TCR Targeting Antibodies for the Treatment of T cell Cancers

项目摘要 抗体介导的靶向免疫疗法在杀死癌细胞方面非常有效。T细胞白血病 和淋巴瘤，统称为T细胞癌，每年影响全球约100，000名患者。复发 T细胞癌对侵袭性化疗反应不佳，5年生存率在7%至38%之间。因此，T 细胞癌特别需要抗体介导的靶向免疫疗法来改善患者的结果。 然而，开发T细胞癌症靶向免疫疗法是具有挑战性的，因为免疫疗法必须 保留足够的健康T细胞来维持免疫系统的功能。T细胞表达T细胞受体 (TCR)在细胞表面。尽管所有的T细胞都表达TCR，但是可以根据TCR β来区分它们。 链恒定区（TRBC），其来源于两个基因片段TRBC 1或TRBC 2之一。我带领一个团队 这表明，在健康的T细胞群中，约45%的细胞表达TRBC 1，而其他55%的细胞表达TRBC 1。 表达TRBC 2。然而，克隆T细胞癌表达TRBC 1或TRBC 2（Paul et al.，Sci. Transl. Med. 2021年）。因此，我假设抗体介导的特异性TRBC 1或TRBC 2靶向将根除克隆性TRBC 1或TRBC 2。 T细胞癌，同时保留一半的健康多克隆T细胞群。我还开发了一个TRBC 1- 靶向双特异性抗体（α TRBC 1），选择性杀死TRBC 1 + T细胞癌（和TRBC 1+健康T细胞） 同时在体外保存健康的TRBC 2 + T细胞。这些体外观察结果需要在 在未来的人类临床试验开始之前的动物模型。对于目标1，我将确定本发明化合物的体内活性。 aTRBCl双特异性抗体。我将测试α TRBC 1抗体诱导肿瘤消退的能力， T细胞癌的小鼠模型。然后，我将检查剩余的健康TRBC 2 + T细胞是否保留了所有的免疫原性。 免疫细胞亚群需要一个正常运作的免疫系统。我还将测试是否有来自 α TRBC 1双特异性抗体将产生低TCR表达的T细胞群，其将对抗TCR 1抗体具有抗性。 疗法对于目标2，我将测试TRBC 2靶向T细胞癌的可行性。作为TRBC 2靶向抗体， 目前还没有，我将使用噬菌体展示来开发TRBC 2特异性抗体。然后我将测试 TRBC 2靶向抗体在体外和多种T细胞癌小鼠模型中的细胞毒性。我们的TRBC- 定向抗体将满足治疗T细胞癌患者的未满足的需要。建议在体内和 机制研究将提供临床前验证所需的启动早期人类 临床试验将测试TRBC 1和TRBC 2靶向抗体的安全性和有效性。 我的长期目标是成为一名独立的实验室医生科学家，专注于 为T细胞癌开发新的治疗方法。通过这项提议，我还将获得 研究技能和职业经验需要达到这一目标。这些技能对于发展 在人类T细胞白血病和淋巴瘤中进行相关的、有影响力的转化研究计划。

Project Summary Antibody-mediated targeted immunotherapies are highly effective in killing cancer cells. T cell leukemias and lymphomas, collectively known as T cell cancers, affect ~100,000 patients worldwide each year. Relapsed T cell cancers respond poorly to aggressive chemotherapy with a 5-year survival between 7% to 38%. Thus, T cell cancers particularly warrant antibody-mediated targeted immunotherapy to improve patient outcomes. However, developing a T cell cancer targeting immunotherapy is challenging as the immunotherapy will have to preserve enough healthy T cells to maintain a functioning immune system. T cells express the T cell receptor (TCR) on the cell-surface. Although all T cells express TCR, they can be distinguished based on the TCR beta chain constant region (TRBC) which is derived from one of two gene segments, TRBC1 or TRBC2. I led a team that demonstrated that in healthy T cell populations, about 45% of cells express TRBC1 while the other 55% express TRBC2. However, clonal T cell cancers express either TRBC1 or TRBC2 (Paul et al., Sci. Transl. Med. 2021). Thus, I hypothesize that antibody-mediated specific TRBC1 or TRBC2 targeting will eradicate the clonal T cell cancers while preserving half of the healthy polyclonal T cell population. I also developed a TRBC1- targeting bispecific antibody (αTRBC1) that selectively kills TRBC1+ T cell cancers (and TRBC1+ healthy T cells) while preserving the healthy TRBC2+ T cells in vitro. These in vitro observations will require confirmation in animal models before initiation of future human clinical trials. For Aim 1, I will determine the in vivo activity of the αTRBC1 bispecific antibody. I will test the ability of αTRBC1 antibodies to induce tumor regression in multiple mouse models of T cell cancers. I will then examine if the remaining healthy TRBC2+ T cells retain all of the immune cell subsets required for a functioning immune system. I will also test if therapeutic pressure from the αTRBC1 bispecific antibody will give rise to a low TCR expressing T cell population that will be resistant to therapy. For Aim 2, I will test feasibility of TRBC2-targeting on T cell cancers. As a TRBC2-targeting antibody is currently unavailable, I will use phage display to develop TRBC2-specific antibodies. I will then test the cytotoxicity of TRBC2 targeting antibodies in vitro and in multiple mouse models of T cell cancers. Our TRBC- directed antibodies will fill an unmet need for the treatment of T cell cancer patients. The proposed in vivo and mechanistic studies will provide the pre-clinical validation required for the initiation of an early-phase human clinical trials that will test the safety and efficacy of TRBC1- and TRBC2-targeting antibodies. My long-term goal is to become an independent laboratory-based physician-scientist focusing on developing novel therapeutic approaches for T cell cancers. Through this proposal, I will also acquire the research skills and career experience needed to reach this goal. These skills will be critical to the development of a relevant, impactful translational research program in human T cell leukemias and lymphomas.