by contract manufacturing and development organizations and contract research organizations, most of which is related to the petosemtamab clinical trials. The increase is also due to increases in personnel related expenses including share-based compensation of $7.2 million . General and administrative expense for the three months ended June 30, 2025 increased by $2.7 million as compared to the three months ended June 30, 2024 , primarily as a result of increases in personnel related expenses including share-based compensation of $5.0 million , increases in facilities and depreciation expense of $0.7 million , increases in legal expenses of $0.6 million , and increases in travel expenses of $0.2 million , partially offset by decreases in consulting expenses of $3.6 million and decreases in intellectual property and license expenses of $0.3 million . Total revenue for the six months ended June 30, 2025 increased by $20.1 million as compared to the six months ended June 30, 2024 , primarily as a result of commercial material revenue sold to PTx of $13.3 million and increases in collaboration revenue of $6.8 million . The collaboration revenue increase is primarily due to increases in Biohaven upfront payment amortization of $5.1 million . Research and development expense for the six months ended June 30, 2025 increased by $86.3 million as compared to the six months ended June 30, 2024 . The increase in R&D expense is primarily driven by an increase of $73.7 million in clinical trial support provided by contract manufacturing and development organizations and contract research organizations, most of which is related to the petosemtamab clinical trials. General and administrative expense for the six months ended June 30, 2025 increased by $8.7 million as compared to the six months ended June 30, 2024 , primarily as a result as a result of increases in personnel related expenses including share-based compensation of $10.3 million , increases in facilities and depreciation expense of $1.0 million , increases in legal expenses of $0.8 million , increases in finance and human resources expenses of $0.1 million and increases in travel expenses of $0.1 million , partially offset by decreases in consulting expenses of $3.4 million . Other income (loss), net consists of interest earned and fees paid on our cash and cash equivalents held on account, accretion of investment earnings and net foreign exchange (losses) gains on our foreign denominated cash, cash equivalents and marketable securities. Other gains or losses relate to the issuance and settlement of financial instruments. About Merus N.V. Merus is an oncology company developing innovative full-length human bispecific and trispecific antibody therapeutics, referred to as Multiclonics®. Multiclonics® are manufactured using industry standard processes and have been observed in preclinical and clinical studies to have several of the same features of conventional human monoclonal antibodies, such as long half-life and low immunogenicity. For additional information, please visit Merus’ website, LinkedIn and Bluesky. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation, statements regarding the content and timing of clinical trials, data readouts and clinical, regulatory, strategy and development updates for our product candidates; our ongoing LiGeR-HN1, LiGeR-HN2 and phase 2 mCRC trials for petosemtamab; our planned initial clinical data update on the phase 2 investigation of petosemtamab in mCRC in the 2H of 2025; the potential impact, if any, on the receipt of BTD by the FDA for petosemtamab in combination with pembrolizumab in 1L PD-L1+ r/m HNSCC and petosemtamab monotherapy for the treatment of patients with recurrent or metastatic HNSCC whose disease has progressed following treatment with platinum based chemotherapy and a PD-1 or PD-L1 antibody; our expectation that the LiGeR-HN1 and LiGeR-HN2 trials will be substantially enrolled by year-end; our expectation of reporting a topline interim readout of one or both phase 3 registration trials in 2026; our belief that a randomized registration trial in HNSCC with an overall response rate endpoint could potentially support accelerated approval and the overall survival results from the same study could potentially verify its clinical benefit to support regular approval in our phase 3 trial in 1L, and in phase 3 trial in 2/3L HNSCC; our statements regarding the sufficiency of our cash, cash equivalents and marketable securities, and expectation that it will fund the Company at least into 2028; the continued investigation of MCLA-129 and enrolling of patients in the investigation of MCLA-129 in combination with chemotherapy in 2L+ EGFRm NSCLC; the benefits of the license from Merus to PTx for the commercialization of Bizengri® in the US for NRG1+ cancer, collaborations between Incyte and Merus, Lilly and Merus, Gilead and Merus, Biohaven and Merus, and license agreement between Ono and Merus; and the potential of those licenses and collaborations for future value generation, including whether and when Merus will receive any future payments, including milestones or royalties, and the amounts of such payments; whether any programs under the collaboration will be successful; and our collaboration and license agreement with Betta, which permits Betta to develop MCLA-129 and potentially commercialize exclusively in China , while Merus retains full ex- China rights, including any future clinical development by Betta of MCLA-129. These forward-looking statements are based on management’s current expectations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: our need for additional funding, which may not be available and which may require us to restrict our operations or require us to relinquish rights to our technologies or antibody candidates; potential delays in regulatory approval, which would impact our ability to commercialize our product candidates and affect our ability to generate revenue; the lengthy and expensive process of clinical drug development, which has an uncertain outcome; the unpredictable nature of our early stage development efforts for marketable drugs; potential delays in enrollment of patients, which could affect the receipt of necessary regulatory approvals; our reliance on third parties to conduct our clinical trials and the potential for those third parties to not perform satisfactorily; impacts of the volatility in the global economy, including global instability, including the ongoing conflicts in Europe and the Middle East ; we may not identify suitable Biclonics® or bispecific antibody candidates under our collaborations or our collaborators may fail to perform adequately under our collaborations; our reliance on third parties to manufacture our product candidates, which may delay, prevent or impair our development and commercialization efforts; protection of our proprietary technology; our patents may be found invalid, unenforceable, circumvented by competitors and our patent applications may be found not to comply with the rules and regulations of patentability; we may fail to prevail in potential lawsuits for infringement of third-party intellectual property; and our registered or unregistered trademarks or trade names may be challenged, infringed, circumvented or declared generic or determined to be infringing on other marks. These and other important factors discussed under the caption “Risk Factors” in our Quarterly Report on Form 10-Q for the period ended June 30, 2025 , filed with the Securities and Exchange Commission , or SEC , on August 5, 2025 , and our other reports filed with the SEC , could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management’s estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change, except as required under applicable law. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this press release. Multiclonics®, Biclonics®, Triclonics®, ADClonics® and BIZENGRI® are registered trademarks of Merus N.V. Please see full Prescribing Information, including Boxed WARNING, at BIZENGRI.com/pi. Reference: 1. BIZENGRI. Prescribing information. Merus N.V.; 2024. Source: Merus N.V.