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。
“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。”
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
Hits: 277
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.