Preclinical Development of BILT, a Next-Generation Immunotoxin Therapy for CTCL

描述(由申请人提供)：该项目的长期目标是推进BILT的临床批准，这将为临床医生提供强大的补充，用于治疗CTCL和通过耗尽CD25+Treg进行癌症免疫治疗。Ontak(R)(Denileukin Diftitox)自1999年FDA批准以来，在CTCL的治疗方面取得了长足的进步，直到它停止使用。BILT的功能类似于Ontak(R)，但效力更大。这两种疗法之间的功能平行提供了一条明确的临床前和临床前进道路。理想的癌症治疗应该是有效的、选择性的、永久性的和安全的。免疫系统有能力特异性地识别和攻击肿瘤细胞及其支持的微环境，同时保留附近的正常细胞。我们已经开发出一种新的疗法，通过使用基因工程的二价人IL-2融合到截断的白喉毒素(BILT)来满足这些标志。此外，我们开发了一个健壮、可扩展和高效的酵母表达系统，大大提高了纯化产量。虽然Ontak(R)是CTCL患者治疗方案中不可或缺的一部分，但由于供应中断而停止使用，造成了缺口。这里提出的工作是朝着推进下一代疗法迈出的重要一步，这种疗法以CD25+肿瘤细胞为靶标，具有比Ontak(R)更大的效力。在小鼠模型中，二价融合毒素对CD25+肿瘤有效，并在体内有效地耗尽CD25+肿瘤细胞，而没有明显的毒性。BILT有可能对人类疾病具有显著疗效，安全性与批准的产品相似，并改进了临床医生对抗CTCL的工具包。除了最初对CTCL的作用外，BILT很可能对其他CD25+肿瘤有效，也可能影响以CD25+T细胞为关键治疗目标的器官移植。在这一阶段的SBIR方案中，我们将确定BILT的体内抗肿瘤效果，我们将确定最大耐受量(MTD)和毒性机制，我们将开发一种发酵SOP来支持临床开发。这些研究将推进BILT，如果成功，将把这种疗法应用于大型动物的临床前和后续临床 发展。在这个第一阶段项目结束时，我们将在关键路径上实现关键目标，将这一有希望的干预措施推向临床。

DESCRIPTION (provided by applicant): The long-term aim of this project is to advance BILT for clinical approval which will provide clinicians with a powerful addition to the armamentarium for treating CTCL and cancer immunotherapy through depleting CD25+ Treg. Ontak(R) (denileukin diftitox) was making great strides in the treatment of CTCL since its FDA approval in 1999 until its discontinuation. BILT functions analogously to Ontak(R) but with greater potency. The functional parallel between these two therapies provides a clear pre-clinical and clinical path forward. An ideal cancer therapy would be effective, selective, permanent, and safe. The immune system has the ability to specifically recognize and attack tumor cells and their supportive microenvironments, while sparing nearby normal cells. We have developed a novel therapy that has met these marks through the use of a genetically engineered bivalent human IL-2 fused to a truncated diphtheria toxin (BILT). In addition, we developed a robust, scalable and efficient yeast expression system with greatly enhanced purification yields. Although Ontak(R) was an integral part of the treatment regimen for patients with CTCL, its discontinuation due to a supply interruption has introduced a gap. The work proposed here is a major step toward advancing a next-generation therapy that targets CD25+ tumor cells with greater potency than Ontak(R). In murine models, the bivalent fusion toxin was efficacious against CD25+ tumors and effectively depleted CD25+ tumor cells in vivo, while exhibiting no overt toxicity. BILT has the potential for significant efficacy against human disease, safety profile similar to that of an approved product, and improve the clinicians' toolkit against CTCL. Beyond its initial effect on CTCL, BILT is likely to efficacious against other CD25+ tumors, and may also impact organ transplantation where targeting CD25+ T cells is a key therapeutic goal. In this Phase I SBIR proposal, we will determine the anti-tumor efficacy of BILT in vivo, we will determine the maximum tolerated dose (MTD) and the mechanism of toxicity, and we will develop a fermentation SOP to support clinical development. These studies will advance BILT and, if successful, will position this therapy for large-animal preclinical and subsequent clinical development. At the end of this Phase I project, we will have achieved key goals on the critical path to move this promissing intervention toward the clinic.