Preclinical toxicology and pharmacology evaluation of a newTNFR2 antagonistic monoclonal antibody for CTCL therapy

新型TNFR2拮抗单克隆抗体用于CTCL治疗的临床前毒理学和药理学评价

基本信息

批准号：
10772580
负责人：
Kenneth Olivier
金额：
$ 122.17万
依托单位：
BOSTON IMMUNE TECHNOLOGIES AND THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10772580
关键词：
Antibodies Antibody Therapy Autoimmunity Benchmarking Binding Boston Cancer Patient Cancerous Capital Cells Clinical Clinical Trials Colon Carcinoma Cutaneous T-cell lymphoma Cyclic GMP Data Development Dose Drug Kinetics Effector Cell Evaluation Formulation Frequencies Funding Future Growth Guidelines Health Health Care Costs Health Expenditures Human Immune Immune checkpoint inhibitor Immune system Immunooncology Immunotherapy In Vitro Infiltration International Investigational Drugs Investigational New Drug Application Macaca fascicularis Malignant Neoplasms Malignant neoplasm of ovary Marketing Mediating Molecular Target Monoclonal Antibodies Mus New Drug Approvals Oncogenes Oncogenic Patients Persons Pharmacologic Substance Pharmacology and Toxicology Phase Process Production Productivity Receptors, Tumor Necrosis Factor, Type II Regulatory Affairs Regulatory T-Lymphocyte Reporting Resistance Safety Sampling Secure Signal Transduction Small Business Innovation Research Grant Societies Surface TNFRSF1A gene Technology Testing Therapeutic Time Tissues Toxic effect Toxicology Validation antagonist anti-tumor immune response antitumor effect cGMP production cancer cell cancer infiltrating T cells cancer therapy design dimer in vitro activity in vivo innovation interest large scale production manufacturing run novel strategies novel therapeutic intervention novel therapeutics overexpression pharmacologic pre-clinical prevent programmed cell death protein 1 programs receptor research clinical testing selective expression targeted cancer therapy targeted treatment therapeutic target therapy outcome tool tumor tumor microenvironment tumor necrosis factor receptor binding validation studies

项目摘要

PROJECT SUMMARY Cancer has killed over 600,000 people in US in 2020. The cost for healthcare and society is unbearable: because of cancer, $180B healthcare expenditure and $134B lost productivity are recorded every year. This is happening despite recent advancements in therapy and the emergence of an ever expanding array of new therapeutics for the over 1.8M new cancer patients every year. Indeed, because of the multitude and redundancy of mechanisms contributing to cancer growth, therapies are often ineffective. Several components should be targeted at the same time in order to maximize therapy outcome. However, this is particular hard to attain because of 1) the striking variability among cancers and the limited number of cancer specific targets 2) the ability of cancer cells to orchestrate a microenvironment of healthy tissue and cells around them, that promote cancer growth and therapy resistance. Boston Immune Technologies and Therapeutics (BITT) is developing BITT-1492, able to target both cancer cells and their microenvironment. BITT-1492 is an antagonist antibody against TNFR2 – a receptor highly expressed in cancer tissue and immune suppressive cells in the microenvironment, where it mediates pro-survival signaling. Thanks to BITT’s proprietary antibody design platform, BITT-1492 is the first and only antibody able to dominantly shut down TNFR2 signaling. Due to selective expression and key role of TNFR2 for a variety of cancers and tumor microenvironment cells, BITT-1492 will find application in the therapy of several cancers, starting with Cutaneous T cell Lymphoma (CTCL), where TNFR2 is known to act as an extremely potent oncogene. BITT has already completed extensive pre-clinical validation for BITT-1492, demonstrating potent activity in CTCL, colon and ovarian cancers. In the proposed Fast-Track project, BITT will complete a pre-clinical toxicology and pharmacology assessment of BITT-1492 to obtain relevant data for an Investigational New Drug (IND) application. This will be accomplished by performing, in line with ICH guidelines, an exploratory small-scale toxicology study to be carried out in Phase I, that will demonstrate the safety of use of BITT-1492 for a wider IND-enabling toxicology and pharmacokinetic studies in Phase II. As part of the PhaseII BITT will also test the suitability of BITT-1492 production process for cGMP standard compliance. At the end of the SBIR project, BITT will be ready to advance BITT-1492 to clinical testing for which a combination of Venture Capital seed funds and SBIR PhaseIIb are expected to be leveraged. The successful completion of this project and initial clinical testing evidence will help to secure the already expressed interest of pharmaceutical companies with whom BITT will engage to complete late-stage clinical testing and launch BITT-1492 into international markets.

项目概要 2020 年，癌症在美国已导致超过 60 万人死亡。医疗保健和社会的成本难以承受：因为每年记录的癌症、$180B 医疗支出和 $134B 生产力损失都在发生。尽管出现了越来越多的新疗法，但治疗方面的最新进展事实上，由于机制的众多和冗余，每年新增癌症患者超过 180 万。导致癌症生长的几种疗法通常无效。然而，这是特别难以实现的，因为 1) 癌症之间存在显着的差异，且癌症特异性靶标的数量有限2) 癌细胞的能力协调周围健康组织和细胞的微环境，促进癌症生长和波士顿免疫技术和治疗公司 (BITT) 正在开发 BITT-1492，能够 BITT-1492 是一种针对 TNFR2 的拮抗剂抗体，同时靶向癌细胞及其微环境。受体在癌组织和微环境中的免疫抑制细胞中高表达，得益于 BITT 的专有抗体设计平台，BITT-1492 是第一个介导促生存信号传导的药物。由于 TNFR2 的选择性表达和关键作用，这是唯一能够显着关闭 TNFR2 信号传导的抗体。 TNFR2针对多种癌症和肿瘤微环境细胞，BITT-1492将在治疗中找到应用多种癌症的治疗，首先是皮肤 T 细胞淋巴瘤 (CTCL)，其中 TNFR2 被认为是一种极其有效的致癌基因。 BITT 已经完成了 BITT-1492 的广泛临床前验证，在拟议的快速通道项目中，BITT 将展示对 CTCL、结肠癌和卵巢癌的有效活性。完成BITT-1492的临床前毒理学和药理学评估，以获得相关数据研究性新药 (IND) 申请将按照 ICH 指南进行：将在第一阶段进行探索性小规模毒理学研究，该研究将证明使用的安全性 BITT-1492 用于 II 期更广泛的 IND 毒理学和药代动力学研究。 BITT 还将在年底测试 BITT-1492 生产工艺是否符合 cGMP 标准。在 SBIR 项目中，BITT 将准备将 BITT-1492 推进临床测试，为此将结合 Venture 资本种子基金和 SBIR PhaseIIb 预计将顺利完成该项目。初步的临床测试证据将有助于确保制药公司已经表达的兴趣 BITT 将与其合作完成后期临床测试并将 BITT-1492 推出到国际市场。