Immunocore 宣布在 EASL 国际肝病大会上展示 ImmTAV 慢性乙型肝炎

StephenW

Immunocore 宣布在 EASL 国际肝病大会上展示 ImmTAV 慢性乙型肝炎 1 期试验的初步数据

    类别：抗体
    发表于 2022 年 6 月 25 日星期六 12:37
    点击次数：277

IMC-I109V，T 细胞受体双特异性，靶向包膜抗原

1 期研究的单次递增剂量部分，用于评估安全性、抗病毒活性和药代动力学

在最初的队列中，HBsAg 下降和 ALT 升高表明单次、非常低剂量的 IMC-I109V 引发了靶向活性，与作用机制一致并且没有任何不良事件

OXFORDSHIRE, UK & CONSHOHOCKEN, PA & ROCKVILLE, MD, USA I 2022 年 6 月 25 日 I Immunocore Holdings plc（纳斯达克股票代码：IMCR）（“Immunocore”或“公司”），一家商业阶段的生物技术公司，率先开发一种新型一类 T 细胞受体 (TCR) 双特异性免疫疗法旨在治疗广泛的疾病，包括癌症、自身免疫和传染病，今天宣布来自 IMC-I109V 首次人体临床试验的前三名患者的初步数据在英国伦敦的 EASL 国际肝脏大会上发表。

IMC-I109V 是一种 TCR 双特异性药物，旨在通过 T 细胞重定向特异性消除表达乙型肝炎表面抗原 (HBsAg) 的 HBV 感染肝细胞。 IMC-I109V 旨在通过募集未耗尽的 T 细胞来消除含有共价闭合环状 DNA 或整合的 HBV DNA 的肝细胞，从而克服 T 细胞功能障碍。除了治疗后 6 个月检测不到 HBV DNA 外，消除这些细胞对于实现“功能治愈”状态是必要的，该状态定义为持续 HBsAg 消失。由于该机制导致肝细胞溶解，预计肝酶会短暂升高，因此在公司的 IMC-I109V 首次人体研究中需要保守的给药方案。

在第一个队列中，根据最低预期生物效应水平 (MABEL)，三名患者每人接受 0.8 mcg 的单剂量。该初始队列中的剂量耐受性良好，并且与任何患者报告的不良事件无关。 IMC-I109V的最大血清浓度与剂量水平一致。到第 12 小时，血清浓度下降到定量下限以下。所有三名患者的前 24 小时内 IL-6 细胞因子水平均升高，这与 IMC-I109V 的作用机制一致。在给药后的最初几天观察到丙氨酸转氨酶 (ALT) 的小而短暂的升高，尽管在正常范围内，然后才恢复到正常水平。在三名患者中的两名中，血清 HBsAg 水平在输注后第 3-15 天期间以与 ALT 相同的动力学瞬时下降 11-15%，然后在输注后 3 周内恢复到基线。

“我们设计了基于 T 细胞受体的双特异性蛋白，以利用免疫系统潜在地实现 HBV 的功能性治愈，”Immunocore 研发主管 David Berman 说。 “虽然只有少数患者接受了单次、极低剂量的 IMC-I109V，但我们观察到 HBV 表面抗原的短暂下降以及 ALT 和细胞因子的短暂升高，这与我们假设的情况相符，我们对此感到非常鼓舞。基于IMC-I109V的作用机制。我们期待在第一阶段计划中招募更多更高剂量的患者。”

该试验是一项开放标签研究，评估 IMC-I109V 在 HLA-A*02:01 阳性的慢性乙型肝炎患者中的安全性、抗病毒活性和药代动力学，这些患者非肝硬化、HBeAg 阴性且核仁病毒受到抑制（t )ide 类似物。第 1 部分是确定安全和药理活性剂量的单次递增剂量。第 2 部分是多次递增剂量，用于评估 24 周内重复剂量的安全性和抗 HBV 活性。

关于 ImmTAV 分子和传染病
ImmTAV（免疫动员单克隆 TCRs 抗病毒）分子是新型双特异性分子，与 ImmTAC（免疫动员单克隆 TCRs 抗癌）分子一样，旨在使免疫系统能够识别和消除病毒感染的细胞。

Immunocore 正在推进临床候选药物治疗 HIV 和 HBV 患者。该公司的目标是减少病毒库，以便在停止抗逆转录病毒治疗 (ART) 后能够持续控制 HIV，而不存在病毒学复发或继续传播的风险。这被称为“功能性治愈”。对于 HBV 的治疗，公司的目标是在慢性乙型肝炎患者停药后实现循环病毒抗原和病毒复制标志物的持续丢失。
关于免疫核心
Immunocore 是一家商业阶段的生物技术公司，率先开发了一种名为 ImmTAX 的新型 TCR 双特异性免疫疗法——免疫动员单克隆 TCR 对抗 X 疾病——旨在治疗广泛的疾病，包括癌症、自身免疫和传染病。利用其专有的、灵活的、现成的 ImmTAX 平台，Immunocore 正在多个治疗领域开发一条深入的管道，包括肿瘤学和传染病的五个临床阶段项目、自身免疫性疾病的先进临床前项目和多个早期临床前项目程式。 Immunocore 最先进的肿瘤 TCR 治疗药物 KIMMTRAK (tebentafusp-tebn) 已获得美国 FDA 批准，用于治疗 HLA-A*02:01 阳性、不可切除或转移性葡萄膜黑色素瘤 (mUM) 的成年患者，已证明总生存期在转移性葡萄膜黑色素瘤的随机 3 期临床试验中受益，这是一种历史上被证明对其他免疫疗法不敏感的癌症。

资料来源：免疫核心

StephenW

Immunocore announces the presentation of initial data from the Phase 1 ImmTAV trial for chronic Hepatitis B at the EASL International Liver Congress

    Category: Antibodies       
    Published on Saturday, 25 June 2022 12:37
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IMC-I109V, T cell receptor bispecific, targets an envelope antigen

Single Ascending Dose portion of Phase 1 study to evaluate safety, antiviral activity, and pharmacokinetics

In the initial cohort, HBsAg declines and ALT elevations indicated that a single, very low dose of IMC-I109V elicited on-target activity, consistent with mechanism of action and without any adverse events

OXFORDSHIRE, UK & CONSHOHOCKEN, PA & ROCKVILLE, MD, USA I June 25, 2022 I Immunocore Holdings plc (Nasdaq: IMCR) (“Immunocore” or the “Company”), a commercial-stage biotechnology company pioneering the development of a novel class of T cell receptor (TCR) bispecific immunotherapies designed to treat a broad range of diseases, including cancer, autoimmune and infectious diseases, today announced that initial data from the first three patients in the first-in-human clinical trial of IMC-I109V was presented at the EASL International Liver Congress in London, UK.

IMC-I109V is a TCR bispecific designed to specifically eliminate HBV-infected hepatocytes expressing hepatitis B surface antigen (HBsAg) via T cell redirection. IMC-I109V is designed to overcome T cell dysfunction by recruiting non-exhausted T cells to eliminate hepatocytes harbouring covalently closed circular DNA or integrated HBV DNA. Elimination of these cells is necessary to achieve a state of ‘functional cure’ defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post-treatment. Since the mechanism results in hepatocyte lysis, transient liver enzyme increases are expected, necessitating a conservative dosing schedule in the Company’s first-in-human study of IMC-I109V.

In this first cohort, three patients each received a single dose of 0.8 mcg, based on the minimum anticipated biological effect level (MABEL). The dose in this initial cohort was well tolerated and was not associated with adverse events were reported in any patient. The maximum serum concentrations of IMC-I109V were consistent with the dose level. By hour 12, serum concentrations declined below the lower limit of quantification. IL-6 cytokine levels increased within the first 24 hours in all three patients, which is consistent with the IMC-I109V mechanism of action. Small and transient increases in alanine transaminase (ALT), albeit within the normal range, were observed in the first few days after dosing, before returning to normal levels. In two of the three patients, serum HBsAg levels transiently decreased, with the same kinetics as ALT, by 11-15% during Days 3-15 post infusion, before returning to baseline within 3 weeks post-infusion.

“We designed our T cell receptor based bispecific proteins to harness the immune system to potentially achieve a functional cure for HBV,” said David Berman, Head of Research & Development at Immunocore. “Although only a few patients received a single, very low dose of IMC-I109V, we are very encouraged by our observations of transient decrease in HBV surface antigen, as well as transient elevations in ALT and cytokines, which match the profile we had hypothesized based on the IMC-I109V mechanism of action. We look forward to enrolling more patients at higher doses in the Phase 1 program.”

The trial is an open label study evaluating the safety, antiviral activity, and pharmacokinetics of IMC-I109V in HLA-A*02:01 positive patients with chronic hepatitis B who are non-cirrhotic, HBeAg-negative and virally suppressed on nucleos(t)ide analogues. Part 1 is a single ascending dose to identify a safe and pharmacologically active dose. Part 2 is a multiple ascending dose to evaluate safety and anti-HBV activity of repeated doses over 24 weeks.

About ImmTAV molecules and infectious diseases
ImmTAV (Immune mobilising monocolonal TCRs Against Virus) molecules are novel bispecific molecules that, like ImmTAC (Immune mobilising monoclonal TCRs Against Cancer) molecules, are designed to enable the immune system to recognize and eliminate virally infected cells.

Immunocore is advancing clinical candidates to cure patients with HIV and HBV. The Company aims to achieve a reduction in viral reservoirs to enable sustained control of HIV after stopping antiretroviral therapy (ART), without the risk of virological relapse or onward transmission. This is known as ‘functional cure’. For the treatment of HBV, the Company aims to achieve sustained loss of circulating viral antigens and markers of viral replication after stopping medication for people living with chronic hepatitis B.
About Immunocore
Immunocore is a commercial-stage biotechnology company pioneering the development of a novel class of TCR bispecific immunotherapies called ImmTAX – Immune mobilizing monoclonal TCRs Against X disease – designed to treat a broad range of diseases, including cancer, autoimmune, and infectious disease. Leveraging its proprietary, flexible, off-the-shelf ImmTAX platform, Immunocore is developing a deep pipeline in multiple therapeutic areas, including five clinical stage programs in oncology and infectious disease, advanced pre-clinical programs in autoimmune disease and multiple earlier pre-clinical programs. Immunocore’s most advanced oncology TCR therapeutic, KIMMTRAK (tebentafusp-tebn), has been approved by the U.S. FDA for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma (mUM) having demonstrated an overall survival benefit in a randomized Phase 3 clinical trial in metastatic uveal melanoma, a cancer that has historically proven to be insensitive to other immunotherapies.

SOURCE: Immunocore