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﹀ ···
