Phase I study of the safety and clinical activity of the interleukin-8 inhibitor AMY109 combined with atezolizumab in patients with advanced solid cancers

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作者: Yamamoto, Noboru ; Narikiyo, Takatsugu ; Ogami, Chika ; Nakagawa, Yuki ; Koyama, Takafumi ; Mizugaki, Hidenori ; Takubo, Ryoko ; Sekiya, Mayuko ; Ikeda, Masafumi ; Kuboki, Yasutoshi ; Yamaguchi, Yuki ; Ishida, Takaaki ; Kitano, Shigehisa

BackgroundImmunosuppressive conditions within the tumor microenvironment (TME) can allow tumors to evade the immune system, including by hampering programmed death ligand 1 (PD-L1) inhibitor activity. Interleukin (IL)-8 contributes to immunosuppression and fibrosis in the TME. AMY109, a humanized anti-IL-8 monoclonal antibody, reduced fibrosis and decreased immunosuppressive cells in tumor tissue in animals. Combining AMY109 with atezolizumab (anti-PD-L1 antibody) may enhance its antitumor effects by making the TME more favorable to PD-L1 inhibition.MethodsThis multicenter, open-label, dose-escalation study evaluated the safety, pharmacokinetics, and clinical activity of AMY109 plus atezolizumab in patients with previously treated advanced solid tumors and Eastern Cooperative Oncology Group performance status 0 or 1. Patients received AMY109 (2–45 mg/kg) plus atezolizumab (1200 mg) intravenously every 3 weeks in part 1, and AMY109 (15–45 mg/kg) plus atezolizumab (1200 mg) in part 2. Primary endpoints were the dose-limiting toxicity (DLT), safety, and pharmacokinetics of AMY109 and atezolizumab in Part 1, and safety and antitumor activity per investigator-assessed Response Evaluation Criteria in Solid Tumors 1.1 in part 2. Exploratory analyses of peripheral and tumor biomarker were conducted.ResultsOverall, 38 patients (18 in part 1 and 20 in part 2) were enrolled. Part 1 showed no DLTs and a dose-proportional increase in AMY109 exposure over 2–45 mg/kg, with no apparent change in mean atezolizumab serum concentrations across AMY109 dosing. Plasma IL-8 concentration accumulation was seen in all dose cohorts after AMY109 initiation. Grade 1–3 treatment-related adverse events (AEs) occurred in 21 of 38 patients (55%). Treatment-related serious AEs occurred in two patients (5%). No AEs led to treatment withdrawal. Partial responses (PRs) occurred in 2 of 38 patients; the confirmed objective response rate was 5%. These patients had uterocervical and pancreatic cancer, respectively, and had been treated for >500 days at the cut-off date: one had received 45 mg/kg of AMY109 throughout, and the other received 30 mg/kg of AMY109 until cycle 5, then 45 mg/kg thereafter.ConclusionsWith no DLTs, AMY109 plus atezolizumab was well tolerated in patients with advanced solid tumors, with no new safety signals. AMY109 showed a dose-proportional increase in exposure. The PRs in two patients were durable.

2023-02-22·Science Translational Medicine1区 · 医学

A long-acting anti–IL-8 antibody improves inflammation and fibrosis in endometriosis

1区 · 医学

Article

作者: Sankai, Tadashi ; Konno, Ryo ; Ohmori, Hiroshi ; Nishimoto-Kakiuchi, Ayako ; Yamamoto, Sachiya ; Tanimura, Hiromi ; Sakamoto, Yuichiro ; Kayukawa, Yoko ; Nakano, Kiyotaka ; Asanuma, Kentaro ; Yamada-Okabe, Hisafumi ; Maeda, Atsuhiko ; Nakamura, Genki ; Sato, Izumi ; Kato, Atsuhiko

Current pharmacological treatments for endometriosis are limited to hormonal agents that can relieve pain but cannot cure the disease. Therefore, the development of a disease-modifying drug for endometriosis is an unmet medical need. By studying human endometriotic samples, we found that the progression of endometriosis was associated with the development of inflammation and fibrosis. In addition, IL-8 expression was highly up-regulated in endometriotic tissues and closely correlated with disease progression. We created a long-acting recycling antibody against IL-8 (AMY109) and evaluated its clinical potency. Because rodents do not produce IL-8 and do not experience menstruation, we analyzed the lesions in cynomolgus monkeys that spontaneously developed endometriosis and in a surgically induced endometriosis monkey model. Both spontaneously developed and surgically induced endometriotic lesions demonstrated pathophysiology that was highly similar to that of human endometriosis. Once-a-month subcutaneous injection of AMY109 to monkeys with surgically induced endometriosis reduced the volume of nodular lesions, lowered the Revised American Society for Reproductive Medicine score as modified for monkeys, and ameliorated fibrosis and adhesions. In addition, experiments using cells derived from human endometriosis revealed that AMY109 inhibited the recruitment of neutrophils to endometriotic lesions and the production of monocyte chemoattractant protein-1 from neutrophils. Thus, AMY109 may represent a disease-modifying therapy for patients with endometriosis.

100 项与 AMY-109 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
子宫内膜异位症	临床2期	英国	Chugai Pharma France SAS	-
实体瘤	临床1期	日本	Chugai Pharmaceutical Co., Ltd.	2022-10-07

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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


JPRN-jRCT2080225101 (ESMO2023) 人工标引	临床1期	晚期恶性实体瘤	38	AMY109 2–45 mg/kg+atezolizumab 1200 mg	(餘壓積鑰廠膚簾襯衊鏇) = 壓淵襯壓窪顧製餘鏇襯構鹽鑰網鏇廠簾願膚鏇 (遞膚蓋網選獵糧壓膚願 )	积极	2023-10-23
				AMY109 15–45 mg/kg+atezolizumab 1200 mg	(襯餘積齋築憲廠繭窪憲) = 獵醖範鑰鹹選遞齋廠鬱糧簾鏇鹽網觸糧鑰選鏇 (鹽壓觸鏇願齋積艱顧淵 ) 更多