Development of a protein drug for pancreatic cancer treatment

摘要 胰腺癌是一种毁灭性的疾病，五年生存率不到9%。目前， 对晚期疾病没有有效的治疗方法。抗肿瘤药效的一大障碍 治疗是致密的促结缔组织间质反应。有证据表明，癌症 相关的胰腺星状细胞(CaPSC)产生间质胶原。ECM制定了 被认为是对已有疗法产生抵抗的主要因素之一 这些疾病。消耗CaPSC和改变血管密度可显著提高疗效 现有的胰腺导管腺癌(PDAC)治疗方法。但目前有以下几种 没有批准的治疗方法能够耗尽PDAC中的CaPSCs。我们开发了一部小说 治疗性蛋白质(ProAgio)采用合理的蛋白质设计。ProAgio旨在针对整合素 α与β3在一个新的位点(而不是配体结合部位)。ProAgio特异性诱导整合素细胞凋亡 通过一种新的药物作用机制高效表达αvβ3细胞(Recruiting& 激活β3胞浆区域的caspase8)。我们的理由是，由于CAPSC和 新生血管内皮细胞表达高水平的整合素αvβ3，由于ProAgio非常 ProAgio在诱导整合素αvβ3表达细胞凋亡中的作用 CAPSC和消除胰腺肿瘤内和周围的新血管。这一独特的战略 可能在治疗PDAC方面具有优势。我们的STTRI和II期研究表明 ProAgio通过各种癌症模型潜在地作为PDAC治疗的有效性。这些研究 支持我们的假设，即ProAgio可以通过同时消耗 支持肿瘤间质增生和癌细胞生长的胶原生成的CaPSCs，而 也消除了新生长的癌症相关血管，这些血管为癌细胞提供营养，并使 癌症转移。我们第一和第二阶段研究的数据为未来的原则提供了证据 临床测试。我们第二阶段研究的结果导致ProAgio作为一种 治疗胰腺癌的药物。此阶段IIB应用程序的主要目标是生成 一个明确的数据集，使ProAgio成为PDAC的可行治疗选择 病人。目标1将表征毒性和耐受性，并确定最大耐受性 ProAgio单药剂量(MTD)和推荐II期剂量(RP2D) 联合应用G-NP。目的2将表征癌症患者ProAgio的PK特性，并 初步获得ProAgio和ProAgio+G-NP在PDAC患者中的抗癌活性数据。目标 3将分析ProAgio在患者肿瘤中的作用，以验证药物作用机制 病人。本研究将为PDAC患者探索新的治疗途径。

Abstract Pancreatic cancers are devastating diseases with five year survival rate less than 9%. Currently, there is no effective treatment for advanced disease. One major barrier to efficacy of anti-tumor therapeutics is the dense desmoplastic stromal response. Evidence suggests that cancer associated pancreatic stellate cells (CaPSC) produce the stromal collagen. The ECM laid down by CaPSC is considered to be one of the major contributors of resistance to established therapies of the diseases. Depleting CaPSC and altering vessel density could significantly improve efficacy of existing pancreatic ductal adenocarcinoma (PDAC) treatments. However, currently, there are no approved therapies that are able to deplete CaPSCs in PDAC. We have developed a novel therapeutic protein (ProAgio) using rational protein design. ProAgio is designed to target integrin αvβ3 at a novel site (not the ligand binding site). ProAgio specifically induces apoptosis of integrin αvβ3 expressing cells with high efficacy by a novel mechanism of drug action (recruiting & activating caspase 8 at cytoplasmic domain of β3). We reasoned that, since both CaPSC and angiogenic endothelial cells express high levels of integrin αvβ3, and since ProAgio is very effective in inducing apoptosis of integrin αvβ3 expressing cells, ProAgio should both deplete CaPSC and eliminate new blood vessels in and around pancreatic tumors. This unique strategy may prove advantageous in treatment of PDAC. Our STTR phase I&II studies demonstrated efficacy of ProAgio potentially as a PDAC treatment via various cancer models. The studies support our hypothesis that ProAgio can provide treatment benefit by simultaneously depleting the collagen-producing CaPSCs that support tumor desmoplasia and cancer cell growth, while also eliminating newly grown cancer associated blood vessels that feed cancer cells and enable cancer metastasis. Data from our STTR phase I&II studies provides proof of principle for future clinical tests. Results from our phase II studies have led to IND application of ProAgio as a pancreatic cancer treatment drug. The main objective of this phase IIB application is to generate a definitive dataset to enable the development of ProAgio as a viable therapeutic option for PDAC patients. Aim 1 will characterize the toxicity and tolerability and determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of ProAgio as a single agent and in combination with G-nP. Aim 2 will characterize PK property of ProAgio in cancer patients and to obtain preliminary anti-cancer activity data of ProAgio and ProAgio + G-nP in PDAC patients. Aim 3 will analyze the effects of ProAgio in patient tumor to validate the mechanism of drug action in patients. This study will explore new therapeutic avenue for PDAC patients.