This Master Protocol for Avelumab Continuation Sub-Studies is to provide continued treatment access, safety follow-up, and when applicable, overall survival follow-up for eligible participants who continue to derive a benefit from study intervention in the Pfizer-sponsored Avelumab parent studies.

开始日期2021-09-29

申办/合作机构

Pfizer Inc.

NCT03971409 / Recruiting临床2期IIT

Innovative Combination Immunotherapy for Metastatic Triple Negative Breast Cancer (TNBC): A Multicenter, Multi-Arm Translational Breast Cancer Research Consortium Study

This phase II trial studies how well the combination of avelumab with liposomal doxorubicin with or without binimetinib, or the combination of avelumab with sacituzumab govitecan works in treating patients with triple negative breast cancer that is stage IV or is not able to be removed by surgery (unresectable) and has come back (recurrent). Immunotherapy with checkpoint inhibitors like avelumab require activation of the patient's immune system.
This trial includes a two week induction or lead-in of medications that can stimulate the immune system. It is our hope that this induction will improve the response to immunotherapy with avelumab. One treatment, sacituzumab Govitecan, is a monoclonal antibody called sacituzumab linked to a chemotherapy drug called SN-38. Sacituzumab govitecan is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of tumor cells, known as Tumor-associated calcium signal transducer 2 (TROP2) receptors, and delivers SN-38 to kill them. Another treatment, liposomal doxorubicin, is a form of the anticancer drug doxorubicin that is contained in very tiny, fat-like particles. It may have fewer side effects and work better than doxorubicin, and may enhance factors associated with immune response. The third medication is called binimetinib, which may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth, and may help activate the immune system. It is not yet known whether giving avelumab in combination with liposomal doxorubicin with or without binimetinib, or the combination of avelumab with sacituzumab govitecan will work better in treating patients with triple negative breast cancer.

开始日期2019-07-08

申办/合作机构

Pfizer Inc.

[+5]

NCT03704298 / Terminated临床1期

A Phase 1/2 Multi-center Study Evaluating the Safety and Efficacy of Axicabtagene Ciloleucel in Combination With Utomilumab in Subjects With Relapsed/Refractory Large B-Cell Lymphoma

The primary objectives of this study are:
Phase 1: To evaluate the safety of axicabtagene ciloleucel in combination with utomilumab and to identify the most appropriate dose and timing of utomilumab to carry forward into Phase 2
Phase 2: To evaluate the efficacy of axicabtagene ciloleucel and utomilumab in participants with refractory large B-cell lymphoma

开始日期2018-11-20

申办/合作机构

Kite Pharma, Inc.

[+1]

100 项与 Utomilumab 相关的临床结果

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100 项与 Utomilumab 相关的转化医学

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100 项与 Utomilumab 相关的专利（医药）

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项与 Utomilumab 相关的文献（医药）

2024-02-02·Cancer immunology research

M9657 Is a Bispecific Tumor-Targeted Anti-CD137 Agonist That Induces MSLN-Dependent Antitumor Immunity without Liver Inflammation

Article

作者: Belousova, Natalya ; Brewis, Neil ; Webb, Lindsay ; Brandstetter, Susanne ; Jenkins, Molly H ; Saha, Somdutta ; Alimzhanov, Marat ; Schweickhardt, Rene ; Zhou, Xueyuan ; Helming, Laura ; Rabinovich, Brian ; Zheng, Wenxin ; Soloviev, Maria ; Xu, Chunxiao ; Yalavarthi, Sireesha ; Deshpande, Amit M

Abstract:

The costimulatory receptor CD137 (also known as TNFRSF9 or 4-1BB) sustains effective cytotoxic T-cell responses. Agonistic anti-CD137 cancer immunotherapies are being investigated in clinical trials. Development of the first-generation CD137-agonist monotherapies utomilumab and urelumab was unsuccessful due to low antitumor efficacy mediated by the epitope recognized on CD137 or hepatotoxicity mediated by Fcγ receptors (FcγR) ligand–dependent CD137 activation, respectively. M9657 was engineered as a tetravalent bispecific antibody (mAb2) in a human IgG1 backbone with LALA mutations to reduce binding to FCγRs. Here, we report that M9657 selectively binds to mesothelin (MSLN) and CD137 with similar affinity in humans and cynomolgus monkeys. In a cellular functional assay, M9657 enhanced CD8+ T cell–mediated cytotoxicity and cytokine release in the presence of tumor cells, which was dependent on both MSLN expression and T-cell receptor/CD3 activation. Both FS122m, a murine surrogate with the same protein structure as M9657, and chimeric M9657, a modified M9657 antibody with the Fab portion replaced with an anti-murine MSLN motif, demonstrated in vivo antitumor efficacy against various tumors in wild-type and human CD137 knock-in mice, and this was accompanied by activated CD8+ T-cell infiltration in the tumor microenvironment. The antitumor immunity of M9657 and FS122m depended on MSLN expression density and the mAb2 structure. Compared with 3H3, a murine surrogate of urelumab, FS122m and chimeric M9657 displayed significantly lower on-target/off-tumor toxicity. Taken together, M9657 exhibits a promising profile for development as a tumor-targeting immune agonist with potent anticancer activity without systemic immune activation and associated hepatotoxicity.

2024-02-01·Cancer

Phase 1/2 trial of avelumab combined with utomilumab (4‐1BB agonist), PF‐04518600 (OX40 agonist), or radiotherapy in patients with advanced gynecologic malignancies

Article

作者: Song, Juhee ; Zarifa, Abdulrazzak ; Hong, David Sanghyun ; Ahmed, Jibran ; Rodon Ahnert, Jordi ; Stephen, Bettzy ; Karp, Daniel ; Knisely, Anne ; Piha-Paul, Sarina A ; Fu, Siqing ; Alshawa, Anas ; Yang, Yali ; Dumbrava, Ecaterina E ; Jazaeri, Amir A ; Yap, Timothy A ; Naing, Aung ; Tsimberidou, Apostolia M ; Meric-Bernstam, Funda

Abstract:

Background:

Immune checkpoint blockade has shown mixed results in advanced/recurrent gynecologic malignancies. Efficacy may be improved through costimulation with OX40 and 4‐1BB agonists. The authors sought to evaluate the safety and efficacy of avelumab combined with utomilumab (a 4‐1BB agonist), PF‐04518600 (an OX40 agonist), and radiotherapy in patients with recurrent gynecologic malignancies.

Methods:

The primary end point in this six‐arm, phase 1/2 trial was safety of the combination regimens. Secondary end points included the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors and immune‐related Response Evaluation Criteria in Solid Tumors, the disease control rate (DCR), the duration of response, progression‐free survival, and overall survival.

Results:

Forty patients were included (35% with cervical cancer, 30% with endometrial cancer, and 35% with ovarian cancer). Most patients (n = 33; 83%) were enrolled in arms A–C (no radiation). Among 35 patients who were evaluable for efficacy, the ORR was 2.9%, and the DCR was 37.1%, with a median duration of stable disease of 5.4 months (interquartile range, 4.1–7.3 months). Patients with cervical cancer in arm A (avelumab and utomilumab; n = 9 evaluable patients) achieved an ORR of 11% and a DCR of 78%. The median progression‐free survival was 2.1 months (95% CI, 1.8–3.5 months), and overall survival was 9.4 months (95% CI, 5.6–11.9 months). No dose‐limiting toxicities or grade 3–5 immune‐related adverse events were observed.

Conclusions:

The findings from this trial highlight that, in heavily pretreated patients with gynecologic cancer, even multidrug regimens targeting multiple immunologic pathways, although safe, did not produce significant responses. A DCR of 78% in patients with cervical cancer who received avelumab and utomilumab indicates that further research on this combination in select patients may be warranted.

2024-01-01·Annals of hematology

A multi-cohort phase 1b trial of rituximab in combination with immunotherapy doublets in relapsed/refractory follicular lymphoma

Article

作者: Davids, Matthew S ; Merryman, Reid W ; Mei, Matthew ; Fisher, David C ; Kuntz, Thomas M ; Ng, Samuel ; Kim, Austin I ; Crombie, Jennifer L ; Odejide, Oreofe O ; Bartlett, Nancy L ; Parry, Erin M ; Cohen, Jonathon B ; Mehta-Shah, Neha ; Jacobsen, Eric D ; Ahn, Inhye E ; Isufi, Iris ; Jacobson, Caron A ; Wolff, Jacquelyn ; LaCasce, Ann S ; Redd, Robert A ; Brown, Jennifer R ; Freedman, Arnold S ; Armand, Philippe ; Kline, Justin ; Rodig, Scott J

Antibodies targeting PD-1 or 4-1BB achieve objective responses in follicular lymphoma (FL), but only in a minority of patients. We hypothesized that targeting multiple immune receptors could overcome immune resistance and increase response rates in patients with relapsed/refractory FL. We therefore conducted a phase 1b trial testing time-limited therapy with different immunotherapy doublets targeting 4-1BB (utomilumab), OX-40 (ivuxolimab), and PD-L1 (avelumab) in combination with rituximab among patients with relapsed/refractory grade 1-3A FL. Patients were enrolled onto 2 of 3 planned cohorts (cohort 1 - rituximab/utomilumab/avelumab; cohort 2 - rituximab/ivuxolimab/utomilumab). 3+3 dose escalation was followed by dose expansion at the recommended phase 2 dose (RP2D). Twenty-four patients were enrolled (16 in cohort 1 and 9 in cohort 2, with one treated in both cohorts). No patients discontinued treatment due to adverse events and the RP2D was the highest dose level tested in both cohorts. In cohort 1, the objective and complete response rates were 44% and 19%, respectively (50% and 30%, respectively, at RP2D). In cohort 2, no responses were observed. The median progression-free survivals in cohorts 1 and 2 were 6.9 and 3.2 months, respectively. In cohort 1, higher density of PD-1+ tumor-infiltrating T-cells on baseline biopsies and lower density of 4-1BB+ and TIGIT+ T-cells in on-treatment biopsies were associated with response. Abundance of Akkermansia in stool samples was also associated with response. Our results support a possible role for 4-1BB agonist therapy in FL and suggest that features of the tumor microenvironment and stool microbiome may be associated with clinical outcomes (NCT03636503).

项与 Utomilumab 相关的新闻（医药）

2024-03-14

·同写意

油门+刹车+化疗，肿瘤免疫三药联用临床二期获批

自2016年至今，同写意医药项目合作与交易论坛和估值班已举办多次，被业界誉为国内“医药BD黄埔军校”。应业界人士的要求，今年3月，同写意BD俱乐部将邀请专业导师、实战派总裁就医药BD交易与并购的新逻辑、新策略、新方法进行系统和全面分析与讲解。2024年3月14日，礼进生物宣布4-1BB激动抗体LVGN6051 （Exlinkibart, 艾林奇拜单抗）联合抗PD-1抗体及紫杉醇治疗头颈鳞癌的临床二期申请在中国获得批准。该研究旨在评估联合治疗方案用于治疗不适用含铂一线治疗或者既往多模式治愈性治疗后快速进展的复发/转移性头颈鳞癌的安全性和有效性。头颈部肿瘤已成为全球癌症负担的重要组成部分。最新数据表明，全世界每年约有90多万新发病例和40多万死亡病例，发病率居第7位。在我国，其发病率位于恶性肿瘤的第6位。据统计，我国每年新发头颈癌14.8万例左右，死亡近7.8万例。头颈部肿瘤是一个广泛的术语，包括起源于鼻窦、鼻腔、口腔、咽、喉、和唾液腺等的恶性肿瘤，其中90%以上为鳞状细胞癌。头颈部鳞癌（HNSCC）作为我国最常见的恶性肿瘤之一。复发转移是目前头颈癌临床治疗难点，约2/3患者初诊时即已到了晚期，复发率高，预后差。复发或转移性头颈癌中位总生存期少于1年，创新手段是患者最为迫切的期待。新辅助性/辅助性/治愈性治疗后快速复发/转移或不适铂化疗一线治疗的复发/转移的HNSCC患者，目前可用的治疗方案的治疗效果很不理想，有很大提升空间，急需新的治疗改善这部分患者的预后。越来越多的研究表明，4-1BB/CD137免疫激动剂抗体联合PD-1免疫检查点抑制剂可进一步增强免疫疗效。近期有研究证明紫杉醇在头颈癌的治疗中可协同PD-1抑制剂的免疫效应，包括降低Treg细胞、增加促炎性巨噬细胞、促进MDSC分化为DC细胞、增加MHC I类分子的表达及抗原的呈递，招募CD8+细胞杀伤T细胞穿行进入肿瘤，从而逆转免疫耐药。因此，将CD8+ T细胞的共刺激激动剂LVGN6051和共抑制剂阻断剂PD-1联合紫杉醇的三药联用方式，有望在进一步提升肿瘤免疫细胞激活效果的同时兼顾安全性的改善，提高患者生存质量和预后。“该临床实验将率先在东方医院启动”，领导这项试验的主要研究者同济大学东方医院郭晔教授说，“头颈鳞癌有很大的未满足临床需求，我们很高兴参与这个全新的疗法临床研究， CD8+ T细胞的共刺激4-1BB激动剂LVGN6051和共抑制剂阻断剂PD-1抗体联合化疗紫杉醇的临床研究结果值得期待”。肿瘤免疫逃逸CD8+ T细胞的共刺激激动剂LVGN6051和共抑制剂阻断剂PD-1联合紫杉醇的三药联用：“踩油门”和“去刹车”协同激活免疫+化疗触发肿瘤抗原释放。▪ 4-1BB（又称CD137）激动的抗肿瘤生物学原理 T细胞免疫反应已被证明在肿瘤控制中是必不可少的。为了诱导稳健和长期的T细胞免疫应答，需要T细胞受体（TCR）激活（信号1）以及足够的共刺激（信号2）。因此，包括4-1BB在内的几种共刺激TCRs已被评估用于癌症免疫治疗的可能性。TNF受体超家族成员4-1BB（CD137, TNFRSF9）于1989年首次被发现，随后被描述为T细胞和其他免疫细胞上的重要共刺激受体。4-1BB对T细胞的激活已被证明可以通过促进细胞因子分泌、增强细胞毒性和免疫记忆的形成等多种方式实现。4-1BB的激活效果尤其针对CD8+ T细胞最为明显。▪ 4-1BB激动抗体LVGN6051（Exlinkibart, 艾林奇拜单抗）研发在过去的十年中，4-1BB激动剂持续处于癌症免疫治疗的临床开发热点。第一代进入临床的4-1BB激动抗体中，urelumab（BMS-663513）因（肝）毒性，和utomilumab（PF-05082566）因缺乏疗效，均开发失败。礼进生物通过早期研究发现，IgG亚型（IgG的Fc与其受体FcγR相互作用）和4-1BB结合域共同决定了4-1BB激动抗体的抗肿瘤疗效和毒性。虽然超强4-1BB激动抗体可以在缺乏FcγR的情况下，通过4-1BB结合域直接激活CD137，但是大部分弱4-1BB激动抗体依赖FcγR激活4-1BB。这表明可以通过平衡4-1BB结合域活性和Fc与FcγR相互作用，来提升4-1BB激动抗体临床治疗窗口。LVGN6051是一种人源4-1BB单克隆抗体，通过对其Fc工程化改造，使其只选择性结合FcγRIIB，并仅在FcγRIIB存在的情况下条件性激活4-1BB。FcγRIIB在肿瘤微环境中的树突状细胞和巨噬细胞上有稳定高表达。相对于其它FcγR，它是唯一不会Fc效应功能的受体，且在正常组织中表达量更低。通过FcγRIIB严格依赖性的设计，LVGN6051实现了肿瘤微环境中的局部高度激活4-1BB，而在正常组织中相对“静默”，对于4-1BB激动单抗的临床治疗窗口拓展实现关键性突破。LVGN6051在单药或者和PD-1联用时都表现出良好临床安全性。另外，LVGN6051在既往PD-1治疗无应答/复发的末线实体瘤患者中显示出令人鼓舞的活性。值得强调的是，在美国前期研究中，LVGN6051、PD-1抗体和紫杉醇联用方案临床耐受性良好，且在末线头颈癌患者中实现50% ORR的显著疗效。▪ 化疗联合免疫检查点抑制剂紫杉烷类药物被广泛用于治疗实体肿瘤，包括乳腺癌、肺癌和胰腺癌等。众所周知，紫杉烷通过稳定微管抑制细胞分裂，但它们也可以作为脂多糖模拟物，激活巨噬细胞介导对肿瘤细胞的直接细胞毒性。紫杉烷还可能提供长期的免疫益处，已被证明可以增加肿瘤浸润淋巴细胞，并已证明对乳腺癌肿瘤中T细胞增殖和天然免疫细胞介导的肿瘤细胞溶解有积极作用。肿瘤浸润性淋巴细胞的大量涌入与化疗的良好反应曾被证明有正相关性。紫杉醇可能是一种特别强的免疫刺激剂，因为它既能激活CD8+ T细胞，又能减少免疫抑制细胞，如调节性T细胞。因此对于免疫疗法如PD-1抗体的单药治疗效果有限的适应症，免疫治疗和化疗药物联用如紫杉醇等已在临床积极探索和应用。更多优质内容，欢迎关注↓↓↓

免疫疗法临床2期

2024-01-06

·佰傲谷BioValley

第二代4-1BB激动剂的两条路

4-1BB（CD137，TNFRSF9）是T细胞上的重要共刺激受体（4-1BB/CD137，走过25年的风雨...），1989年被发现，1997年BMS的科学家在Nature Medicine发文：4-1BB单克隆抗体能够诱导改善的抗肿瘤T细胞活化，从而根除小鼠模型肿瘤。之后，BMS开发了4-1BB激动型抗体urelumab，但是有明显的肝毒性。第一代4-1BB激动剂第一代4-1BB激动剂有两个代表：urelumab（BMS-663513）和utomilumab（PF-05082566）。4-1BB抗体激动剂临床开发始于2005年，urelumab（BMS-663513）用于治疗晚期癌症（NCT00309023）。初步结果很有希望，但发生了两起肝毒性引起的死亡的不良事件。随后，当以安全剂量（0.1mg / kg）治疗，疗效有限。第二个4-1BB激动抗体utomilumab（PF-05082566），于2011年进入临床（NCT01307267）。与urelumab不同，utomilumab没有诱导重大毒性，但疗效非常有限，即使联用利妥昔也是如此，最终停止开发。第二代4-1BB激动剂两条路首要问题，需要搞明白4-1BB的定位：共刺激分子(免疫调节剂），起辅助角色。单药使用，安全剂量下，4-1BB激动剂不足以充分激活T细胞等。加大剂量，需要面临肝毒性的风险。和强力药物联合使用或者做成双特异/多特异性抗体是第二代4-1BB激动剂的两条路。CD137/4-1BB联合用药（Cancer Discov 2023）1.联合疗法虽然4-1BB表达与实体瘤中抗肿瘤CD8 + TIL的功能呈正相关，但T细胞上的4-1BB表达是多种多样的，且是动态变化的。为了充分发挥4-1BB激动剂作用，联合促进4-1BB表达的疗法是理想状态。联合免疫检查点抑制剂（最多的联用）在临床前研究中，PD1 / PD-L1抑制与4-1BB激动剂的组合显示出协同作用。因此，曾经临床试验中，有12种4-1BB激动剂联合使用PD-(L)1抑制剂。通过受体占用率优化以实现最佳MoA。如图所示，~50%的PD-L1受体占用率将导致最大的4-1BB激动作用，而在PD-L1受体占用率接近100%时，将达到最佳的PDL1抑制。然而，PD-L1的100%受体占有率会降低基于钟形曲线假说的4-1BB活化。因此，与非竞争性 PD-1 或 PD-L1 抑制剂的额外联合使用可能是有益的。Gen1046/BNT311和INBRX-105/ES101，PD-L1和4-1BB双特异性抗体，都与PD-1阻断抗体pembrolizumab联合。除免疫检查点抑制剂外，罗氏RO7227166(CD19X4-1BB)选择联用Cibisatamab(CEAXCD3) 或抗CD20 单抗 Obinutuzumab（奥妥珠单抗，商品名 Gazyva），治疗B细胞非霍奇金淋巴瘤。礼进生物LVGN6051 联用VEGFR抑制剂Anlotinib。2.双/三/四特异性4-1BB激动剂另一组第二代4-1BB激动剂是双特异性、三特异性或四特异性4-1BB激动剂。4-1BB抗体是其中一臂，第二靶点多样，包括肿瘤细胞表面分子（HER2，PSMA，EGFRvIII，Claudin18.2，ROR1，Nectin-4，CD47，CD19等），肿瘤基质和肿瘤浸润淋巴结表面分子（如FAP），肿瘤细胞和抗原呈递细胞表面分子（如PD-L1），仅在免疫细胞上表达的分子（CD40，OX40，CD3）。4-1BB是双特异性抗体排名第6的靶点，非T细胞衔接器双抗排名第1位，与PD-L1搭档。Acta Pharm Sin B. 2023小结在过去的5年中，对第二代4-1BB激动剂的研究已经大大扩展，克服第一代4-1BB激动剂的缺陷，实现安全有效的 4-1BB 超聚集。到目前为止，所有4-1BB激动剂都显示出良好的安全性和耐受性，并且具有可控的irAEs。但是有效性仍待时间证明。进行中的4-1BB激动剂临床试验NCT#Study TitleNCT05159388A Study of PRS-344/S095012 (PD-L1x4-1BB Bispecific Antibody-Anticalin Fusion) in Patients With Solid TumorsNCT05117242Safety and Efficacy Study of GEN1046 as a Single Agent or in Combination With Pembrolizumab for Treatment of Recurrent (Non-small Cell) Lung CancerNCT04144842Phase 1 Study in Patients With Advanced Solid Malignancies to Evaluate the Safety of ATOR-1017NCT033643484-1BB Agonist Monoclonal Antibody PF-05082566 With Trastuzumab Emtansine or Trastuzumab in Treating Patients With Advanced HER2-Positive Breast CancerNCT04826003Study To Evaluate Safety, Pharmacokinetics, Pharmacodynamics, And Preliminary Anti-Tumor Activity Of RO7122290 In Combination With Cibisatamab With Obinutuzumab Pre-TreatmentNCT05523947Clinical Trial of YH32367 in Patients With HER2 Positive Locally Advanced or Metastatic Solid TumorNCT05564806Study of YH004 (4-1BB Agonist Antibody) in Advanced Solid Tumors And Relapsed Or Refractory Non-Hodgkin LymphomaNCT03330561PRS-343 in HER2-Positive Solid TumorsNCT05301764A Study of LVGN6051 Combined With Anlotinib in Patient With Soft Tissue SarcomaNCT04740424FS222 First in Human Study in Patients With Advanced MalignanciesNCT04121676Anti-CD137 and Anti-CTLA-4 Monoclonal Antibody in Patients With Advanced CancerNCT05360381HLX35(EGFR/4-1BB Bispecific) in Patients With Advanced or Metastatic Solid TumorsNCT04648202FS120 First in Human Study in Patients With Advanced MalignanciesNCT05614258Study of ADG206 in Subjects With Advanced/Metastatic Solid TumorsNCT04077723A Study to Evaluate the Safety, Pharmacokinetics and Preliminary Anti-Tumor Activity of RO7227166 in Combination With Obinutuzumab and in Combination With Glofitamab Following a Pre-Treatment Dose of Obinutuzumab Administered in Participants With Relapsed/Refractory B-Cell Non-Hodgkin's LymphomaNCT05040932Study of YH004 (4-1BB Agonist Antibody) in Advanced or Metastatic MalignancyNCT04762641This is a Study to Evaluate the Safety and Tolerability of ABL503, and to Determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of ABL503 in Subjects With Any Progressive Locally Advanced or Metastatic Solid TumorsNCT03809624Study of INBRX-105 and INBRX-105 With Pembrolizumab in Patients With Solid Tumors Including Head and Neck Cancer参考文献Melero I, Shuford WW, Newby SA, Aruffo A, Ledbetter JA, Hellström KE, Mittler RS, Chen L. Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat Med. 1997;3(682–685):682–85Ignacio Melero et al,CD137 (4-1BB)-Based Cancer Immunotherapy on Its 25th Anniversary，Cancer Discov 2023;13:552–69Neil H Segal et al, Results from an Integrated Safety Analysis of Urelumab, an Agonist Anti-CD137 Monoclonal Antibody,Clin Cancer Res. 2017 Apr 15;23(8):1929-1936Sun Y, Yu X, Wang X, Yuan K, Wang G, Hu L, Zhang G, Pei W, Wang L, Sun C, Yang P. Bispecific antibodies in cancer therapy: Target selection and regulatory requirements. Acta Pharm Sin B. 2023 Sep;13(9):3583–97. doi: 10.1016/j.apsb.2023.05.023. Epub 2023 May 23. PMCID: PMC10501874.本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处﹀ ···

免疫疗法临床结果临床终止

2023-11-09

·生物制品圈

T细胞共刺激靶点：4-1BB (CD137) 附国内外研发管线

T细胞免疫反应对于肿瘤的控制有很重要的作用。为了诱导强劲和长效的T细胞免疫反应，首先需要T细胞受体（TCR）激活的信号（信号1）。信号1是抗原特异性的，该信号是通过T细胞受体和抗原呈递细胞（antigen-presenting cell, APC）上的多肽-主要组织相容性复合体（MHC）相互作用而实现的。但仅有信号1无法有效激活T细胞的免疫反应，还需要足够的共刺激信号（信号2）。不同于信号1，信号2不是抗原特异性的。信号2是通过抗原呈递细胞上表达的共刺激信号分子和T细胞的相互作用而实现的。共刺激信号对于T细胞的增殖，分化和存活是必要的（图1）。如果没有共刺激信号，可能会出现T细胞无应答/应答低下，细胞死亡或者会有免疫耐受的情况。比较常见的共刺激分子蛋白家族包括了IgSF(球型免疫蛋白超级家族)，TNRSF（肿瘤坏死因子受体超级家族），除此之外，还有一些来自于TIM家族，CD2/SLAM家族的共刺激因子。由于共刺激因子在T细胞免疫激活上的重要作用，它们也一直是肿瘤治疗领域备受关注的一类分子。我们今天所要介绍的4-1BB就是共刺激分子的一种，也是国内生物医药行业近几年来有不少关注并投入较多资源所开发的一个靶点。 4-1BB（又被称为CD137或者TNFRSF9）最早于1989年发现，是T细胞和其它免疫细胞上非常重要的共刺激受体，属于上文所说的TNRSF蛋白家族。 1997年Melero等人发现4-1BB的单克隆抗体在老鼠上展现出了诱导T细胞的抗肿瘤活性。4-1BB对于T细胞的激活主要包括以下效应：细胞增殖，细胞因子的释放，细胞毒性，长期免疫记忆的形成等等。大部分的T细胞激活是发生在CD8+ T细胞。 FDA已经批准的两款二代CAR-T细胞疗法，包括Kymriah (诺华)以及CARVYKTI（强生）就是使用了4-1BB作为其共刺激域。其它的二代CAR-T疗法使用CD28作为其共刺激域。虽然两者作为共刺激域在癌症患者身上展现出了相似的肿瘤控制率，但两者也发现了一些差异：CD28似乎有更高的细胞因子释放效应，能更好地促进T细胞增殖，但同时也有更高地神经毒性风险，而4-1BB能够促进更长期的T细胞持续性（persistence）。 4-1BB是一个糖基化的一型膜蛋白。它共有四个功能域（称为“CRD”， cysteine-rich pseudo repeats domain）。4-1BB配体（4-1BBL）是4-1BB的结合伴侣，它通常以同源三聚体复合物的形式表达在细胞表面。在受到抗原的刺激时，4-1BB和4-1BBL的有效结合可以激活迅速的受体激活。为了达到最佳的共刺激效果（信号2），4-1BB需要在细胞表面聚集成簇（图2）。 2.1 第一代4-1BB激动型药物 4-1BB激动型抗体的临床开发始于2005年，该款药物是由百时美施贵宝（BMS）公司开发的抗体药物urelumab (BMS-663513)。urelumab是一个人源化的抗4-1BB的IgG4亚型抗体。虽然一开始的研发数据不错，但之后发生了两起由于肝毒性的不良事件。随后的研究发现当urelumab以安全剂量（0.1 mg/kg）进行注射时,它的药效十分有限。第二款4-1BB的抗体药物是由辉瑞开发的utomilumab (PF-05082566)。该抗体药物是全人源的IgG2亚型抗体，并于2011年进入临床试验。虽然它没有像urelumab所展示出的安全性问题，但是它的疗效（单独用药或与利妥昔单抗联合有用）很有限，这个也是导致其最终临床开发的停止。 Urelumab和utomilumab，作为第一代的4-1BB抗体，展现出不同的激动剂活性以及肝脏毒性。这些差异目前认为是由于这两个分子在Fc端效应功能以及表位结合方面的差异而导致的。Fc端效应功能，尤其是和FcγRIIB的结合，通常被认为和肝脏毒性有关联（FcγRIIB在肝脏中的交联作用）。Urelumab，作为IgG4亚型，会有更强的FcγRIIB结合，这个可能是其与utomilumab（IgG2亚型）在肝脏毒性方面有差异的原因。表位结合是另一个urelumba与utomilumab有活性差异的原因。Urelumab和4-1BB是通过CRD1上的表位，该结合不影响4-1BB与天然4-1BB配体的结合。 Utomilumab与4-1BB结合的表位在CRD2和CRD3（图3）。这种结合方式所造成的结果就是：大量内源性的4-1BB配体会和utomilumab竞争去和4-1BB受体进行结合，限制了4-1BB受体成簇的活性（4-1BB受体的成簇是4-1BB的激动剂活性的促进因素）。这个解释了为什么urelumab（不影响4-1BB受体的成簇）相较于utomilumab（影响4-1BB受体的成簇）有更高的激动剂活性。 2.2 第二代4-1BB激动型药物 urelumab在utomilumab在临床试验中差强人意的表现并没有浇灭众多医药公司对于4-1BB靶点进一步探索。自从2017年初到如今，已经有超过40款4-1BB激动型药物进入了临床试验。虽然在2020年由于新冠疫情的原因，4-1BB药物的临床试验有暂时的下降但之后又展示出了强势反弹。之后可能会有越来越多的4-1BB激动型药物进入临床，因为不少国内外医药/生物科技公司都在积极进行4-1BB药物的临床前研究。这些在urelumab和utomilumab之后出现的4-1BB药物在本文都归类为第二代4-1BB激动型药物。第二代4-1BB激动型药物主要分为两大类：IgG类型(单抗结构)以及双/多抗的4-1BB激动型药物。IgG类型的二代4-1BB激动型药物和第一代药物（urelumab以及utomilumab）的作用机制有部分的一致性：它们大多数依赖Fcγ受体的交联作用，但它们的结合表位相较于第一代做了一定的改动（图3）。例如由苏州天演药业所开发的药物ADG106，该款药物和urelumab一样采取了IgG4亚型，但它却不结合urelumab的表位CRD1（如图3所示）。这个设计背后的逻辑是：让药物既有药效但减少其毒副作用，也就是更精准的调控了药物有效性和安全性之间的平衡（“sweet point” of functionality）。第二类的二代4-1BB激动型药物是双/多抗类型的激动型药物。这类药物除了结合4-1BB还会结合另一个靶点上至少一个的位点。增加一个靶点除了可以增加药物的特异性，交联作用，同时也让药物有了额外的激动或抑制活性，赋予药物额外的抗肿瘤性质。比较常见与4-1BB搭配的靶点包括了：PD-L1（例如天境生物的TJ-L14B，维立志博的LBL-024，普米斯生物的PM1003），FAP(例如罗氏的RG7827，勃林格殷格翰的BI765179)等。除此之外，这一类药物的Fc端也做了工程化改造以去除和Fcγ受体结合的能力但又保持了和新生儿Fc受体（FcRn）结合的能力以保证药物的体内半衰期。去除和Fcγ受体结合的能力旨在抑制urelumab中所看到的肝脏毒性，使药物有更好的安全性。采用了该设计策略的药物包括了罗氏的RG7827和RG6076，科望生物的ES101,天境生物的TJ-L14B等。表格1. 国内外生物医药企业4-1BB激动剂研发情况汇总（部分）免疫治疗和手术，放疗以及化疗一起构成了癌症的四种治疗手段。为了增加疗效，手术/化疗/放疗可以和免疫治疗作为联合治疗策略来。目前4-1BB联合放疗和化疗显示出不错的协同效应。除此之外，抗4-1BB的抗体也显示可以提高其它抗体（例如利妥昔单抗，曲妥珠单抗等）的疗效。基于4-1BB抗体的联合治疗方案可能是之后癌症治疗的一个发展方向。参考文献：[1] Claus C, Ferrara-Koller C, Klein C. The emerging landscape of novel 4-1BB (CD137) agonistic drugs for cancer immunotherapy.MAbs. 2023;15(1):2167189.[2] Wang YT, Ji WD, Jiao HM, Lu A, Chen KF, Liu QB. Targeting 4-1BB for tumor immunotherapy from bench to bedside. Front Immunol. 2022;13:975926.[3] Hodge JW, Greiner JW, Tsang KY, et al. Costimulatory molecules as adjuvants for immunotherapy.Front Biosci. 2006;11:788-803. 内容来源于网络，如有侵权，请联系删除。

细胞疗法免疫疗法

100 项与 Utomilumab 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10997	Utomilumab	-	DB15113

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
铂耐药性卵巢癌	临床2期	美国	National Cancer Institute	2018-07-16
复发性卵巢癌	临床2期	美国	National Cancer Institute	2018-07-16
HER2阳性转移性乳腺癌	临床2期	美国	Pfizer Inc.	2018-06-21
HPV16阳性口咽癌	临床2期	美国	Pfizer Inc.	2018-04-04
HPV16阳性口咽癌	临床2期	美国	ISA Pharmaceuticals BV	2018-04-04
唇肿瘤	临床2期	美国	ISA Pharmaceuticals BV	2018-04-04
唇肿瘤	临床2期	美国	Pfizer Inc.	2018-04-04
晚期癌症	临床2期	美国	National Cancer Institute	2017-08-02
晚期恶性实体瘤	临床2期	美国	National Cancer Institute	2017-08-02
去势抵抗性前列腺癌	临床2期	美国	National Cancer Institute	2017-08-02

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03414658 (AVIATOR/TBCRC045, CTgov)	临床2期	乳腺癌 \| HER2阳性乳腺癌 \| HER2阳性转移性乳腺癌	100	Trastuzumab+Vinorelbine (NH: Trastuzumab + Vinorelbine)	糧衊蓋製鹹蓋膚觸窪鹹(範艱製鑰遞艱築觸膚鬱) = 齋遞構範顧壓選鬱醖鏇壓艱鏇襯積鏇網鹹鏇艱 (艱廠選鏇遞膚窪選壓艱, 鹽蓋餘鹽網網壓淵壓艱 ~ 網蓋網壓製積廠網願鏇) 更多	-	2024-04-18
NCT03414658 (AVIATOR/TBCRC045, CTgov)	临床2期	乳腺癌 \| HER2阳性乳腺癌 \| HER2阳性转移性乳腺癌	100	Trastuzumab+Avelumab+Vinorelbine (NHA: Trastuzumab + Vinorelbine + Avelumab)	糧衊蓋製鹹蓋膚觸窪鹹(範艱製鑰遞艱築觸膚鬱) = 簾繭繭廠糧蓋鬱衊夢艱壓艱鏇襯積鏇網鹹鏇艱 (艱廠選鏇遞膚窪選壓艱, 顧夢網蓋淵鏇鏇鏇範願 ~ 製蓋夢壓顧鹽衊網選範) 更多	-	2024-04-18
NCT03414658 (AVIATOR/TBCRC045, SABCS2023)	临床2期	HER2阳性转移性乳腺癌 PD-L1 \| TIL	100	NH	簾簾艱廠衊網襯蓋淵繭(構獵遞鑰鹽衊鬱構鹽餘) = 鬱窪蓋鬱壓壓觸製廠糧淵願製選襯獵構艱鑰獵 (繭襯齋願艱遞願襯簾構, 0.37 ~ 0.86)	积极	2023-03-01
NCT03414658 (AVIATOR/TBCRC045, SABCS2023)	临床2期	HER2阳性转移性乳腺癌 PD-L1 \| TIL	100	NHA	簾簾艱廠衊網襯蓋淵繭(構獵遞鑰鹽衊鬱構鹽餘) = 膚襯衊憲築鏇衊構觸願淵願製選襯獵構艱鑰獵 (繭襯齋願艱遞願襯簾構 )	积极	2023-03-01
NCT03258008 (CTgov)	临床2期	HPV16阳性口咽癌 \| 唇肿瘤	3	Utomilumab	範遞構醖窪觸衊壓襯淵(鏇簾網膚積簾壓鏇憲網) = 憲構顧衊廠醖範鑰鏇夢鬱鑰艱獵網選網範製蓋 (顧網膚獵簾觸獵齋醖齋, 製網餘築願糧廠衊膚襯 ~ 製襯醖製憲淵窪積築齋) 更多	-	2022-12-16
NCT03364348 (CTgov)	临床1期	复发性乳腺癌 \| 晚期 HER2 阳性乳腺癌 \| 转移性乳腺癌 ... 更多	18	Trastuzumab+Utomilumab (Cohort 1A (Trastuzumab + Utomilumab))	構餘鏇範繭網鹽壓壓鹹(積願鏇獵簾廠積築積繭) = 窪選鬱廠遞糧顧積齋鏇鹹觸鹽鏇願窪顧餘簾顧 (鬱構醖壓構淵鏇選顧艱, 願夢壓製積簾膚鬱製觸 ~ 夢壓製膚衊壓構簾鑰壓) 更多	-	2022-10-19
NCT03364348 (CTgov)	临床1期	复发性乳腺癌 \| 晚期 HER2 阳性乳腺癌 \| 转移性乳腺癌 ... 更多	18	Trastuzumab+Utomilumab (Cohort 1B (Trastuzumab + Utomilumab))	構餘鏇範繭網鹽壓壓鹹(積願鏇獵簾廠積築積繭) = 衊鬱顧淵遞顧廠鑰廠築鹹觸鹽鏇願窪顧餘簾顧 (鬱構醖壓構淵鏇選顧艱, 獵獵窪夢積構壓醖製顧 ~ 膚鹽壓餘膚鹹廠繭範艱) 更多	-	2022-10-19
NCT02315066 (Pubmed)	临床1期	HR阳性/HER2低表达实体瘤	174	Ivuxolimab+Utomilumab	壓積築廠鏇醖獵製醖醖(觸鏇願鹹構夢鹽願窪鏇) = Grade 3-4 treatment-emergent AEs were reported in 28 (49.1%) patients versus 11 (36.7%) patients in dose-escalation and dose-expansion, respectively 醖壓範製願夢鬱顧觸窪 (願遞齋醖築鹹鹹壓衊鬱 ) 更多	积极	2022-10-01
NCT01307267 (Pubmed \| Clin Cancer Res) 人工标引	临床1期	CD20阳性的B细胞非霍奇金淋巴瘤 CD20 Positive	67	Utomilumab+Rituximab	願繭醖鏇願願範範觸餘(積簾醖廠範膚淵齋鬱製) = The majority of the utomilumab treatment-related adverse events (AE) were grade 1 to 2; the most common AE was fatigue (16.4%). 衊襯積顧壓繭觸醖範壓 (願餘鏇鏇襯鏇簾鑰選鏇 ) 更多	积极	2020-06-01
NCT02444793 (Pubmed \| J Immunother Cancer) 人工标引	临床1期	HR阳性/HER2低表达实体瘤 CRR4 Positive	24	Utomilumab+Mogamulizumab	顧製衊膚築願鑰廠憲鬱(鬱鏇鬱遞餘窪範遞鑰窪) = 築齋蓋蓋艱壓鏇網獵膚鹽鏇鹽艱廠選築築衊鬱 (窪淵願鏇鏇獵製顧鏇糧 ) 更多	积极	2019-12-04
NCT01307267 (Pubmed \| Clin Cancer Res) 人工标引	临床1期	晚期癌症	55	Utomilumab	艱蓋築淵範製製膚餘蓋(顧選鏇壓製網鹹夢淵壓) = 鏇構網鹽積鹽窪淵構鹽鏇範製衊餘憲遞壓積繭 (廠鬱選構蓋夢憲鬱遞窪 ) 更多	积极	2018-04-15
NCT02179918 (KEYNOTE-0036 \| B1641003, Pubmed \| Clin Cancer Res) 人工标引	临床1期	HR阳性/HER2低表达实体瘤	23	Utomilumab+Pembrolizumab	築觸觸餘衊願繭襯餘襯(製夢衊願窪願窪積觸膚) = 範鑰鹽遞願築鹽鏇鬱壓構醖鬱製簾衊簾觸顧鑰 (獵淵淵膚廠夢選壓鏇憲 )	积极	2017-09-15
not available (ICML2017)	临床1期	CD20 +	48	Utomilumab	構築築選願築願膚鹽襯(淵網網夢網餘窪餘壓簾) = The most common treatment-related AEs were fatigue (25%), infusion-related reaction (23%), and diarrhea (10%) 顧餘齋遞衊遞糧顧齋積 (鹽鹽艱糧網醖衊構鹽夢 ) 更多	积极	2017-06-07