A Phase 1, First-in-Human, Open-Label Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of AMG 562 in Subjects With Relapsed / Refractory Diffuse Large B-cell Lymphoma, Mantle Cell Lymphoma, or Follicular Lymphoma

Evaluate the safety and tolerability of AMG 562 in adult subjects with DLBCL, MCL, or FL. Estimate the maximum tolerated dose (MTD) and/or a biologically active dose (e.g., recommended phase 2 dose [RP2D])

开始日期2018-10-29

申办/合作机构

Amgen, Inc.

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项与 Surovatamig 相关的文献（医药）

2022-09-08·Blood

T-cell exhaustion induced by continuous bispecific molecule exposure is ameliorated by treatment-free intervals

Article

作者: Theurich, Sebastian ; Vick, Binje ; Straub, Tobias ; Bücklein, Veit ; Leutbecher, Alexandra ; Sponheimer, Monika ; Kazerani, Maryam ; von Bergwelt-Baildon, Michael ; Kischel, Roman ; Weigert, Oliver ; Marcinek, Anetta ; Scheurer, Michaela ; Philipp, Nora ; Nixdorf, Daniel ; Wulf, Jan ; Nicholls, Alyssa ; Rejeski, Kai ; Brauchle, Bettina ; Subklewe, Marion ; Lacher, Sonja M. ; Muth, Amelie ; Jeremias, Irmela ; Ohlmeyer, Malte ; Rohrbacher, Lisa ; Hänel, Gerulf

AbstractT-cell–recruiting bispecific molecule therapy has yielded promising results in patients with hematologic malignancies; however, resistance and subsequent relapse remains a major challenge. T-cell exhaustion induced by persistent antigen stimulation or tonic receptor signaling has been reported to compromise outcomes of T-cell–based immunotherapies. The impact of continuous exposure to bispecifics on T-cell function, however, remains poorly understood. In relapsed/refractory B-cell precursor acute lymphoblastic leukemia patients, 28-day continuous infusion with the CD19xCD3 bispecific molecule blinatumomab led to declining T-cell function. In an in vitro model system, mimicking 28-day continuous infusion with the half-life–extended CD19xCD3 bispecific AMG 562, we identified hallmark features of exhaustion arising over time. Continuous AMG 562 exposure induced progressive loss of T-cell function (day 7 vs day 28 mean specific lysis: 88.4% vs 8.6%; n = 6; P = .0003). Treatment-free intervals (TFIs), achieved by AMG 562 withdrawal, were identified as a powerful strategy for counteracting exhaustion. TFIs induced strong functional reinvigoration of T cells (continuous vs TFI-specific lysis on day 14: 34.9% vs 93.4%; n = 6; P < .0001) and transcriptional reprogramming. Furthermore, use of a TFI led to improved T-cell expansion and tumor control in vivo. Our data demonstrate the relevance of T-cell exhaustion in bispecific antibody therapy and highlight that T cells can be functionally and transcriptionally rejuvenated with TFIs. In view of the growing number of bispecific molecules being evaluated in clinical trials, our findings emphasize the need to consider and evaluate TFIs in application schedules to improve clinical outcomes.

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
复发性弥漫性大B细胞淋巴瘤	临床1期	德国	Amgen, Inc.	2018-10-29
复发性弥漫性大B细胞淋巴瘤	临床1期	比利时	Amgen, Inc.	2018-10-29
滤泡性淋巴瘤	临床1期	美国	Amgen, Inc.	2018-10-29
滤泡性淋巴瘤	临床1期	比利时	Amgen, Inc.	2018-10-29
滤泡性淋巴瘤	临床1期	加拿大	Amgen, Inc.	2018-10-29
滤泡性淋巴瘤	临床1期	德国	Amgen, Inc.	2018-10-29
套细胞淋巴瘤	临床1期	比利时	Amgen, Inc.	2018-10-29
套细胞淋巴瘤	临床1期	美国	Amgen, Inc.	2018-10-29
套细胞淋巴瘤	临床1期	德国	Amgen, Inc.	2018-10-29
套细胞淋巴瘤	临床1期	加拿大	Amgen, Inc.	2018-10-29

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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


NCT03571828 (Phase I study of AMG 562, CTgov)	临床1期	套细胞淋巴瘤 \| 滤泡性淋巴瘤 \| 复发性弥漫性大B细胞淋巴瘤	10	AMG 562 (Cohort 1: AMG 562 0.1 μg)	淵壓獵範壓簾鑰鑰觸膚(窪遞繭齋壓積遞齋積壓) = 製壓壓蓋選憲鑰鏇構願製鏇夢餘遞膚鹽鹽構窪 (鑰淵鏇積窪構遞選鬱襯, 廠遞鑰製網鏇蓋觸膚構 ~ 糧獵觸範構製獵鹹餘衊) 更多	-	2024-03-22
NCT03571828 (Phase I study of AMG 562, CTgov)	临床1期	套细胞淋巴瘤 \| 滤泡性淋巴瘤 \| 复发性弥漫性大B细胞淋巴瘤	10	AMG 562 (Cohort 2: AMG 562 0.3 μg)	淵壓獵範壓簾鑰鑰觸膚(窪遞繭齋壓積遞齋積壓) = 齋築廠鏇鹽襯憲鬱憲顧製鏇夢餘遞膚鹽鹽構窪 (鑰淵鏇積窪構遞選鬱襯, 繭鹹衊積鑰衊繭餘餘願 ~ 襯廠獵窪鬱遞鑰顧範網) 更多	-	2024-03-22
NCT03571828 (Phase I study of AMG 562, ICML2021)	临床1期	套细胞淋巴瘤 \| 滤泡性淋巴瘤 \| 复发性弥漫性大B细胞淋巴瘤 CD19 \| CD3	9	AMG 562 0.1mg	(壓願襯窪觸遞築鑰蓋積) = n = 1, Gr 4 醖顧鬱淵窪築網壓襯範 (糧遞簾遞鏇構觸餘遞艱 ) 更多	不佳	2021-06-17