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默克雪兰诺启动抗PD-L1免疫疗法II期临床研究

  1. MSB0010718C
  2. PD-1PD-L1通路
  3. 免疫疗法
  4. 单抗
  5. 抗PD-L1
  6. 默克雪兰诺

来源:生物谷 2014-07-31 14:40

默克雪兰诺启动抗PD-L1免疫疗法MSB0010718C II期研究。MSB0010718C是一种单抗,通过靶向结合PD-L1分子,阻断PD-1/PD-L1信号通路,恢复抗肿瘤T细胞反应,抑制肿瘤生长。

2014年7月30日讯 /生物谷BIOON/ --默克(Merck KGaA)旗下默克雪兰诺(EMD Serono)7月29日宣布,启动一项II期研究,评估抗PD-L1免疫疗法MSB0010718C治疗转移性Merkel细胞癌(mMCC)的疗效和安全性。该项研究是一项多中心、单组、开放标签研究,预计将在亚太、澳大利亚、欧洲和北美招募84例既往接受过一线化疗的mMCC患者,研究的主要终点是总缓解率。

PD-1/PD-L1作为免疫球蛋白超家族协同刺激分子的重要成员,参与自身免疫、移植免疫以及肿瘤免疫等机体免疫调节过程。PD-1是一种主要表达于活化T细胞上的抑制性受体,与其配体PD-L1结合,可显著抑制T细胞的活化和增殖,并调节细胞因子的表达和分泌。PD-L1则广泛表达于多种免疫细胞、上皮细胞以及肿瘤细胞上。目前诸多研究表明,多种人类肿瘤大量表达的PD-L1分子与患者临床病理特征及预后紧密相关,成为肿瘤检出和预后判断的新的生物学指标。肿瘤细胞通过高表达PD-L1分子,与T细胞上的受体PD-1结合,传递负调控信号,导致肿瘤抗原特异性T细胞的诱导凋亡和免疫无能,使肿瘤细胞逃避机体的免疫监控和杀伤。

鉴于PD-1/PD-L1信号转导机制在肿瘤免疫应答中的重要作用,尝试将阻断该信号通路应用于肿瘤免疫治疗,对进-步拓展肿瘤治疗的思路和方法具有重要价值。

PD-L1(程序性死亡配体-1)在多种肿瘤中均过量表达,包括mMCC,该病是一种罕见、侵袭性皮肤肿瘤,缺乏有效的治疗药物。MSB0010718C是一种实验性全人源化IgG1单克隆抗体,靶向结合PD-L1。通过竞争性阻断PD-L1与其受体PD-1的相互作用,MSB0010718C有望恢复抗肿瘤T细胞反应,从而抑制肿瘤生长。

除了在mMCC患者中开展的该项II期研究外,默克雪兰诺正在I期临床中评估MSB0010718C对数个实体瘤的疗效。(生物谷Bioon.com)

英文原文:EMD Serono Initiates Phase II Study of Anti-PD-L1 Antibody MSB0010718C in Metastatic Merkel Cell Carcinoma

ROCKLAND, Massachusetts, July 29, 2014 /PRNewswire/ --

——First patient begins treatment in an international Phase II study investigating the efficacy and safety of MSB0010718C in patients with metastatic Merkel cell carcinoma (mMCC)

——mMCC is a rare and aggressive skin cancer lacking effective treatments 

——MSB0010718C is also currently being explored in a seven cohort Phase I clinical trial for the treatment of solid tumors that aims to recruit 590 patients

EMD Serono, Inc., a subsidiary of Merck KGaA, Darmstadt, Germany, today announced the initiation of an international Phase II study designed to assess the efficacy and safety of MSB0010718C, an investigational fully human IgG1 monoclonal antibody that binds to programmed death-ligand 1 (PD-L1). This multicenter, single-arm, open-label study is being conducted in patients with metastatic Merkel cell carcinoma (mMCC), a rare and aggressive type of skin tumor,[1],[2] who have previously received one line of chemotherapy. It is expected to recruit 84 patients across Asia Pacific, Australia, Europe and North America. The primary endpoint of the study is overall response.

The PD-L1/PD-1 pathway is implicated as a major mechanism by which tumors evade elimination by the immune system.[3] The PD-L1 molecule is expressed in many cancer types, including mMCC.[3],[4] MSB0010718C, which blocks the interaction of PD-L1 with its receptor PD-1, may have the potential to restore effective anti-tumor T-cell responses and thereby to inhibit tumor growth.

Immune mechanisms are implicated in the pathogenesis of MCC, with an increased risk observed in immunosuppressed individuals.[5] MCC also is associated with the presence of the Merkel cell polyomavirus, which may have a role in tumor formation.[6] Globally, the incidence of MCC is increasing, and outcomes for patients with this disease are poor.[1],[2] Therefore, new treatment approaches are required to improve the outcome of patients with this type of cancer.

"We believe that modulating the immune system by targeting PD-L1 represents a promising new approach in the treatment of this aggressive cancer, especially considering that many of the predisposing factors for mMCC seem to be related to functional disruptions of the immune system," said Helen Sabzevari, Senior Vice President of Immuno-Oncology at the biopharmaceutical division of Merck KGaA, Darmstadt, Germany. "Our anti-PD-L1 compound may present a potential new approach for the treatment of mMCC patients. The initiation of this Phase II study is an important milestone, as we endeavor to help those suffering from mMCC, a devastating disease with significant unmet need."

In addition to this new study in mMCC, MSB0010718C is currently being explored in a Phase I clinical trial for the treatment of solid tumors. The study aims to recruit 590 patients and has enrolled 422 patients to date. On June 1, 2014, EMD Serono presented initial data from this dose escalation study in solid tumors at the annual American Society of Clinical Oncology (ASCO) meeting in Chicago.[7] This study is currently recruiting patients into expansion cohorts in seven cancer types: castrate-resistant prostate cancer, colorectal cancer, gastric/gastroesophogeal cancer, melanoma, metastatic breast cancer, non-small cell lung cancer and ovarian cancer.

About MSB0010718C

MSB0010718C is an investigational fully human IgG1 monoclonal antibody that binds to the PD-L1 (programmed death-ligand 1) protein, which is present at high levels in many cancer types. By competitively blocking the interaction with PD-1 receptors, it is believed that MSB0010718C thereby restores anti-tumor T-cell responses.

About Merkel cell carcinoma (MCC)

MCC is a rare and aggressive disease in which cancer cells form in the top layer of the skin, close to nerve endings. MCC, which is also known as neuroendocrine carcinoma of the skin or trabecular cancer, often starts in those areas of skin that are most often exposed to the sun, including the head and neck, arms, legs, and trunk. Risk factors for MCC include sun exposure and having a weak immune system (i.e., solid-organ transplant recipients, people with HIV/AIDS and people with other cancers, such as chronic lymphocytic leukemia, are at higher risk). Caucasian males over age 50 are at increased risk.

MCC tends to metastasize at an early stage, spreading initially to nearby lymph nodes, and then potentially to more distant areas in the body, including other lymph nodes or areas of skin, lungs, brain, bones, or other organs.

Current treatment options for MCC include surgery, radiation and chemotherapy. Treatment for metastatic or Stage IV MCC is generally palliative.

About EMD Serono, Inc. 

EMD Serono, Inc., a subsidiary of Merck KGaA, Darmstadt, Germany, is a specialized biopharmaceutical company dedicated to developing therapies with groundbreaking potential. The company has strong market positions in neurology, endocrinology and in reproductive health. In addition, EMD Serono has an enduring commitment to solve the unsolvable, with state-of-the-art science dedicated to developing new therapies in our core focus areas of neurology, oncology, immuno-oncology and immunology. With a long-standing history of industry expertise and a dedication to shape the future of healthcare, the company's US footprint continues to grow, with approximately 1,000 employees around the country and fully integrated commercial, clinical and research operations in the company's home state of Massachusetts.

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