A Phase 2 Study Exploring the Use of Bispecific Antibodies to Improve Progression Free Survival in Patients With High-Risk Newly Diagnosed Multiple Myeloma (MMulti-Immune HR)

The purpose of this research is to learn whether using teclistamab and talquetamab at different time points will improve survival in participants with high-risk Multiple Myeloma (MM).
The treatment on this study will consist of Induction chemotherapy and stem cell collection, Immunotherapy 1 chemotherapy and Immunotherapy 2 chemotherapy. For participants whose testing show they are Minimal Residual Disease (MRD) positive (still have myeloma cells present in the bone marrow testing), a Melphalan-based stem cell transplant will be performed. For participants whose testing show they are MRD negative, the stem cell transplant will not be performed. All participants will go on to receive Immunotherapy 3 chemotherapy, Immunotherapy 4 chemotherapy, and Maintenance therapy.

开始日期2027-03-01

申办/合作机构

University of Arkansas Fort Smith

[+1]

NCT07474961

/ Not yet recruiting临床4期IIT

A Multicentre, Adaptive, Randomised, Multidomain, Platform Trial for Dose Optimization in the Treatment of Adult Patients With Haematological Diseases (BLOOD-dose): Core Protocol

BLOOD-dose is a multicentre, adaptive, randomized, multidomain platform trial designed to optimize treatment dosing strategies in adult patients with haematological diseases.
The BLOOD-dose core protocol outlines the overall clinical trial design that applies to all included interventions, while domain-specific appendices (DSA) detail the unique characteristics of each domain and specify domain-specific interventions.
New domains will be incorporated over time to address distinct dose-optimization research questions across different haematological conditions and interventions.

开始日期2027-03-01

申办/合作机构

Rigshospitalet

NCT07887984

/ Not yet recruiting临床2/3期IIT

Bispecific Antibody Therapy vs Autologous Stem Cell Transplantation as Consolidation for Newly Diagnosed, Standard Risk Multiple Myeloma

This phase II/III trial compares the usual treatment (daratumumab and hyaluronidase, lenalidomide, bortezomib and dexamethasone [DaraRVd] regimen followed by autologous stem cell transplant [ASCT] followed by maintenance therapy) to DaraRVd treatment followed by bispecific antibody therapy (teclistamab and/or talquetamab) followed by maintenance therapy in treating patients with newly diagnosed, standard risk multiple myeloma. Daratumumab is in a class of medications called monoclonal antibodies. Daratumumab and hyaluronidase works by helping the body to slow or stop the growth of cancer cells. Hyaluronidase is an endoglycosidase. It helps to keep daratumumab in the body longer so that the medication will have a greater effect. Lenalidomide is in a class of medications called immunomodulatory agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells in the bone marrow. Bortezomib blocks several molecular pathways in a cell and may cause cancer cells to die. It is a type of proteasome inhibitor and a type of dipeptidyl boronic acid. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Teclistamab and talquetamab are bispecific monoclonal antibodies that can bind to targets on both cancer cells and immune cells (T-cells) that may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Giving DaraRVd followed by teclistamab and/or talquetamab may work better in increasing the likelihood of reducing the cancer burden to the point that it is undetectable, and prolonging the time until the cancer returns compared to DaraRVd followed by ASCT.

开始日期2026-12-23

申办/合作机构

Alliance for Clinical Trials in Oncology

[+1]

100 项与塔奎妥单抗相关的临床结果

登录后查看更多信息

100 项与塔奎妥单抗相关的转化医学

登录后查看更多信息

100 项与塔奎妥单抗相关的专利（医药）

登录后查看更多信息

165

项与塔奎妥单抗相关的文献（医药）

2026-12-31·Hematology

Clinical features and management of GPRC5D-associated adverse events in novel GPRC5D × CD3 bispecific talquetamab-treated relapsed/refractory multiple myeloma patients: the MonumenTAL-1 China cohort experience

Article

作者: Campagna, Michela ; Qiu, Lugui ; Zhang, Hong ; Jin, Jie ; Gai, Xue ; Renaud, Thomas ; Xu, Qianqian ; Cai, Zhen ; Heuck, Christoph ; Fu, Chengcheng ; Lau, Bonnie W. ; Masterson, Tara J. ; Zhu, Dian ; Jing, Hongmei ; Li, Liang ; An, Gang ; Luo, Xinchao ; Liu, Rui ; Xia, Zhongjun ; He, Pengcheng

OBJECTIVES:

Talquetamab (G-protein-coupled receptor class C group 5 member D [GPRC5D] × CD3 bispecific antibody) demonstrated antitumor activity in relapsed/recurrent multiple myeloma (RRMM) in the phase I/II MonumenTAL-1 study. We report the safety profile of talquetamab in Chinese patients from MonumenTAL-1, focusing on GPRC5D-associated on-target/off-tumor adverse events (AEs).

METHODS:

Adult Chinese patients with heavily pretreated RRMM and measurable disease received subcutaneous talquetamab 0.4 mg/kg once weekly (QW) or 0.8 mg/kg biweekly (Q2W). Incidence, time to onset, duration, and recovery status of GPRC5D-associated AEs were reported. Data cutoffs: 29 February 2024 (QW cohort); 26 August 2024 (Q2W cohort).

RESULTS:

A total of 41 adult Chinese patients were included in this study (QW cohort, n = 29; Q2W cohort n = 12). Median treatment duration was 7.7 months (QW cohort) and 7.1 months (Q2W cohort); median follow-up was 16.3 and 13.9 months, respectively. GPRC5D on-target/off-tumor AEs, predominantly grade 1-2 (one grade 3 non-rash skin toxicity; QW cohort), were most commonly oral AEs (dysgeusia, dry mouth), skin AEs (rash, non-rash skin toxicity), and nail disorders; 50%-100% resolved by data cutoff. AEs were managed with supportive therapies. Talquetamab dose modification was needed in one case (grade 2 weight decrease).

DISCUSSION:

The generally mild GPRC5D-associated AEs were well tolerated and consistent with the known safety profile of talquetamab. Supportive management of these AEs without need for dose modification enabled prolonged treatment.

CONCLUSIONS:

Education of patients with RRMM on potential GPRC5D-associated AEs before starting treatment, and timely management upon experience, may ensure optimum exposure and thus maximum benefit with talquetamab.

2026-12-31·JOURNAL OF MEDICAL ECONOMICS

Costs per responder for patients with relapsed or refractory multiple myeloma treated with Talquetamab compared with usual care

Article

作者: Mu, Fan ; Patel, Neel ; Yang, Chelsey ; Jiao, Tianze ; Liu, Yi-Hsuan ; Wang, Jiamin ; Grajales-Cruz, Ariel F. ; Zhang, Xinke ; Lee, Hans C. ; Goble, Joseph

AIMS:

To evaluate costs per responder for patients with triple-class exposed (TCE) relapsed or refractory multiple myeloma (RRMM) receiving talquetamab (Tal) on weekly (QW) and biweekly (Q2W) dosing schedules, compared with usual care from a United States commercial payer's perspective.

METHODS:

A cost per responder model was developed over a 6-month time horizon, incorporating pre-progression and post-progression costs. For Tal QW and Tal Q2W, pre-progression costs included costs of drug acquisition, inpatient step-up doses (hospitalization, pre-medication, and tocilizumab), outpatient visits, and monitoring. Pre-progression costs for usual care were estimated based on a weighted average of the 10 most used regimens in a real-world LocoMMotion/MoMMent study, including costs of acquisition, administration, co-medication, and monitoring. Post-progression costs included subsequent treatment for a subset of patients and terminal care costs prior to death. All costs were reported in 2025 United States Dollars. Clinical data of overall response rate (ORR), progression-free survival, and overall survival were obtained from an indirect treatment comparison using MonumenTAL-1 (September 2024 data cut) and LocoMMotion/MoMMent (October 2022 and August 2023 data cuts) as data sources. Deterministic sensitivity analyses and scenario analyses were conducted to assess the robustness of model results.

RESULTS:

Over the 6-month period, the total cost of care was $179,556 for usual care, $295,993 for Tal QW, and $315,135 for Tal Q2W. Despite higher costs, Tal demonstrated superior ORR, resulting in lower cost per responder: $575,962 for usual care, $405,470 for Tal QW, and $443,165 for Tal Q2W, representing a 23-30% reduction in cost per responder with Tal. Sensitivity and scenario analyses showed consistent findings.

CONCLUSION:

Although Tal QW and Q2W are associated with higher total per-patient costs compared with usual care, they offer improved clinical effectiveness, resulting in lower cost per responder. These findings suggest greater economic value for Tal in the treatment of TCE RRMM.

2026-12-01·LEUKEMIA RESEARCH

Outpatient step-up dosing of teclistamab and talquetamab in relapsed or refractory

Article

作者: Forrest, Paul ; Kolluru, Pranav ; Garg, Ananya ; Davies, Faith E ; Lahoud, Oscar ; Morgan, Gareth J ; Kaminetzky, David ; Shah, Kunal ; Braunstein, Marc

BACKGROUND:

Bispecific T-cell-engaging antibodies against BCMA and GPRC5D demonstrate high efficacy in relapsed/refractory multiple myeloma (RRMM) but are associated with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), traditionally prompting inpatient monitoring when commencing therapy. Contemporary step-up dosing and prophylactic strategies may enable safe outpatient administration.

PATIENTS AND METHODS:

We conducted a single-center retrospective study evaluating outpatient step-up dosing (SUD) of teclistamab or talquetamab in adults with RRMM. Patients met institutional outpatient eligibility criteria and received standard pre-medications; prophylactic tocilizumab was administered at physician discretion. The primary endpoint was incidence and severity of CRS/ICANS. Secondary endpoints included SUD completion, healthcare utilization, and need for hospitalization.

RESULTS:

Thirty-eight patients underwent 43 outpatient SUD initiations (teclistamab n = 30; talquetamab n = 13). Median age was 72 years, and disease burden was high. SUD completion occurred in 93%. CRS occurred in 26% of initiations and was exclusively grade 1-2; no grade ≥ 3 CRS occurred. One possible grade III ICANS event (2%) occurred after completion of SUD. CRS incidence was similar with and without prophylactic tocilizumab (29% vs 32%). Most events occurred during the first two step-up doses. Hospitalization occurred in 5 (12%) SUD initiations for CRS/ICANS events and overall healthcare utilization was modest.

CONCLUSION:

Outpatient administration of teclistamab and talquetamab SUD in RRMM is feasible and safe with low rates of low-grade CRS. Toxicities occur early and are manageable with structured monitoring, supporting outpatient delivery in appropriately selected patients.

777

项与塔奎妥单抗相关的新闻（医药）

2026-10-24

·十亿分子

ESMO 2026 TCE研究进展纵览

2026年ESMO的T细胞衔接器（T-cell engager，TCE）研究覆盖了多个研发阶段。Tarlatamab已有铂后小细胞肺癌（SCLC）随机III期生存数据，并公布了一线维持III期公司顶线阳性结果；obrixtamig、alveltamig和SHR-7787提供了不同联合方案、分子形式和给药途径的数据。DLL3之外，ENPP3、PRAME、STEAP1、EGFR、CLDN6和GPRC5D等研究进一步说明了实体瘤与血液瘤TCE的疗效、安全性及临床实施问题。本文从摘要合集中筛选了相关进展，试图对TCE的进展进行概览以飨读者。一、ESMO 2026 TCE研究进展总览 1.1 主要临床结果研究/分子设计与人群主要结果解释与限制 DeLLphi-305；tarlatamab+durvalumab [1] 随机III期；广泛期SCLC（ES-SCLC）一线诱导后未进展；n=563 公司顶线结果：OS主要终点、PFS和ORR均达到统计学显著改善 HR、中位数、事件数和分组安全性待正式报告 DeLLphi-304；tarlatamab [2] 随机III期延长随访；铂类一线后SCLC；n=509 OS 13.6 vs 8.4个月，HR 0.62；PFS 4.2 vs 3.2个月，HR 0.69 提供铂后治疗的确证性生存证据 DeLLphi-303；tarlatamab+PD-L1 [3] Ib期；一线维持；n=88；中位随访29.4个月 24个月OS率58.1%；mPFS 5.6个月单臂研究，支持长期随访，不替代随机对照 DAREON-7；obrixtamig+化疗 [4] Ib期单臂；初治晚期神经内分泌癌（NEC）；n=44 确认ORR 77%；mPFS 7.7个月；mDoR 12.5个月无法拆分TCE与化疗贡献；DLL3亚组为探索性 XmAb819；ENPP3×CD3 [5] I期；透明细胞肾细胞癌（ccRCC）；目标剂量且可评估n=60 ORR 27%；DCR 68% ORR含未确认缓解；≥3级TRAE 61%来自静脉给药安全集n=101；随访较短 IMA402；PRAME TCR-TCE [6] 首次人体；总治疗n=80、疗效可评估n=57；RP2D范围n=20 RP2D范围确认ORR 6/20（30%）癌种混合、样本量小；≥3级淋巴细胞减少38%来自总治疗n=80 LBL-034；GPRC5D×CD3 [7] I期；复发/难治性多发性骨髓瘤（RRMM）；400–1200 μg/kg合并剂量n=40 ORR 82.5%；≥CR 57.5%；18个月PFS率58.0% 合并剂量队列；总体mPFS使用另一分母，详见第三部分 Xaluritamig；STEAP1×CD3 [8] 转移性去势抵抗性前列腺癌（mCRPC）门诊缩短观察队列；n=20 PSA50 11/18；确认ORR 3/6；4–6小时观察重点为给药与监测；G3 TRAE 70%，G3肌痛35% 上述结果的分母、随访和研究设计不同。联合治疗与单药、安全集与疗效可评估集、含未确认ORR与确认ORR均应分别解释。1.2 实体瘤新靶点与分子设计 ENPP3。 XmAb819采用双ENPP3结合和单CD3结合的2+1形式。目标剂量且至少有一次基线后扫描的60例患者中，ORR为27%（含确认和未确认）、DCR为68%，中位至缓解时间为12周。既往HIF2α抑制剂暴露的23例中，ORR为26%、DCR为70%。16例缓解者中15例在数据截止时仍在治疗，这些仍在治疗缓解者的中位随访为21周（范围7–87周）；仍在治疗不等同于已经确认持续缓解。静脉给药（IV）安全集101例中，≥3级TRAE为61%，停药为7%，无5级事件。ENPP3表达与疗效的关系仍需结合后续数据。[5] PRAME。 IMA402通过高亲和力TCR结构域识别HLA-A*02:01呈递的PRAME肽，使TCE能够靶向细胞内来源抗原。数据截止2025-09-26，总治疗人群为80例，疗效可评估57例，其中20例位于RP2D范围。RP2D范围确认ORR为6/20（30%）、DCR为13/20（65%），6例缓解在截止时均持续。两例完全代谢缓解分别持续8和18个月，但不能改写为RECIST CR。总治疗80例中，≥3级淋巴细胞减少为38%。后续研究需要明确癌种分层、HLA/PRAME筛选和扩大队列中的安全性。[6] 分子或项目研究类型与设计本届信息研发阶段与限制 CMDE005；掩蔽型EGFR×CD3 [9] I/IIa期剂量递增/扩展；总治疗n=30；肿瘤蛋白酶激活未见DLT或≥3级CRS/ICANS；≥6 mg胃肠AE任何级/≥3级为90%/20% ≥3 mg时NSCLC DCR 60%（n=5）、MSS-CRC 66.7%（n=3）；摘要报告DCR/SD，未报告客观缓解 SAIL66；CLDN6×CD3×4-1BB [10] 首次人体；n=22 无CR/PR；SD 9例；中位治疗1.3个月；ADA 21/22伴暴露下降；≥3级TRAE 27.3%；肝酶DLT ADA/暴露下降和肝酶DLT限制剂量递增 Pasritamig；KLK2×CD3 [17][18] 两项III期TiP 联合docetaxel计划n=800；最佳支持治疗背景计划n=663 目前为研究设计，不是疗效结果 ZGGS34；MUC17/CD3/CD28 [11] 首次人体I/II期TiP（2016TiP）三特异TCE，加入CD28共刺激尚需人体安全性、暴露和疗效数据 AZD6621；STEAP2/CD3/CD8 [12] 前列腺癌I/II期TiP（1080TiP） STEAP2靶点及CD8定向设计尚需验证选择性和治疗窗 CRPA1A2；MAGE-A1 TCR-TCE [13] 首次人体TiP（1079TiP） HLA-A*02:01限制适用人群与肽呈递是开发变量 JANX007；PSMA×CD3 [14] I期TiP（2385eTiP）肿瘤激活型设计目前无本届临床疗效结果 DLL3/CD3/CD2 [15] 临床前（1992P）探索CD2共刺激尚无人体数据 CLD-501/In Situ TCE [16] 临床前（1995P） RedTail肿瘤选择性痘苗病毒载体；在肿瘤局部表达TROP2 TCE及IL-15超级激动剂等载荷基因药物/病毒载体策略；尚无人体数据 CMDE005与SAIL66说明，分子设计需要分别评价免疫毒性、正常组织毒性、免疫原性及其对药物暴露的影响。掩蔽或共刺激的存在本身不能预测临床结果。1.3 给药、真实世界与特殊人群 Tarlatamab的OneOncology研究纳入90例患者，比较门诊、住院和混合给药路径。门诊组CRS均为G1，CRS为30%、ICANS为13%；混合组疾病负担更高且CRS更重，提示明显的非随机选择差异，不能据此认定某一路径本身降低毒性。[19] TriNetX真实世界研究纳入760例患者，30天内住院率为45.8%、重症监护病房（ICU）为5.8%、tocilizumab使用率为22.1%，CRS编码率为18.9%。住院和ICU并非全部为CRS特异结局，tocilizumab也不能直接替代高级别CRS；较低的CRS编码率可能受到编码不足影响。[20] 在265例患者的年龄分析中，≥75岁组50例、较年轻组215例，未观察到疗效和安全性的显著差异；任何级ICANS为26%对21%，延长住院为54.2%对54.0%。该结果支持进一步研究老年患者的选择，但不构成等效性证明。[21] 系统综述同时提示，真实世界中不符合关键试验入组条件的患者比例较高，不同队列的ICANS和住院结果存在异质性。[22] 这些研究支持建立包括预处理、患者与照护者教育、神经监测和快速住院通道的风险分层流程，而不是统一缩短或取消监护。1.4 Biomarker与患者选择方向本届数据解释与限制 DLL3表达 [4] DAREON-7高/低表达组ORR为88%/65%，mPFS为9.5/7.6个月入组均为DLL3>0；低表达为<50%但仍>0；探索性亚组，未证明预测作用 ENPP3 [5] 常规摘要未提供完整的表达–疗效关系截至数据截止点不能认定ENPP3免疫组化（IHC）已验证为预测标志物 PRAME/HLA [6] 通过HLA-A*02:01与PRAME机制进行患者选择属于药物适用性筛选；各癌种表达阈值仍需建立 ctDNA [23] Ubamatamab治疗12周约75%的ctDNA下降与PFS/OS改善相关各组生存相近后合并分析；属于预后/动态药效学信号，不等于已验证的获益预测标志物卵巢癌意义未明克隆性造血（CHIP） [24] DNMT3A改变在临床获益者中富集：20% vs 0%，p=0.018；队列mPFS 3.1个月混合TCE回顾性分析，多重比较和机制不确定，仅用于生成假设目前不同靶点和药物尚不能共用统一的患者选择体系。膜蛋白可及性、抗原密度、HLA/肽呈递、动态ctDNA和宿主免疫状态需要在具体药物和适应症中分别验证。二、DLL3：随机III期结果、联合治疗与适应症扩展2.1 DeLLphi-305：一线维持III期公司顶线结果 DeLLphi-305将完成durvalumab、铂类和依托泊苷诱导且未进展的563例ES-SCLC患者，1:1随机接受durvalumab联合tarlatamab或durvalumab单药维持。公司顶线结果（high-level results）显示，计划中期分析中OS主要终点达到统计学显著改善，PFS和ORR亦达到显著改善，且未见新的安全信号。[1] 截至本文数据截止点，尚未公开OS/PFS的HR、中位数、事件数、具体ORR及分组安全性。因此，当前可确认的是研究达到主要终点，不能量化生存延长幅度。正式报告还需说明脑转移、铂耐药/难治、诱导应答深度等亚组，以及≥3级CRS/ICANS、停药和住院情况。2.2 DeLLphi-304：铂后治疗的延长随访 DeLLphi-304纳入509例铂类一线后SCLC患者，中位随访23个月。Tarlatamab相较化疗的中位OS为13.6个月对8.4个月，HR 0.62（95%CI 0.51–0.76）；中位PFS为4.2个月对3.2个月，HR 0.69（95%CI 0.57–0.84）。[2] 图1｜DeLLphi-304延长随访的OS/PFS风险比、绝对中位数与关键安全性。 18个月OS率为42%对24%，12个月PFS率为21%对6%；mDoR为7.1个月对5.5个月，12个月仍缓解者为42%对10%。PFS中位差为1个月，HR和生存率随访提供了额外的曲线信息。铂耐药亚组OS HR 0.65、基线脑转移亚组HR 0.52属于支持性亚组结果。 ≥3级TRAE为28%对63%，因TRAE停药为3%对7%。这些结果支持tarlatamab在铂后治疗中的生存获益和安全性，但不自动外推至ECOG状态较差、活动性中枢神经系统病变或所有NEC患者。2.3 DeLLphi-303：一线维持的单臂长期随访 DeLLphi-303纳入88例接受tarlatamab联合atezolizumab或durvalumab维持的患者，中位随访29.4个月，24个月OS率为58.1%，mPFS为5.6个月。36例治疗超过12个月的患者中，12个月后新发≥3级TRAE为8.3%。[3] 该研究提供了联合维持方案的长期随访和安全性信息，但无随机对照，不能据此估计相对疗效，也不能替代DeLLphi-305。2.4 Obrixtamig：NEC与SCLC联合治疗 DAREON-7在44例初治晚期NEC患者中评估obrixtamig联合标准化疗，确认ORR为77%，mPFS为7.7个月，mDoR为12.5个月。DLL3高表达与低表达组ORR分别为88%和65%，mPFS分别为9.5和7.6个月；所有入组患者均为DLL3>0，低表达组仍具有表达。[4] ≥3级TEAE为93%，需结合联合化疗背景解释；CRS以1/2级为主，分别为59%和14%，未见≥3级CRS/ICANS。DAREON-NEC-1已披露III期设计：拟纳入约390例DLL3阳性、不可切除局部晚期或转移性肺外NEC（EP-NEC）患者，以OS为主要终点，评估一线obrixtamig联合标准化疗。[26] DAREON-9在60例既往含铂治疗后SCLC患者中评估obrixtamig联合topotecan，确认ORR为65%，mPFS为5.6个月；≥3级中性粒细胞减少为45%。[25] 该研究同样需要区分obrixtamig与topotecan的贡献，不能与tarlatamab单药研究直接比较ORR或血液学毒性。2.5 其他DLL3分子与给药形式分子分子/给药特点本届结果主要限制 Alveltamig（ZG006）[27] 双DLL3表位+CD3三特异TCE n=34；中位随访约18个月；12/18个月OS率67.6%/53.6%；mOS尚未成熟 ≥3级TRAE 52.9%，多为实验室异常；死亡事件成熟度44.1%，无对照 SHR-7787 [28] DLL3×CD3；皮下每2周一次（Q2W）；安全集n=78 SCLC可评估n=69：ORR（含未确认）34.8%、DCR 58.0%；≥3级TRAE 28.2%来自安全集n=78；中位随访4.9个月高剂量组样本较小；需确认ORR、DoR和更长随访 2.6 NEC真实世界数据两项小型真实世界研究提供了临床试验之外的DLL3 TCE结果：[29][30] ·肺大细胞神经内分泌癌（LCNEC）： n=33，DCR 71.0%，真实世界PFS（rwPFS）4.4个月，真实世界OS（rwOS）12.1个月；出现3例G3 CRS、1例G4 CRS和1例G4 ICANS。 ·肺外神经内分泌癌（EP-NEC）： n=26，DCR 40.9%，rwPFS 1.8个月。两个队列的患者来源、治疗线数和治疗背景不同，不能与一线DAREON-7直接比较。DLL3表达与DCR未见显著相关，但表达检测样本分别只有13例和15例，统计能力有限，不能据此判断DLL3表达没有临床价值。2.7 DLL3研究的综合评价 DLL3目前同时具有铂后随机OS证据、一线维持III期公司顶线结果、NEC联合治疗信号和多种后发分子。后续研究评价应重点包括：DeLLphi-305完整效应量与安全性；联合方案中各药物的独立贡献；确认缓解和长期生存；皮下给药与门诊监测；以及DLL3表达阈值在不同药物和癌种中的可重复性。三、LBL-034：靶点是已成药靶点，不过2+1结构对疗效结果与安全性有一些差异化，值得仔细看看3.1 临床结果 LBL-034的I期研究纳入56例RRMM患者，55例疗效可评估。患者中位既往5线治疗，73.2%为三类药暴露，16.1%既往接受BCMA CAR-T，23.2%伴髓外病变（EMD）。[7] 在400–1200 μg/kg合并剂量组40例患者中，ORR为82.5%（33/40），≥CR为57.5%（23/40），18个月PFS率为58.0%。55例疗效可评估患者总体mPFS为15.8个月，mDoR尚未达。 400–1200 μg/kg剂量范围内EMD亚组仅8例，ORR为75.0%（6/8），mPFS为11.5个月。在400–1200 μg/kg且达到≥CR的23例中，18个月PFS率为87.7%；同一≥CR人群段落报告微小残留病（MRD）阴性率72.7%（10^-5）。总体而言，目前LBL-034的ORR数据是同类药物中较高的，可能与其2+1的结构有一定关系。3.2 2+1结构及潜在药理影响公司披露显示，LBL-034采用IgG1样2:1设计，包含两个GPRC5D结合域和一个CD3 scFv。[31] 图2｜LBL-034 2+1结构示意众多临床前数据，包括genentech很早就停止开发的forimtamig的数据显示，双价肿瘤抗原结合可提高表观结合强度（avidity），对GPRC5D低表达的肿瘤杀伤更强。看起来，这种translation还是可信的。3.3 与GPRC5D同靶点研究总结[7][32][33] 分子数据背景疗效数据安全性与限定解释 LBL-034 ESMO 2026 I期；400–1200 μg/kg合并剂量n=40；总体可评估n=55 高剂量组ORR 82.5%、≥CR 57.5%、18个月PFS 58.0%；总体mPFS 15.8个月 ≥G3 TRAE 83.9%；≥G3淋巴细胞减少55.4%；剂量汇总且样本较小需要更大样本、完整安全性和长期随访 Talquetamab MonumenTAL-1三年；未接受T细胞重定向治疗的两队列n=143/154及既往接受者队列n=78；中位随访（mFU）依次38/31/30个月三队列ORR 67–74%；≥CR 33–42%；mPFS依次7.5/11.2/7.7个月味觉改变72–76%；感染61–78%；不同队列不能合并为单一百分比随访更成熟；人群和数据截止与LBL-034不同 Forimtamig I期皮下注射（SC）；全体n=171；condensed n=46、weekly n=34；2026年论文摘要全体ORR 59.6%；condensed 71.7%；weekly 47.1%；并非随机方案比较 CRS 75.4%；on-target/off-tumor毒性常见；可及摘要未给≥CR/PFS/DoR及上皮分项给药队列差异不能作因果比较；2+1未消除正常组织毒性 3.4 安全性：血液学事件与GPRC5D相关上皮毒性 LBL-034的≥3级TRAE为83.9%，≥3级淋巴细胞减少为55.4%；≥3级CRS仅1例，未见≥3级ICANS或治疗相关死亡。摘要未报告任意级CRS/ICANS发生率。后续还需披露感染、血细胞减少持续时间、支持治疗、住院和停药情况。 GPRC5D相关上皮毒性可参考talquetamab。FDA 2023标签中，皮肤反应为62%、指甲疾病为50%、dysgeusia复合组为70%；复合定义存在重叠，不能相加，也不能与LBL-034的≥3级TRAE直接比较。[34] LBL-034的ESMO摘要没有给出皮肤、指甲或味觉事件的分级和发生率，因此目前不太确定，披露的83.9%大于三级副作用是不是2价的GPRC5D靶向正常皮肤角质细胞导致的。四、STEAP1×CD3：4.1 Xaluritamig的分子设计与临床活性 Xaluritamig（AMG 509）采用两个STEAP1 Fab和一个CD3 scFv的2+1设计。临床前资料显示，双STEAP1 Fab构建体较单Fab构建体的体外杀伤效力提高65倍；人CD3重组蛋白结合KD为27.6 nM。[38] 原始首次人体I期研究纳入97例mCRPC患者，剂量为0.001–2.0 mg、每周或每2周一次；最大耐受剂量（MTD）为每周1.5 mg并采用3步阶梯给药。97例为总治疗人群；确认PSA50为43/87（49%），确认RECIST ORR为16/67（24%）。目标剂量≥0.75 mg时，确认PSA50为26/44（59%），确认RECIST ORR为15/37（41%）。[39]4.2 原始I期安全性治疗相关事件全部97例 ≥3级备注 CRS 72% 2% 无G4/5 CRS；主要发生于第1周期疲劳 45% 11% 全身性事件，不能单独用于器官定位肌痛 34% 12% 严重TRAE中肌痛4%；3例因肌痛停药关节痛 24% 7% 2例因关节痛停药皮疹 28% 0 严重斑丘疹2%；“严重”不等于“≥3级” 严重TRAE 39% — 包括CRS、肌痛、肌筋膜炎等因TRAE停药 19% — CRS与肌痛各3例，关节痛2例；无治疗相关死亡 2.0 mg队列的DLT包括G3肌痛、肢端疼痛和关节痛，支持剂量或暴露与肌骨事件严重度之间可能存在关系。原始研究指出肌骨痛机制不清，受累患者肌酸激酶（CK）未见相应升高。[39] 严重肌骨/结缔组织事件为11%，包括肌痛、肌筋膜炎、关节痛、关节炎和背痛。该事件谱提示筋膜、结缔组织及免疫炎症应与肌细胞损伤同时纳入鉴别。4.3 ESMO 2026门诊缩短观察队列 2234P报告20例mCRPC患者采用2/3阶梯给药、地塞米松预处理及患者/照护者教育，阶梯剂量后的观察缩短至4–6小时。G3 TRAE为70%，G3治疗相关严重不良事件为55%，G3肌痛为35%；CRS G1/G2分别为50%和10%。2例患者在首剂后24小时内住院，其中1例为G2 CRS合并G3 ICANS。[8] 确认PSA50为11/18（61%），确认PSA90为7/18（39%），确认影像学ORR为3/6（50%）。披露的门诊队列显示，任何级别肌痛发生率为35%，≥3级肌痛为12%。这些安全性信号提示，尽管STEAP1×CD3双特异性抗体目前的ORR数据展现出较大的临床成功潜力，但其脱靶毒性仍对临床应用构成显著制约；后续分子开发应重点优化这一方面。总结总体而言，这次ESMO的TCE更新并不多，但这或许恰恰说明，实体瘤TCE正在从“概念验证的兴奋期”进入“转化瓶颈的深水区”。近些年，业内围绕共刺激信号、三抗、条件激活等方向做了大量探索，但现实并不轻松：共刺激CD2等策略的临床数据迟迟未公布，DLL3×CD3×4-1BB的ADA成因仍不清楚，遮蔽型TCE目前也仅在PSMA这类“差临门一脚”的靶点上获得初步验证，距离真正意义上的广泛成功仍有明显距离。有点撞上了实体瘤的“叹息之墙”的感觉。但作为业内从业者，笔者还是乐观的认为，这并不是对方向的否定，而是提醒我们，实体瘤TCE的难点从来不只是“把分子做出来”，而是如何在靶点异质性、T细胞浸润不足、免疫抑制微环境、脱靶毒性、免疫原性和治疗窗之间取得系统平衡。未来真正值得期待的，未必是分子数量上的快速堆叠，而是机制更清晰、安全窗更宽、患者选择更精准、联合策略更合理的下一代设计。实体瘤TCE的下一程，或许不是更快地“造分子”，而是更耐心地理解生物学；只有把ADA、条件激活、共刺激和微环境屏障逐一拆解，才有可能从零散缓解走向可复制的临床成功。主要参考文献与数据源 [1] AstraZeneca. DeLLphi-305 Phase III high-level results. 2026.链接 [2] ESMO 2026 Abstract 3808O. DeLLphi-304 extended follow-up.链接 [3] ESMO 2026 Abstract 3821P. DeLLphi-303.链接 [4] ESMO 2026 Abstract 2397RO. DAREON-7.链接 [5] ESMO 2026 Abstract 3588O. XmAb819 in ccRCC.链接 [6] ESMO 2026 Abstract 1955RO. IMA402 first-in-human study.链接 [7] ESMO 2026 Abstract 1456O. LBL-034 in RRMM.链接 [8] ESMO 2026 Abstract 2234P. Xaluritamig outpatient monitoring cohort.链接 [9] ESMO 2026 Abstract 1982P. CMDE005.链接 [10] ESMO 2026 Abstract 1022P. SAIL66 first-in-human study.链接 [11] ESMO 2026 Abstract 2016TiP. ZGGS34 MUC17/CD3/CD28 Phase I/II design.链接 [12] ESMO 2026 Abstract 1080TiP. AZD6621 STEAP2/CD3/CD8 Phase I/II design.链接 [13] ESMO 2026 Abstract 1079TiP. CRPA1A2 MAGE-A1 TCR-TCE first-in-human design.链接 [14] ESMO 2026 Abstract 2385eTiP. JANX007 tumor-activated PSMA×CD3 Phase I design.链接 [15] ESMO 2026 Abstract 1992P. DLL3/CD3/CD2 preclinical study.链接 [16] ESMO 2026 Abstract 1995P. CLD-501/In Situ TCE RedTail vaccinia platform.链接 [17] ESMO 2026 Abstract 2387eTiP. Pasritamig plus docetaxel Phase III design.链接 [18] ESMO 2026 Abstract 2388eTiP. Pasritamig Phase III design on best supportive care background.链接 [19] ESMO 2026 Abstract 3852P. Tarlatamab outpatient/inpatient/hybrid administration.链接 [20] ESMO 2026 Abstract 3848P. Real-world tarlatamab outcomes in TriNetX.链接 [21] ESMO 2026 Abstract 3834P. Tarlatamab in older adults.链接 [22] ESMO 2026 Abstract 3865eP. Real-world TCE systematic review.链接 [23] ESMO 2026 Abstract 1957P. ctDNA and ubamatamab.链接 [24] ESMO 2026 Abstract 1295P. ENGAGE-OV/DNMT3A exploratory analysis.链接 [25] ESMO 2026 Abstract 3827P. DAREON-9.链接 [26] ESMO 2026 Abstract 2432TiP. DAREON-NEC-1 Phase III design.链接 [27] ESMO 2026 Abstract 3826P. Alveltamig/ZG006.链接 [28] ESMO 2026 Abstract 3825P. Subcutaneous SHR-7787.链接 [29] ESMO 2026 Abstract 4165P. Real-world DLL3 TCE in pulmonary LCNEC.链接 [30] ESMO 2026 Abstract 2409P. Real-world DLL3 TCE in EP-NEC.链接 [31] Leads Biolabs. Opamtistomig and LBL-034 at ESMO 2026.链接 [32] MonumenTAL-1 three-year follow-up. Blood. PubMed 42561120.链接 [33] Forimtamig subcutaneous Phase I study. Blood Advances, 2026. PubMed 42815880.链接 [34] US FDA. TALVEY prescribing information, 2023 initial label.链接 [35] Forimtamig preclinical 2+1 GPRC5D mechanism. Blood; PMC11738037.链接 [36] GPRC5D expression in hard-keratin-producing cells. Journal of Investigative Dermatology, 2004. PubMed 15086536.链接 [37] Human Protein Atlas v23. GPRC5D versioned gene page https://v23.proteinatlas.org/ENSG00000111291-GPRC5D ; GTEx, consensus, single-cell and normal_tissue data layers; download documentation链接 [38] Li C, et al. Preclinical characterization of AMG 509/xaluritamig. SITC 2020 Abstract 718, JITC 8(Suppl 3).链接 [39] Kelly WK, Danila DC, et al. Xaluritamig first-in-human Phase I. Cancer Discovery. 2024;14:76–89.链接 [40] Human Protein Atlas v23. STEAP1 versioned gene page https://v23.proteinatlas.org/ENSG00000164647-STEAP1 ; GTEx, consensus, single-cell and normal_tissue data layers; download documentation链接 [41] Zarrabi KK, Kelly WK. AME Clinical Trials Review. 2026;4:11. Correspondence on xaluritamig musculoskeletal toxicity and management.链接三个专题分析推荐摘要本文梳理ESMO 2026 TCE随机III期、新靶点、分子设计、真实世界和Biomarker研究，并分析三个专题：DLL3一线维持与铂后生存证据；LBL-034的2+1结构、疗效分母及GPRC5D相关毒性；xaluritamig的肌骨事件、门诊监测，以及肌细胞膜和筋膜/结缔组织的待验证机制。封面短文案 ESMO 2026 TCE研究进展 DLL3、GPRC5D与STEAP1 临床证据 · 分子设计 · 正常组织毒性排版建议 ·图1置于研究进展总览开头；图2置于DeLLphi-304；图3和图4置于LBL-034；图5置于STEAP1机制分析；图6用于总结。 ·主要临床结果表和其他分子表用于Word编辑参考；公众号移动端可按研究拆分为卡片，避免横向表格过宽。 ·首次出现时补全ORR、DoR、PFS、TRAE、CRS、ICANS等缩写；保持G3与≥3级的原始表述，不自行互换。 ·所有图均为原创重绘，PNG可直接上传，SVG用于后续编辑。发布前事实核查 ·DeLLphi-305截至数据截止点仅有公司顶线阳性结果；若正式数据已公开，应同步更新正文、图1和摘要。 ·LBL-034的82.5%来自合并剂量40例；总体mPFS使用55例可评估人群；EMD为同剂量范围8例；MRD分母未披露。 ·不将不同研究的ORR直接表述为分子优劣；不将联合治疗结果与单药研究直接比较。 ·不将LBL-034高级别TRAE直接归因为皮肤毒性；GPRC5D正常组织表达与具体分子的上皮毒性需要分别证明。 ·不将STEAP1肌痛直接归因为骨骼肌杀伤；分别表述肌细胞膜与筋膜/结缔组织假说。 ·TiP和临床前项目仅作为研究设计或机制信息，不表述为临床疗效结果。免责声明本文用于医药研发与学术交流，不构成诊疗、用药或投资建议。会议摘要和公司公告可能随正式报告、论文或监管资料更新。

临床结果临床3期临床1期临床2期

2026-10-23

·风城土猫

Chugai三抗大溃败，共刺激TCE前路几何？

2026年10月，日本中外制药（Chugai）于ESMO大会公布了一项令人沮丧的临床结果。一款精心设计的CLDN6/CD3/CD137三特异性抗体SAIL66，在22名晚期实体瘤患者中，没有产生一例客观缓解。更令人震惊的是，22名患者中竟然有21人产生了抗药抗体（anti-drug antibody，ADA）。[1] 0%的ORR，95.5%的ADA。这几乎是抗体药物开发最不希望看到的临床结果。而Chugai绝非抗体工程开发的等闲之辈。就在一个多月前，有“诺奖风向标”之称的拉斯克奖颁给了Chugai的三位科学家：服部有宏（Kunihiro Hattori）、北泽刚久（Takehisa Kitazawa）和井川智之（Tomoyuki Igawa），表彰他们发明了改变A型血友病治疗格局的双特异性抗体艾美赛珠单抗（emicizumab）。历经十余年研发、数万种抗体组合筛选及数千次工程优化，Chugai的科学家在Fc异源二聚化、共同轻链、等电点工程、人源化改造、降低免疫原性、稳定性与药代优化等多个领域实现了蛋白质工程学突破。最终，利用抗体特异性识别、结合生物大分子的能力，将FIXa与FX拉近，以完全不同的蛋白结构，模拟了天然凝血因子VIIIa的功能。[2,3] 艾美赛珠单抗于2017年获批，成为全球首个获批的重组全长IgG型双特异性抗体药物。其开发历史，我在前文最自然的人造美女艾美赛珠折桂“诺奖风向标”中有过详尽介绍。 Chugai的科学家一直走在抗体工程学的前沿，敢于想前人不敢想的事情，也一次次将看似不可能的设计变成真正的药物。然而，从模仿凝血因子到重塑T细胞免疫反应，从双抗到三抗，分子工程越来越复杂，人体生物学也开始显露出更加难以预测的一面。一、Chugai的第一代TCE：时代领先的设计，并不顺利的临床开发近年来，T细胞连接器（T-cell engager，TCE）成为双特异性抗体最热门的应用方向。TCE的原理十分精妙。一端识别肿瘤细胞表面抗原，另一端结合T细胞上的CD3，通过空间拉近和受体聚集，绕开天然TCR对pMHC的特异性识别，诱导T细胞杀伤肿瘤。其实早在2016年，Chugai基于TRAB（T-cell Redirecting Antibody）平台开发的GPC3/CD3双抗ERY974，就已进入临床探索。这是一款IgG样TCE，通过Fc工程降低FcγR介导的非特异性CD3交联，同时利用相对较弱的CD3结合，尽可能使T细胞激活依赖肿瘤抗原的识别。[4] ERY974的GPC3/CD3结合亲和力分别为1.46 nM和207 nM，与2014年获批的TCE blinatumomab（CD19：1.49 nM，CD3：260 nM）处于相近数量级，其CD3结合甚至比后来获批的实体瘤TCE tarlatamab（DLL3：0.64 nM，CD3：14.9 nM）弱了一个数量级。[4,5] 虽然上述数值来自不同测量体系，不宜严格进行头对头比较，但从设计逻辑看，ERY974刻意弱化CD3结合，理应降低系统性激活风险，提高安全性。然而，进入临床以后，ERY974在0.81 μg/kg附近便遭遇严重的细胞因子释放综合征（CRS）相关耐受性问题，剂量难以继续提高。当然，这里面也有早期临床开发经验不足的问题。随着TCE应用越来越广泛，研究者逐渐认识到，初始剂量、阶梯给药（step-up dosing）、糖皮质激素及IL-6受体拮抗剂，都可以显著改变CRS的发生率与严重程度。 2026年AACR公布的日本I期研究中，Chugai通过预防性使用tocilizumab，并逐步引入糖皮质激素和阶梯给药，将ERY974的最大耐受剂量（MTD）显著提升至2.7 μg/kg QW。然而，在38名患者中，CRS仍发生于21人（55%），23人（61%）出现三级及以上不良事件，并且没有观察到客观缓解。[6] 与之形成鲜明对比的，是CD3结合亲和力高出一个数量级的tarlatamab。在10 mg Q2W的获批方案下，其III期临床ORR达到35%，CRS发生率约56%，但三级及以上CRS仅约1–2%。[15] 这些结果至少告诉我们两件事情。第一，即使将CD3亲和力降低至数百nM，并依靠肿瘤抗原实现条件性激活，仍可能产生显著的系统性毒性。第二，改善给药方案确实能够提高TCE耐受性，但将剂量推得更高，并不意味着一定能将更高暴露转化为更好的抗肿瘤疗效。靶点选择、抗原密度、分子几何构型、患者T细胞状态、实体瘤微环境及临床给药方案，都会影响最终结果。ERY974绝不是一个设计粗糙的分子。恰恰相反，它体现了第一代TCE工程师对激活强度与系统性毒性之间平衡的深刻思考。但它依然没能跨过实体瘤临床疗效的门槛。二、第二信号，是突破实体瘤TCE困境的希望吗？随着靶向CD19、CD20、BCMA和GPRC5D的多款TCE获批，T细胞连接器已经在血液肿瘤治疗中取得巨大成功。然而，同样的设计迁移到实体瘤，表现却天差地别。我在前文一种设计，两种命运：TCE为何在血液瘤与实体瘤中天差地别中，展开讨论过其中的生物学原因。传统TCE解决的主要是T细胞激活的第一信号，即通过CD3启动TCR信号通路。但高质量、可持续的T细胞免疫反应还需要共刺激信号，以及支持T细胞扩增、存活和代谢的细胞因子环境。血液肿瘤处在相对友好的免疫生态中。B细胞本身是专业抗原递呈细胞，部分恶性B细胞仍保留共刺激配体表达，能够为CD3激活的T细胞提供额外支持。而实体瘤通常缺乏共刺激配体，却可能表达PD-L1等免疫抑制分子。同时，大量肿瘤浸润T细胞已经历慢性刺激，增殖能力下降、代谢储备不足。因此，实体瘤TCE对于补充第二信号，有着更加明确的需求。 CD28、4-1BB（CD137）、OX40等共刺激受体，由此成为下一代TCE的重要工程方向。其中CD137尤其具有吸引力。它属于TNF受体超家族，通常在T细胞激活后上调，通过TRAF及NF-κB等信号通路支持T细胞存活、增殖和效应功能，理论上可以改善TCE诱导的T细胞功能衰减。但问题随之而来。如果简单地把CD3结合臂和CD137激动臂放在同一个分子上，药物便可能在没有肿瘤抗原参与的情况下，同时结合甚至交联T细胞上的CD3和CD137。这相当于把第一信号和第二信号同时交给了一个不受肿瘤空间约束的激动剂。对于原本就容易引起CRS的TCE而言，显然不是一个理想的设计。三、Dual-Ig：两条Fab、三种特异性、次序激活 Chugai给出了一个巧妙的解法。不是简单在双抗上增加一个CD137结合臂，而是开发一种能够识别两种不同抗原的Fab。这就是Dual-Ig平台。传统抗体的Fab通常主要识别一种抗原。Dual-Ig则通过大规模抗体筛选和CDR工程改造，让同一个Fab既能识别CD3，又能识别CD137。更精妙的是，这两个结合过程相互竞争：同一个Dual-Fab无法同时结合CD3和CD137。因此，整个三特异性抗体的构造依然接近普通IgG，同时Fc经过工程改造，降低FcγR和C1q介导的非预期效应。 SAIL66的三个抗原结合亲和力分别为：CLDN6为3.82 nM，CD137为27.3 nM，CD3为1,340 nM。与ERY974相比，SAIL66的CD3亲和力进一步降低了约6.5倍，比tarlatamab弱约90倍。与此同时，CD137结合比CD3强约49倍。[7] 这种悬殊的亲和力差异具有明确的设计逻辑。静息T细胞表达CD3，但CD137表达通常较低。SAIL66可以先通过CD3结合诱导初始激活；随着CD3信号诱导CD137表达，Dual-Fab又可以凭借更强的CD137亲和力，逐渐转向结合CD137，提供后续共刺激。Chugai的SPR实验也证明，CD137能够竞争性地取代已经结合在Dual-Fab上的CD3。当然，这并不意味着每个SAIL66分子都严格按照同步的时间程序依次工作。真实细胞膜上的受体密度、结合动力学和空间分布更为复杂。这种设计提供的是有利于阶段性信号转换的条件，而非绝对的时间开关。此外，CD3与CD137的激活机制本身也存在重要差异。CD3信号依赖TCR-CD3复合体的适当聚集及下游信号组织，而CD137作为TNFR超家族受体，通常需要更高阶的受体聚集，才能有效招募TRAF等信号蛋白，启动共刺激程序。因此，单个游离的SAIL66分子即使结合CD137，也未必能够产生充分的激动活性。但在CLDN6阳性肿瘤细胞表面，多个SAIL66分子通过CLDN6结合，富集在肿瘤细胞膜上。当T细胞接近肿瘤时，局部高密度的Dual-Fab能够分别结合相邻T细胞上的CD137，促进受体在细胞接触界面聚集，从而启动下游信号。CLDN6不仅决定药物在哪里富集，还为CD137的有效激活提供了空间支架。在缺乏CLDN6的外周组织，单价CD137结合与Fc失活设计，理论上可以减少非预期的受体交联。同时，由于CD3与CD137竞争同一个Dual-Fab，也避免了单个抗体分子直接交联这两个不同受体。这正是Dual-Ig最精妙的地方：不是简单拼接三个抗原结合域，而是利用受体聚集对几何构型的要求，为T细胞信号激活建立空间约束。 2024年发表的临床前研究中，SAIL66确实显示出令人鼓舞的结果。在CLDN6阳性肿瘤细胞与Jurkat报告细胞的共培养体系中，SAIL66不仅能够激活CD3下游NFAT信号，也能够激活CD137相关NF-κB信号；而在CLDN6阴性细胞存在时，这些信号明显减弱或消失。在小鼠肿瘤模型中，与传统CLDN6/CD3 TCE相比，SAIL66还能够增加肿瘤内T细胞浸润，改善部分T细胞功能状态，并产生更强的肿瘤抑制作用。[7] 从结构设计、结合动力学，到体外和动物药效，Chugai似乎已经找到了增强T细胞激活、同时控制系统性毒性的办法。然而，进入临床，真正的考验才刚刚开始。四、实体瘤TCE临床转化的天坑我在之前的文章实体瘤TCE临床前疗效预测的天坑—从动物模型说起中，讨论过实体瘤TCE从临床前迈向人体研究时可能遭遇的诸多挑战。尽管经过详尽优化与筛选，SAIL66同样没能逃过这一关。 SAIL66于2023年进入首次人体I期研究，纳入CLDN6阳性的晚期实体瘤患者。根据ESMO 2026公开摘要1022P，共有22名患者接受治疗，涵盖卵巢癌、结直肠癌、肺癌、胰腺癌等肿瘤类型。[1] 试验探索了0.086、0.5、2.6、9、18和30 μg/kg，Q3W的固定剂量方案，以及以9或15 μg/kg QW的阶梯给药方案。最终，MTD被确定为18 μg/kg Q3W。临床疗效令人失望。22名患者中，没有观察到CR或PR，中位治疗持续时间仅1.3个月，6人（27.3%）发生三级及以上治疗相关不良事件。其中，肝酶升高是重要的剂量限制性毒性。更严重的是，21人产生ADA，发生率高达95.5%，并伴随药物暴露下降。在这些数据公开之前，Chugai已于2025年7月宣布终止SAIL66的内部开发。[8] 一款在临床前证明了肿瘤抗原依赖性CD3/CD137激活、T细胞浸润改善及更强抗肿瘤作用的三抗，最终没能在人体中产生任何客观缓解，反而在几乎所有患者体内诱发ADA，并遭遇明显的毒性限制。究竟是什么原因，让临床前的明日之星，进入人体后迅速坠落？五、意料之外的怪物：95.5%的ADA ADA并不是TCE开发中的罕见问题。但SAIL66的95.5%，仍然是一个极端的数字。历史上获批的首个双抗，靶向EpCAM/CD3的catumaxomab，曾报告接近95%的抗药抗体阳性率。但作为诞生于2000年代的早期抗体，它采用未经人源化的大鼠/小鼠杂交抗体结构，具有明显的异种蛋白免疫原性。[17] 随着人源化技术和抗体工程能力进步，这类问题已经得到很大改善。例如，艾美赛珠单抗的抗体结合域虽然同样源于鼠源筛选体系，但经过人源化及降低免疫原性的改造，七项III期及IIIb期研究汇总分析中，668名可评价患者只有34人（5.1%）产生治疗后ADA，仅极少数患者因此出现明显的药物暴露下降或疗效丧失。[9] 已获批的血液瘤TCE，大多数ADA发生率也通常低至个位数。即使偶有例外，例如靶向GPRC5D的talquetamab，报告了18–25%的ADA发生率，但尚未发现对临床疗效的明确影响。[16] 部分血液瘤TCE会直接清除B细胞或浆细胞，患者既往接受的治疗也可能削弱体液免疫，因此较低的ADA发生率，未必完全来自分子本身的低免疫原性。但对于不直接靶向B细胞的实体瘤TCE tarlatamab，在接受推荐剂量方案的445名患者中，ADA发生率也只有约8%。[11] 这些例子说明，不清除B细胞、通过CD3激活T细胞，都不足以单独解释SAIL66如此之高的ADA发生率。 SAIL66绝不是粗制滥造的分子。出身Chugai名门的它，经历过复杂的人源化及蛋白工程优化。然而，22人中21人产生ADA，提示这可能并非少数患者的免疫原性风险，而是分子存在某种普遍的免疫识别倾向。既可能来自分子本身，也可能来自生产、制剂及聚集状态。尤其值得怀疑的，是Dual-Ig为了实现两种不同抗原的竞争性结合，所引入的特殊序列与构象。 Chugai在DLL3/CD3/CD137 Dual-Ig的原始论文中披露，研究者以CD3抗体为起点，保留关键CD3结合残基，同时通过CDR-H3延长及其他CDR位点的多样化改造，获得能够竞争性结合CD3与CD137的Dual-Fab。[12] 这种设计具有极高的工程价值，但也可能产生常规抗体中罕见的氨基酸序列组合，以及不同于天然抗体的局部构象，从两个层面增加免疫原性。第一，产生新的B细胞识别表位。抗体可变区经过大量突变后，可能在蛋白表面形成特殊的空间构象。即使单个氨基酸残基并不陌生，它们在三维结构中的排列，也可能成为B细胞受体容易识别的构象表位（conformational epitope）。第二，产生新的T细胞表位。药物被抗原递呈细胞摄取、加工后，相关肽段可能通过HLA-II呈递给CD4 T细胞。如果工程改造引入了具有较强HLA结合能力、又缺乏充分免疫耐受的肽段，就可能诱发药物特异性的辅助T细胞反应。两种机制相互配合，更加可能促进ADA生成的反应。更值得注意的是，B细胞识别的空间表位，并不一定与CD4 T细胞最终识别的线性肽段位于同一区域。因此，传统的序列相似性、人源化程度，甚至基于已知T细胞表位数据库的免疫原性预测，都可能遗漏部分风险。其他可能性同样不能排除，包括Fc异源二聚化工程引入的特殊序列、Fab恒定区配对工程、局部蛋白不稳定，以及生产或制剂过程形成的高分子量聚集体。 SAIL66的免疫原性究竟来自特殊序列、构象表位，还是不同结合状态下暴露的动态表位，目前仍然没有答案。接近100%的ADA阳性率，并不能证明所有患者都识别同一个表位。但这么多不同患者几乎都识别了这个药物，是否意味着SAIL66存在一个特别突出的免疫优势表位（immunodominant epitope）？如果是，那么通过精准定位和重新工程化设计，或许能够显著降低ADA风险。但如果不同患者分别识别不同表位，或者生产、制剂稳定性造成了异常免疫原性，那么解决方式将完全不同。因此，95.5%的ADA既是一场灾难，也可能是一条异常清晰、值得追查的工程线索。六、Dual-Ig平台，真的凉透了吗？单看临床数据，SAIL66接近100%的ADA发生率、0%的ORR，可以说糟到不能再糟。但这是否意味着临床前体现的CD3/CD137次序激活、肿瘤抗原条件性共刺激设计完全不成立？依土猫鄙见，倒也未必。首先，接近100%的ADA发生率是事实，但这并不意味着观察到的所有毒性都必然来自Dual-Ig本身的CD3/CD137激活设计。对于这样一种高度依赖空间聚集和受体几何构型的三抗，ADA的出现，还可能改变药物原本精密设计的聚集模式。回到SAIL66的作用机制。在没有CLDN6参与的情况下，单个SAIL66分子无法利用肿瘤细胞表面进行高密度锚定，其单价CD137结合也难以有效产生高阶受体聚集。但如果ADA能够同时结合多个SAIL66分子，形成多价免疫复合物，那么原本需要CLDN6提供的局部聚集条件，就可能被部分替代。如果这些复合物仍保留CD3或CD137结合能力，便可能在缺乏肿瘤抗原的情况下，造成异常的受体交联和免疫激活。这并非毫无依据的猜想。Roche在CEA/CD3 TCE cibisatamab的临床研究中发现，ADA阳性患者在后续输注中出现输注相关反应的频率和严重程度增加。研究者提出，ADA可能通过交联CD3结合的TCE，在不依赖肿瘤抗原的情况下促进T细胞激活。[10] 与此同时，也不能排除中和性ADA（neutralizing ADA）的存在。另一项针对cibisatamab ADA的深入分析发现，所检测的10份患者血清样本均出现针对CD3结合结构域的ADA反应，而针对CEA结合结构域的反应较少。这些ADA与功能性药物暴露显著下降相关。[13] 因此，ADA可能通过不同方式影响药物。一种是遮挡结合表位、加速清除，降低功能性药物浓度，导致疗效下降；另一种则可能通过交联药物分子，改变受体聚集方式，诱发非预期的免疫激活。对于多克隆ADA，两种作用甚至可能同时存在。当然，目前尚无直接证据证明SAIL66的ADA能够形成具有CD3或CD137激动活性的免疫复合物。这仍然只是一个需要验证的机制假说。但如果SAIL66的临床表现确实同时受到中和性ADA、药物清除加快及异常聚集的影响，那么在如此严重的干扰下，我们或许还无法充分判断Dual-Ig原本的抗肿瘤潜力。虽然本次临床试验结果是彻头彻尾的阴性，但如果能够彻查ADA识别哪些表位、是否具有中和活性，以及是否改变受体聚集模式，就有机会区分分子本身的缺陷与继发免疫原性造成的干扰。倘若主导ADA反应的表位可以通过合理的蛋白工程改造规避，那么基于Dual-Ig的含共刺激三特异性TCE，仍可能获得更宽的治疗窗口、更低的毒性和更好的疗效。SAIL66的临床失败虽然已经确定，但Dual-Ig平台的药理学潜力，是否也已被彻底否定，仍然值得追究。七、究竟是Dual-Ig设计失败，还是ADA破坏了设计？这是我认为整个事件中最有价值的问题。SAIL66在临床前证明了CD3及CD137信号能够依赖CLDN6激活，但进入人体后，却遭遇药物暴露下降和剂量限制性毒性。我们需要区分几种不同的可能的失败原因。第一种：患者存在针对SAIL66的预存抗体。如果部分患者在首次给药前已经存在能够识别SAIL66的抗体，那么高ADA发生率可能并非完全来自治疗后的免疫诱导，而是某些天然抗体或既往免疫反应与SAIL66发生交叉识别。这需要分析给药前血清，确认基线ADA是否存在、识别哪些表位，以及是否具有中和或交联能力。如果多数患者存在针对共同结构的预存抗体，那么规避这一表位，可能成为明确的工程优化方向。第二种：药物本身的CD3/CD137激活仍然过强。假设多数ADA并非预存，而是在治疗后诱导产生。如果患者在第一次给药、尚未产生ADA时，就出现显著CRS，或者毒性随初始药物暴露同步增加，那么应当首先怀疑分子本身的激活机制、靶抗原正常组织表达及局部免疫反应。这意味着即使通过Dual-Ig降低CD3结合、限制CD137聚集，人体仍可能对这种激活模式过于敏感。尤其值得注意的是，SAIL66的剂量限制性毒性主要涉及肝酶升高。CLDN6在健康成人组织中表达有限，但其潜在低水平表达、正常组织可及性，以及局部免疫激活造成的肝损伤，都需要重新评估，不能简单归咎于ADA。第三种：ADA诱导产生以后，药物暴露下降，毒性反而加重。如果患者最初几次给药耐受性较好，之后随着ADA滴度升高，才出现更加严重的CRS、输注反应或其他炎症性毒性，而且无法用剂量增加解释，就需要认真考虑ADA是否改变了药物的聚集及激活模式。如果与此同时，药物清除加快、有效暴露下降，甚至初始可检测的药效学活性逐渐消失，那么ADA就可能同时成为疗效受限和异常毒性的驱动因素。但即使如此，还需要回答：在ADA尚未出现时，药物是否真正达到足够的肿瘤组织暴露？是否已经诱导T细胞浸润、扩增及肿瘤细胞杀伤？如果连这些早期药效学证据都缺乏，消除ADA也未必能够恢复疗效。 CD137共刺激的初衷，是让T细胞在启动以后获得更好的增殖和功能维持。然而，如果初始CD3信号已经被过度削弱，或者药物尚未建立有效免疫突触就被ADA加速清除，那么后续共刺激便没有机会充分发挥作用。于是，SAIL66面临一个更复杂的问题：究竟是缺乏足够的CD3启动，还是无法维持有效药物暴露，抑或CD137共刺激本身就不足以克服实体瘤微环境的限制？目前SAIL66摘要没有披露个体水平的CRS发生时间、ADA滴度、游离药物浓度及细胞因子动态，因此无法判断是否存在上述模式。真正关键的不只是毒性有多严重，而是毒性发生在什么时候，与药物暴露及ADA出现存在怎样的先后关系。这组纵向临床数据，将直接影响我们如何判断：SAIL66究竟是共刺激条件性激活设计失败，还是一个被异常免疫原性严重干扰、尚未得到充分临床验证的分子？抑或两种问题同时存在？八、失败的临床，能否成为下一代分子设计的突破口？土猫愚见，这组结果虽然令人失望，却未必没有价值。某种意义上，一个异常高、且能重复观察到的失败信号，可能比零星、难以预测的毒性更容易提供明确的工程改进方向。前提是找到原因。最值得做的，不是简单重新开发一个亲和力更低的CD3臂，或者增加几项常规免疫原性预测，而是从患者样本出发，弄清楚ADA到底识别了什么，又改变了什么。首先是ADA表位定位。利用患者血清，分别测试ADA对CLDN6 Fab、CD3/CD137 Dual-Fab、工程化Fc及相关结构域的识别，再通过竞争结合、结构分析和点突变扫描，定位主要的免疫识别区域。如果多数患者的ADA集中识别某个Dual-Fab表位，就可能成为重新设计的直接线索。但如果仅找到B细胞构象表位，并不意味着消除它就一定能消除ADA。与此同时，还需要分析药物来源肽段的HLA-II呈递情况，通过CD4 T细胞实验确认真正的免疫原性序列。其次是分子稳定性与聚集行为。需要重新审视临床制剂批次中的高分子量聚集体、表面疏水区域、化学降解、构象稳定性及生产过程杂质。对于高度工程化的Dual-Fab，局部稳定性变化可能在常规抗体成药性分析中并不突出，却在长期储存或人体给药后产生不同后果。第三，也是最有机制价值的，是ADA对受体聚集及T细胞激活的影响。应利用患者来源ADA或经过表位验证的替代抗体，与SAIL66形成免疫复合物，再检测其是否能够在缺乏CLDN6的条件下，诱导CD3或CD137聚集、NFAT/NF-κB信号、细胞因子释放及T细胞活化。如果结果为阳性，临床ADA就不再只是一个PK问题，而是直接改变药物作用机制的因素。最后，还必须将这些体外实验与患者纵向数据对应。 ADA何时出现？滴度如何变化？是否具有中和活性？药物浓度何时下降？CRS或其他不良事件发生于哪个给药周期？患者是否出现过短暂的肿瘤内免疫活化证据？只有回答这些问题，才能区分可以通过蛋白工程修复的缺陷，以及即使消除ADA也无法挽回的药理学限制。九、阴性结果并非过往努力的墓碑，而应成为下一次突破的基石 Chugai在抗体工程上的成就，绝不仅体现在某一个分子。从ART-Ig利用共同轻链与Fc异源二聚化解决双抗装配，到FAST-Ig通过链间电荷工程扩大不同轻链的设计自由度，再到TRAB利用肿瘤抗原依赖性CD3激活进行T细胞重定向，直至Dual-Ig尝试在一条Fab上实现两种免疫受体的竞争性识别。这些技术不断拓展抗体作为药物的边界。但生命系统的复杂之处恰恰在于，分子能够按照设计结合受体，并不意味着人体一定按照设计产生免疫反应。SAIL66的临床失利，并不一定证明Dual-Ig的设计毫无价值，也不能将失败简单归咎于ADA。它真正暴露的，是一个更深层次的研发挑战：对于高度工程化的免疫治疗药物，设计影响的不仅是分子本身的物理化学特性，更是复杂生命系统内的动态相互作用。在AI药物研发越来越强大的今天，越来越优秀的蛋白结构预测、序列生成、亲和力设计和免疫原性预测工具可以帮助我们探索过去难以想象的设计空间，也让许多原本需要反复试错的工程问题，更快获得候选答案。但一个预测完美的蛋白结构，未必能形成理想的免疫突触；一种在小鼠模型中有效的共刺激模式，未必适合长期处于免疫抑制状态的人类实体瘤；即使完成了详尽的临床前评估，也仍可能在患者身上诱发意料之外的生物学后果。艾美赛珠单抗当年的成功之道，并不是一次理性设计便走向临床的奇迹，而是在早期失败之后，通过数万次功能筛选和数千次工程优化，逐渐找到生物学功能、药代、安全性和制造工艺之间的平衡。 SAIL66如今遭遇了令人沮丧的挫败，Chugai也付出了真实的临床开发成本。但如果能够利用这22名患者提供的宝贵数据，弄清楚ADA的来源、对药物作用机制的影响，以及真正限制疗效的因素，那么这场失败依然有机会成为下一代免疫治疗设计的重要基础。所以，科学的进步，并不总是来自预期中的成功。每一次经过精心设计、又被认真追究的失败，都可能揭示之前尚未理解的自然规律，为下一次突破提供基础。最值得尊敬的科学探索，并不是永远不会失败，而是在即使最精心的设计被真实世界否定之后，仍然有能力找到失败的原因，并据此重新出发。参考文献 [1] Harano K, et al. A first-in-human phase 1 study of SAIL66 in patients with claudin-6-positive locally advanced or metastatic solid tumors.ESMO Congress. 2026. Abstract 1022P. [2] Lasker Foundation. Bispecific antibody for treating hemophilia A. 2026.https://laskerfoundation.org/winners/bispecific-antibody-for-treating-hemophilia-a/ [3] Hattori K, Kitazawa T, Igawa T. From Biological Insight to a New Class of Medicines for Hemophilia A: The 2026 Lasker-DeBakey Clinical Medical Research Award.JAMA. 2026. [4] Determination of starting dose of the T cell-redirecting bispecific antibody ERY974 targeting glypican-3 in first-in-human clinical trial.Sci Rep. 2022. [5] Giffin MJ, et al. AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer.Clin Cancer Res. 2021;27:1526–1537. [6] Murakami H, et al. Phase I study of ERY974 in patients with glypican-3-positive advanced solid tumors.Cancer Res. 2026;86(Suppl). [7] Kamikawa T, Kimura N, Ishii S, et al. SAIL66, a next generation CLDN6-targeting T-cell engager, demonstrates potent antitumor efficacy through dual binding to CD3/CD137.J Immunother Cancer. 2024;12. [8] Chugai Pharmaceutical. Chugai Announces Consolidated 2025 2nd Quarter Results. July 24, 2025. [9] Schmitt C, Emrich T, Chebon S, et al. Low immunogenicity of emicizumab in persons with haemophilia A.Haemophilia. 2021;27:984–992. [10] Segal NH, Melero I, Moreno V, et al. CEA-CD3 bispecific antibody cibisatamab with or without atezolizumab in patients with CEA-positive solid tumours.Nat Commun. 2024;15:4091. [11] Amgen. IMDELLTRA (tarlatamab-dlle). US Prescribing Information. Revised September 2026. [12] Mikami H, Feng S, Matsuda Y, et al. Engineering CD3/CD137 Dual Specificity into a DLL3-Targeted T-Cell Engager Enhances T-Cell Infiltration and Efficacy against Small-Cell Lung Cancer.Cancer Immunol Res. 2024;12:719–730. [13] Lotz GP, Lutz A, Martin-Facklam M, et al. Characterization of anti-drug antibody responses to the T-cell engaging bispecific antibody cibisatamab to understand the impact on exposure.Front Immunol. 2024;15:1406353. [14] ClinicalTrials.gov. NCT07107490. A Phase I Study of ALPS12 in Patients With Extensive Stage Small Cell Lung Cancer. [15] Mountzios G, Sun L, Cho BC, et al. Tarlatamab in Small-Cell Lung Cancer after Platinum-Based Chemotherapy.N Engl J Med. 2025;393:349–361. [16] Janssen Biotech. TALVEY (talquetamab-tgvs). US Prescribing Information. Section 12.6: Immunogenicity. 2025. [17] Heiss MM, Murawa P, Koralewski P, et al. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial.Int J Cancer. 2010. 免责声明与风险提示：本文的分析与推演均基于公开信息。笔者不对相关公开信息的准确性、完整性、及时性及适用性作出任何明示或暗示的保证。所载所有内容及观点仅代表笔者个人立场，与笔者现任职、曾任职的任何机构、雇主或关联方均无任何关联，亦绝不代表上述机构的官方立场、观点或意见。本文所包含的任何内容，均不构成任何实质性的投资建议、财务建议或临床医疗指导 Banner artist: St. after Cigs

2026-10-23

·BioSpace

European Commission approves Johnson & Johnson’s TECVAYLI®▼ (teclistamab) monotherapy for relapsed/refractory multiple myeloma, expanding treatment options from first relapse

Approval is based on Phase 3 results demonstrating significant progression-free and overall survival benefits, with teclistamab reducing risk of disease progression or death by 71% and risk of death by 40%, compared with the standard of care 1 Further expands treatment options for relapsed/refractory multiple myeloma, making teclistamab available in the second line setting through both combination and monotherapy approaches 1, 2 BEERSE, BELGIUM, Oct. 23, 2026 (GLOBE NEWSWIRE) -- Johnson & Johnson, a worldwide leader in multiple myeloma, today announced that the European Commission (EC) has approved an indication extension of TECVAYLI ® (teclistamab) for the treatment of adult patients with relapsed/refractory multiple myeloma (RRMM) who have received at least one prior therapy. Building on the recent EC approval of teclistamab plus daratumumab , this indication extension introduces teclistamab monotherapy as an additional second-line treatment option for patients living with RRMM and reinforces the wider potential of teclistamab across both monotherapy and combination approaches for patients at first relapse. 1, 2 Building momentum for teclistamab-based regimens at first relapse Many patients with multiple myeloma relapse after first-line therapy, and treatment options are increasingly limited once the disease becomes refractory to established treatment classes. 3,4 Despite recent advances, there remains a critical need for additional effective immunotherapy options at first relapse, where treatment decisions can have a meaningful impact on long-term outcomes. 3,4 Expert and company perspectives on expanding treatment options with teclistamab “Patients with relapsed or refractory multiple myeloma often experience shorter remissions and diminishing responses with each subsequent line of therapy, making effective treatment at first relapse increasingly important,” said Cyrille Touzeau, M.D., Ph.D., Professor, University Hospital of Nantes.* “The approval of teclistamab monotherapy gives physicians an additional immunotherapy option in the second-line setting, supported by significant improvements in both progression-free and overall survival. With nearly two-thirds of patients achieving a complete response or better, the results seen with teclistamab are encouraging and demonstrate the depth of response achieved in the study.” “Building on the recent approval of teclistamab plus daratumumab, this European Commission further reinforces the strength of bispecific-based immunotherapy approaches as early as second line,” said Ester in ’t Groen, EMEA Therapeutic Area Head, Haematology, Johnson & Johnson. “Together, the MajesTEC-3 and MajesTEC-9 studies support the potential of teclistamab-based therapies to advance the treatment paradigm and improve outcomes for patients earlier in their disease journey.” “Today's approval marks another important step in our ambition to bring innovative immunotherapies earlier in the treatment journey for patients with multiple myeloma,” said Yusri Elsayed, M.D., M.H.Sc., Ph.D., Global Therapeutic Area Head, Oncology, Johnson & Johnson. “With positive Phase 3 results from both MajesTEC-3 and MajesTEC-9, we continue to build evidence for teclistamab-based regimens across a broad second-line patient population. Together, these studies highlight the potential of teclistamab to become a foundational option at first relapse, while reinforcing our ambition to improve long-term outcomes for patients.” Phase 3 monotherapy data demonstrated significant survival benefits compared with standard of care, supporting the use of teclistamab in second-line RRMM The updated label will replace the current monotherapy indication and posology, and introduce a simplified dosing schedule with monthly dosing frequency from month 7 onwards. Eligible patients may also transition to monthly dosing as early as month 3, further optimising the dosing schedule and potentially reducing the treatment burden for patients. The EC approval is supported by data from the Phase 3 MajesTEC-9 study ( NCT05572515 ), evaluating the efficacy and safety of teclistamab, a bispecific T-cell engager, as a monotherapy versus pomalidomide, bortezomib and dexamethasone (PVd) or carfilzomib and dexamethasone (Kd) in patients with RRMM who have received one to three prior lines of therapy, including an anti-CD38 monoclonal antibody and lenalidomide. 5 Significant improvements were observed in both progression-free survival (PFS) and overall survival (OS). 1 Treatment with teclistamab demonstrated a 71% reduction in the risk of disease progression or death (hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.23-0.38; p <0.001) and a 40% reduction in the risk of death (HR, 0.60; 95% CI, 0.43-0.83; p = 0.002) compared with the standard of care. 1 Teclistamab’s 18-month PFS rate was 69.8% versus 26.9% for the standard of care, and the 18-month OS rate was 79.2% with teclistamab versus 68.6% for the standard of care. 1 Additionally, all key secondary endpoints showed significant improvement with teclistamab versus standard of care, including nearly two-thirds of patients achieving a complete response or better (≥CR; 65.9% vs. 16.8%; p <0.001). 1 Safety pro with that established in prior studies The safety pro teclistamab in the study was consistent with its known safety profile. 1, 6 The median duration of treatment on teclistamab was almost two times longer than standard of care (13.1 months vs. 7.0 months), with similar rates of adverse events (AEs) observed between teclistamab and standard of care (99.7% vs. 97.9%). 1 Grade 3/4 AEs occurred in 84.9% of teclistamab recipients versus 76.3% of PVd or Kd recipients, while Grade 5 AEs occurred in 6.5% versus 3.5%, respectively. 1 Infections were more frequent with teclistamab than with standard of care (Grade 3/4, 41.6% vs. 29.0%), and rates of Grade 3 or higher infections decreased over time. 1 About the MajesTEC-9 study MajesTEC-9 ( NCT05572515 ) is an ongoing, randomised Phase 3 study comparing teclistamab monotherapy with pomalidomide, bortezomib and dexamethasone (PVd) or carfilzomib and dexamethasone (Kd) in patients with relapsed/refractory multiple myeloma (RRMM) who have received 1–3 prior lines including lenalidomide and an anti-CD38 monoclonal antibody. 5 The primary endpoint is progression-free survival (PFS); secondary endpoints include complete response or better (≥CR), duration of response (DoR), overall survival (OS), safety and patient-reported outcomes. 5 About Teclistamab Teclistamab received European Commission (EC) approval in August 2022 for the treatment of patients with RRMM who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody, and have demonstrated disease progression on the last therapy. 7 In August 2026, the EC also approved a Type II variation application for teclistamab in combination with daratumumab as early as second line for RRMM. 2 Teclistamab is an off-the-shelf (or ready-to-use) bispecific antibody. Teclistamab, a subcutaneous injection, redirects T-cells through two cellular targets (BCMA and CD3) to activate the body’s immune system to fight cancer. 6,8 Teclistamab is currently being evaluated in several combination studies. 9,10,11,12 To date, more than 30,700 patients have been treated worldwide with teclistamab. 13 For a full list of adverse events and information on dosage and administration, contraindications and other precautions when using teclistamab, please refer to the Summary of Product Characteristics at: . ▼ In line with EMA regulations for new medicines and those given conditional approval, teclistamab is subject to additional monitoring. 6 About Multiple Myeloma  Multiple myeloma is a complex blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow. 14,15 In multiple myeloma, these malignant plasma cells continue to proliferate, accumulating in the body and crowding out normal blood cells, as well as often causing bone destruction and other serious complications. 16,17 In the European Union, it is estimated that more than 35,000 people were diagnosed with multiple myeloma in 2024, and more than 21,900 patients died. 18 Patients living with multiple myeloma experience relapses which become more frequent with each line of therapy, while remissions become progressively shorter. 19 Whilst some patients with multiple myeloma initially have no symptoms, others can have common signs and symptoms of the disease, which can include bone fracture or pain, low red blood cell counts, fatigue, high calcium levels, infections, or kidney damage. 20 About Johnson & Johnson At Johnson & Johnson, we believe health is everything. Our strength in healthcare innovation empowers us to build a world where complex diseases are prevented, treated, and cured, where treatments are smarter and less invasive, and solutions are personal. Through our expertise in Innovative Medicine and MedTech, we are uniquely positioned to innovate across the full spectrum of healthcare solutions today to deliver the breakthroughs of tomorrow, and profoundly impact health for humanity. Learn more at . Follow us at . Cautions Concerning Forward-Looking Statements This press release contains “forward-looking statements” as defined in the Private Securities Litigation Reform Act of 1995 regarding product development and the potential benefits and treatment impact of teclistamab and daratumumab. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialise, actual results could vary materially from the expectations and projections of Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; competition, including technological advances, new products and patents attained by competitors; challenges to patents; changes in behaviour and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson’s most recent Annual Report on Form 10-K, including in the sections captioned “Cautionary Note Regarding Forward-Looking Statements” and “Item 1A. Risk Factors,” and in Johnson & Johnson’s subsequent Quarterly Reports on Form 10-Q and other filings with the Securities and Exchange Commission. Copies of these filings are available online at , , or on request from Johnson & Johnson. Johnson & Johnson does not undertake to update any forward-looking statement as a result of new information or future events or developments. Key Search Terms MajesTEC-9 Phase 3 clinical trial TECVAYLI Teclistamab Relapsed and or refractory multiple myeloma (RRMM) Early relapse multiple myeloma Second-line multiple myeloma treatment First relapse therapy for multiple myeloma Treatment resistance in multiple myeloma Progression-free survival (PFS) in multiple myeloma Overall survival (OS) in multiple myeloma Multiple myeloma Bispecific antibody therapy CD38-targeted therapy BCMA-targeted bispecific therapy EMEA haematology pipeline Multiple myeloma innovation Multiple myeloma treatment *Cyrille Touzeau, M.D., Ph.D., Professor, University Hospital of Nantes, has provided consulting, advisory, and speaking services to Johnson & Johnson; he has not been paid for any media work. CP-606702 October 2026 END References: 1 Touzeau C, et al. Teclistamab monotherapy in multiple myeloma with 1–3 prior lines of therapy. N Engl J Med. 2026;395(5):440-453. 2 Johnson & Johnson.com. European Commission approves Johnson & Johnson’s TECVAYLI ® ▼ (teclistamab) plus daratumumab for relapsed/refractory multiple myeloma, offering a potential new standard of care. Available at: European Commission approves Johnson & Johnson’s TECVAYLI®▼ (teclistamab) plus daratumumab for relapsed/refractory multiple myeloma, offering a potential new standard of care . Last accessed: October 2026. 3 Johnson & Johnson.com. TECVAYLI® monotherapy demonstrates superior progression-free and overall survival versus standard of care as early as first relapse in patients with multiple myeloma predominantly refractory to anti-CD38 therapy and lenalidomide. Available at: . Last accessed: October 2026. 4 Ramasamy K, et al. Real-World Treatment Patterns and Clinical Outcomes in Patients With Multiple Myeloma Previously Treated With Lenalidomide and an Anti-CD38 Monoclonal Antibody. Clin Lymphoma Myeloma Leuk. 2025 May;25(5):337-348.e2. 5 ClinicalTrials.gov. A Study Comparing Teclistamab Monotherapy Versus Pomalidomide, Bortezomib, Dexamethasone (PVd) or Carfilzomib, Dexamethasone (Kd) in Participants With Relapsed or Refractory Multiple Myeloma (MajesTEC-9). Available at: . Last accessed: October 2026. 6 European Medicines Agency. TECVAYLI Summary of Product Characteristics. Available at: . Last accessed: October 2026. 7 Johnson & Johnson.com. Janssen Marks First Approval Worldwide for TECVAYLI®▼ (teclistamab) with EC Authorisation of First-in-Class Bispecific Antibody for the Treatment of Patients with Multiple Myeloma. Available at: . Last accessed: October 2026. 8 Moreau P, et al. Teclistamab in Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2022;387(6):494-505. 9 ClinicalTrials.gov. A Study of Teclistamab With Other Anticancer Therapies in Participants With Multiple Myeloma (MajesTEC-2). Available at: . Last accessed: October 2026. 1 0 ClinicalTrials.gov. A Study of the Combination of Talquetamab and Teclistamab in Participants With Relapsed or Refractory Multiple Myeloma. Available at: . Last accessed: October 2026. 11 ClinicalTrials.gov. A Study of Subcutaneous Daratumumab Regimens in Combination With Bispecific T Cell Redirection Antibodies for the Treatment of Participants With Multiple Myeloma. Available at: . Last accessed: October 2026. 1 2 ClinicalTrials.gov. A Study of Teclistamab in Combination With Daratumumab Subcutaneously (SC) (Tec-Dara) Versus Daratumumab SC, Pomalidomide, and Dexamethasone (DPd) or Daratumumab SC, Bortezomib, and Dexamethasone (DVd) in Participants With Relapsed or Refractory Multiple Myeloma (MajesTEC-3). Available at: . Last accessed: October 2026. 1 3 J&J Data on File. Number of Patients Treated with TECVAYLI Worldwide as of July 2026. 1 4 Abdi J, et al. Drug Resistance in Multiple Myeloma: Latest Findings on Molecular Mechanisms. Oncotarget. 2013;4(12):2186-2207. 1 5 Myeloma UK. What is myeloma? Available at: . Last accessed: October 2026. 1 6 Lungu O, et al. Mechanistic insights into bone destruction in multiple myeloma: cellular and molecular perspectives. Journal of Bone Oncology. 2025;51:100668. 1 7 Mayo Clinic. Multiple Myeloma. Available at: . Last accessed: October 2026. 1 8 ECIS - European Cancer Information System. Estimates of Cancer Incidence and Mortality in 2024, by Country. Multiple Myeloma. Available at: . Last accessed: October 2026. 1 9 Bhatt P, et al. Relapsed/Refractory Multiple Myeloma: A Review of Available Therapies and Clinical Scenarios Encountered in Myeloma Relapse. Curr Oncol. 2023;30(2):2322-2347. 2 0 American Cancer Society. Multiple Myeloma: Early Detection, Diagnosis and Staging. Available at: . Last accessed: October 2026. CONTACT: Media contact: Jenni Mildon jmildon@its.jnj.com +44 7920 418 552 Investor contact: Jess Margevich investor-relations@its.jnj.com

临床3期临床结果免疫疗法上市批准

100 项与塔奎妥单抗相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
D12180	-	L01FX29	-

研发状态

批准上市

10 条最早获批的记录,

后查看更多信息

适应症	国家/地区	公司	日期
难治性多发性骨髓瘤	日本	Janssen Pharmaceutical KK	2025-06-24
复发性多发性骨髓瘤	日本	Janssen Pharmaceutical KK	2025-06-24
多发性骨髓瘤	美国	Janssen Biotech, Inc.	2023-08-09

未上市

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
残留肿瘤	临床3期	-	Johnson & Johnson	2026-09-01
复发性浆细胞骨髓瘤	临床2期	美国	Janssen Research & Development LLC	2026-07-17
复发性浆细胞骨髓瘤	临床2期	美国	Johnson & Johnson Pharmaceutical Research & Development LLC	2026-07-17
外周干细胞移植	临床2期	美国	Janssen Scientific Affairs LLC	2025-06-05
阴燃多发性骨髓瘤	临床2期	美国	Janssen Scientific Affairs LLC	2023-12-04
多发性骨髓瘤的髓外病变	临床2期	西班牙	Janssen Pharmaceutica NV	2023-09-21
血液肿瘤	临床1期	美国	Janssen Research & Development LLC	2017-12-16
血液肿瘤	临床1期	比利时	Janssen Research & Development LLC	2017-12-16
血液肿瘤	临床1期	荷兰	Janssen Research & Development LLC	2017-12-16
血液肿瘤	临床1期	西班牙	Janssen Research & Development LLC	2017-12-16

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


IMS2026	N/A	复发性多发性骨髓瘤	126	Talquetamab	顧夢製獵鹽選衊積壓壓(築顧膚製觸鬱範獵顧構) = 餘壓鹽廠淵構鹽構積願廠構製襯窪艱觸衊範繭 (衊齋衊醖觸繭鑰餘築淵 ) 更多	积极	2026-09-23
NCT06500884 (TALisman, IMS2026)	临床2期	多发性骨髓瘤	58	Talquetamab	顧鬱壓繭顧糧願糧遞襯(範範積築蓋廠築遞鹹願) = 壓襯膚蓋鏇衊網顧廠夢願鏇製範壓衊鏇網醖網 (餘築鹹憲鏇壓鏇鏇壓鑰 ) 更多	不佳	2026-09-23
				Talquetamab+clonazepam	顧鬱壓繭顧糧願糧遞襯(範範積築蓋廠築遞鹹願) = 遞糧壓齋廠襯網構廠鏇願鏇製範壓衊鏇網醖網 (餘築鹹憲鏇壓鏇鏇壓鑰 ) 更多
IMS2026	N/A	多发性骨髓瘤 GPRC5D	220	Cilta-cel	淵鑰遞網製遞艱築蓋繭(膚鬱鬱製網餘遞築艱願) = 構繭鏇夢積衊願淵鏇衊鹹觸廠製壓糧遞鹽衊築 (範築顧膚憲淵範蓋膚蓋 ) 更多	不佳	2026-09-23
				Ide-cel	觸觸網鏇簾築鹽鑰鑰鹽(糧壓膚簾選艱鹹製夢膚) = 衊觸願夢範襯齋餘齋憲衊鹹憲構選構鏇獵範蓋 (觸衊鹹鹹齋積繭淵範淵 ) 更多
IMS2026	N/A	浆细胞肿瘤	10	Talquetamab	壓憲蓋製襯衊淵選鬱鏇(艱鹹淵願製淵構淵醖鑰) = Taste/oral, skin, and nail changes occurred in 9/10, 6/10, and 6/10, respectively. Talquetmab-induced dizziness-ataxia syndrome occurred in 2/10. 襯窪齋範艱夢鑰鹹壓膚 (選鹹鏇蓋餘襯繭顧鹽鬱 )	积极	2026-09-23
IMS2026	N/A	多发性骨髓瘤	129	Talquetamab	鏇襯蓋蓋網窪鏇鏇願齋(願淵鹹觸壓鑰選糧獵積) = 獵鏇繭獵遞觸壓廠築鬱壓淵構遞夢遞網齋醖廠 (繭襯顧鏇餘鑰鏇膚糧齋 ) 更多	积极	2026-09-23
				Talquetamab (Renal Insufficiency)	獵齋鬱簾衊鑰鏇簾願壓(夢簾壓糧蓋衊齋範願鏇) = 淵憲膚選築齋餘廠衊艱壓餘衊鬱遞廠築醖廠製 (齋積獵築廠築廠齋衊衊 ) 更多
IMS2026	N/A	多发性骨髓瘤	176	Talquetamab	鏇淵淵鹽鏇餘餘艱夢顧(廠簾簾衊壓範網製繭顧) = 鬱襯構壓鬱膚鹽艱繭憲選鹽糧齋窪憲膚窪簾窪 (顧艱衊窪網餘製糧淵蓋, 12.0 ~ NE) 更多	积极	2026-09-23
				Talquetamab (USPI criteria)	鏇淵淵鹽鏇餘餘艱夢顧(廠簾簾衊壓範網製繭顧) = 鬱願鑰窪獵願鑰淵鹽夢選鹽糧齋窪憲膚窪簾窪 (顧艱衊窪網餘製糧淵蓋, 10.8 ~ NE) 更多
NCT05455320 (MonumenTAL-3, IMS2026)	临床3期	复发性多发性骨髓瘤二线	864	Talquetamab (Tal) + Daratumumab (D) + Pomalidomide (P)	鬱願壓夢淵製簾衊積夢(繭餘艱夢膚鏇積壓網憲) = 構鹹淵醖糧醖蓋築願壓鑰鏇蓋鹽壓鏇鬱選蓋鏇 (簾廠築糧糧繭憲糧衊襯, 75.8 ~ 85.7) 更多	积极	2026-09-23
				Talquetamab (Tal) + Daratumumab (D)	鬱願壓夢淵製簾衊積夢(繭餘艱夢膚鏇積壓網憲) = 範觸網蓋壓構廠淵範齋鑰鏇蓋鹽壓鏇鬱選蓋鏇 (簾廠築糧糧繭憲糧衊襯, 71.7 ~ 82.5) 更多
IMS2026	N/A	复发性多发性骨髓瘤	51	Teclistamab	艱築繭鹹鑰餘壓積遞窪(廠築鬱構築鏇膚鹽齋築) = 衊淵鏇繭選鏇壓繭觸憲獵壓醖鏇壓積鹹遞顧網 (積願醖遞廠網襯鑰醖廠 ) 更多	积极	2026-09-23
				Talquetamab	齋窪網壓鑰衊獵選膚衊(夢醖憲構糧願襯築夢餘) = 夢鏇鑰網衊網顧壓壓範夢醖廠繭襯願觸網窪積 (衊鹹築醖製鹽衊簾膚製 ) 更多
MonumenTAL-1 (IMS2026)	临床2期	复发性多发性骨髓瘤	50	Talquetamab+Tocilizumab	齋鹽夢壓衊鏇選廠製廠(網顧糧製鏇壓構窪鹹糧) = 簾遞遞衊鬱願積蓋顧獵願憲簾蓋壓願繭廠築選 (構鏇願顧鹹製鬱觸鹽鏇 ) 更多	积极	2026-09-23
				Talquetamab+Tocilizumab (2 SUDs(0.06 mg/kg and 0.4 mg/kg))	齋鹽夢壓衊鏇選廠製廠(網顧糧製鏇壓構窪鹹糧) = 積憲築鬱網淵鑰襯鬱製願憲簾蓋壓願繭廠築選 (構鏇願顧鹹製鬱觸鹽鏇 ) 更多
IMS2026	N/A	复发性多发性骨髓瘤	9	Teclistamab (Tec) and/or Talquetamab (Tal)	廠艱窪壓願簾繭築襯構(蓋範衊觸鑰夢醖鑰遞憲) = No CRS or major infections were observed, and one patient experienced grade 2 ICANS which resolved within 48 hours. 膚憲蓋鏇獵夢構膚齋網 (鬱鏇鹹鹹膚築選廠憲獵 ) 更多	积极	2026-09-23