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

项目摘要 2020年，癌症在美国造成超过60万人死亡。医疗保健和社会的成本是无法承受的：因为 每年记录的癌症，1800亿美元的医疗保健支出和1340亿美元的生产力损失。会发生这种 尽管最近在治疗方面取得了进展，并且出现了不断扩大的一系列新的治疗方法， 每年有超过180万新的癌症患者。事实上，由于机械装置的众多和冗余， 由于癌症的生长，治疗往往无效。有几个组成部分应针对 以最大化治疗效果。然而，这是特别难以实现的，因为1） 癌症之间的显著差异和癌症特异性靶点的有限数量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， 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 靶向癌细胞及其微环境。BITT-1492是针对TNFR 2- a的拮抗剂抗体， 受体在癌组织和免疫抑制细胞的微环境中高度表达， 介导促生存信号传导。得益于BITT专有的抗体设计平台，BITT-1492是第一个 并且是唯一能够显性关闭TNFR 2信号传导的抗体。由于选择性表达和关键作用， TNFR 2对于多种癌症和肿瘤微环境细胞，BITT-1492将在治疗中找到应用 在几种癌症中，从皮肤T细胞淋巴瘤（CTCL）开始，已知TNFR 2在其中充当免疫调节剂。 极强的致癌基因BITT已经完成了BITT-1492的广泛临床前验证， 在CTCL、结肠癌和卵巢癌中显示出有效的活性。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 研究性新药（IND）申请。根据ICH指导原则， 将在I期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用于II期更广泛的IND毒理学和药代动力学研究。作为第二阶段的一部分 BITT还将检测BITT-1492生产工艺是否符合cGMP标准。结束时 在SBIR项目中，BITT将准备将BITT-1492推进到临床测试， 预计将利用资本种子基金和SBIR第二阶段b。这个项目的顺利完成 初步的临床试验证据将有助于确保已经表达的制药兴趣， BITT将与之合作完成后期临床试验并将BITT-1492投入使用的公司 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.