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.

项目摘要癌症在2020年在美国已有超过60万人丧生。医疗保健和社会的费用是难以忍受的：因为每年记录癌症，180B美元的医疗保健支出和损失$ 134B的生产率。这正在发生尽管最近在治疗方面取得了进步，并且出现了不断扩大的新疗法每年超过180万的新癌症患者。确实，由于机制的众多和冗余促进癌症生长，疗法通常无效。几个组件应针对同一时间为了最大程度地提高治疗结果。但是，由于1）癌症的惊人变异性和癌症特定靶标数量有限2）癌细胞的能力策划健康组织和周围细胞的微环境，从而促进癌症的生长和治疗抗性。波士顿免疫技术和治疗学（BITT）正在开发BITT-1492，能够靶向癌细胞及其微环境。 Bitt-1492是针对TNFR2的拮抗剂抗体接收器在癌组织中高度表达的微环境中的癌组织和免疫抑制细胞介导促生存信号传导。感谢Bitt的专有抗体设计平台，Bitt-1492是第一个并且只有抗体才能主要关闭TNFR2信号传导。由于选择性表达和关键作用 TNFR2用于各种癌症和肿瘤微环境细胞，Bitt-1492将在治疗中找到应用从皮肤T细胞淋巴瘤（CTCL）开始的几种癌症，其中TNFR2被称为非常潜在的癌基因。比特已经完成了Bitt-1492的广泛临床前验证，证明CTCL，结肠和卵巢癌的潜在活性。在拟议的快速轨道项目中，比特将完成BITT-1492的临床前毒理学和药理学评估，以获取相关数据研究新药（IND）应用。这将通过与ICH指南一致来实现一项探索性的小规模毒理学研究将在第一阶段进行，这将证明使用的安全性 II期Bitt-1492用于更广泛的索引毒理学和药代动力学研究。作为第二阶段的一部分 BITT还将测试BITT-1492生产过程中CGMP标准合规性的适用性。在 SBIR项目，BITT将准备好将Bitt-1492推进到临床测试中预计将利用资本种子基金和Sbir阶段性。该项目的成功完成最初的临床测试证据将有助于确保已经表达的药物的兴趣 Bitt将与之互动的公司完成后期临床测试，并将Bitt-1492启动国际市场。