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一个强大的补充，通过消耗CD25+ Treg治疗CTCL和癌症免疫治疗。Ontak(R) （denileukin diftitox）自1999年获得FDA批准直到停药以来，在治疗CTCL方面取得了巨大进展。BILT的作用类似于Ontak(R)，但效力更强。这两种疗法之间的功能相似为临床前和临床提供了明确的途径。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。免疫系统具有特异性识别和攻击肿瘤细胞及其支持性微环境的能力，同时保留附近的正常细胞。我们已经开发了一种新的治疗方法，通过使用基因工程的二价人类IL-2融合到截断白喉毒素（BILT）中来满足这些标记。此外，我们开发了一个强大的，可扩展的和高效的酵母表达系统，大大提高了纯化产量。尽管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用该药物已造成缺口。这里提出的工作是推进下一代靶向CD25+肿瘤细胞的治疗的重要一步，其效力比Ontak(R)更强。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，而无明显毒性。BILT对人类疾病具有显著疗效的潜力，安全性与已批准的产品相似，并改善临床医生针对CTCL的工具包。除了对CTCL的初始作用外，BILT可能对其他CD25+肿瘤有效，也可能影响器官移植，其中靶向CD25+ T细胞是关键的治疗目标。在这项I期SBIR提案中，我们将确定BILT的体内抗肿瘤功效，我们将确定最大耐受剂量（MTD）和毒性机制，我们将制定发酵SOP以支持临床开发。这些研究将推动BILT的发展，如果成功，将使这种疗法在大型动物的临床前和后续临床中得到应用

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.