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

项目总结 2020年，美国已有60多万人死于癌症。医疗保健和社会的成本是无法承受的：因为 在癌症方面，每年记录的医疗支出为1800亿美元，生产力损失为1340亿美元。这件事正在发生 尽管最近在治疗方面取得了进展，出现了一系列不断扩大的新疗法， 每年新增癌症患者超过180万人。事实上，由于机制的多重性和冗余性 导致癌症生长的治疗方法往往是无效的。有几个组件应该针对 同时为了最大限度地提高治疗效果。然而，这一点尤其难以实现，因为1) 癌症之间的显著变异性和癌症特异性靶点的数量有限2)癌细胞的能力 协调健康组织及其周围细胞的微环境，促进癌症生长和 治疗抵抗。波士顿免疫技术和治疗公司(BITT)正在开发BITT-1492，能够 针对癌细胞及其微环境。BITT-1492是一种针对TNFR2-a的拮抗性抗体 受体在肿瘤组织和免疫抑制细胞的微环境中高表达，在那里它 调节支持生存的信号。由于Bitt的专有抗体设计平台，Bitt-1492是第一个 并且只有抗体能够显性地关闭TNFR2信号转导。由于选择性表达和关键作用 针对多种肿瘤和肿瘤微环境细胞，BITT-1492将在治疗中得到应用 在几种癌症中，从皮肤T细胞淋巴瘤(CTCL)开始，TNFR2被认为是一种 极强的致癌基因。BITT已经完成了对BITT-1492的广泛临床前验证， 在CTCL、结肠癌和卵巢癌中表现出很强的活性。在拟议的快速通道项目中，Bitt将 完成BITT-1492的临床前毒理学和药理学评估，以获得 研究用新药(IND)申请。这将通过按照非物质文化遗产指导方针， 将在第一阶段进行的探索性小规模毒理学研究，将证明使用的安全性 BITT-1492在第二阶段进行更广泛的IND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生产工艺是否符合cGMP标准。在…的末尾 SBIR项目，BITT将准备将BITT-1492推进到临床测试，针对该测试，Venture 资本种子基金和SBIR PhaseIIb预计将得到杠杆利用。这项工程的圆满完成 初步的临床测试证据将有助于确保已经表达了对制药的兴趣 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。

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.