An Aptamer-directed IgG1-Fc Drug Conjugate (AFDC) for Treating Pancreatic Cancer

用于治疗胰腺癌的适体导向 IgG1-Fc 药物偶联物 (AFDC)

• 批准号: 10761053
• 负责人: Xiang Gao
• 金额: $ 40万
• 依托单位: ONCOTRAP, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10761053
• 关键词: Animals; Antibody Therapy; Antibody-drug conjugates; Antigens; Apoptotic; Aptamer Technology; Binding; Biodistribution; Bypass; Cancer Etiology; Canis familiaris; Cell Line; Cell Proliferation; Cell Surface Receptors; Cells; Cessation of life; Chemistry; Chemotherapy-Oncologic Procedure; Clinical; Clinical Research; Clinical Trials; Confocal Microscopy; Cysteine; Cytotoxic agent; Data; Derivation procedure; Development; Drug Kinetics; Engineering; Enzyme-Linked Immunosorbent Assay; Event; FDA approved; Fc Immunoglobulins; Flow Cytometry; High Pressure Liquid Chromatography; Homing; Human; IgG1; Immune checkpoint inhibitor; Immunoglobulin G; In Vitro; Inbred BALB C Mice; Ketones; Label; Maleimides; Malignant Neoplasms; Malignant neoplasm of pancreas; Maximum Tolerated Dose; Mediating; Monoclonal Antibodies; Mus; N-terminal; Neoplasm Metastasis; Normal Cell; Nucleic Acids; Paclitaxel; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathology; Patients; Penetration; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Primates; Process; Prognosis; Proteomics; Quantitative Reverse Transcriptase PCR; RNA; Reaction; Recombinants; Regulation; Reporting; Reproducibility; Scheme; Services; Side; Site; Small Business Innovation Research Grant; Solid Neoplasm; Specificity; Sulfhydryl Compounds; Surface; Surface Antigens; Survival Rate; Technology; Testing; Therapeutic; Time; Tissue Sample; Tissues; Toxic effect; Treatment Efficacy; Trypsin; Tumor Antigens; Validation; Vascularization; anti-cancer; antigen binding; aptamer; biophysical properties; cancer cell; cancer type; chemical synthesis; cytotoxic; drug candidate; effective therapy; efficacy study; gemcitabine; human tissue; in vivo; in vivo evaluation; innovation; interest; interstitial; manufacturing cost; mouse model; nanoparticle; neoplastic cell; next generation; pancreatic cancer cells; pancreatic ductal adenocarcinoma cell; phase 2 study; precision medicine; preclinical study; product development; receptor; response; success; technology platform; transamination; tumor; tumor progression

Abstract Pancreatic ductal adenocarcinoma (PDAC) ranks the seventh in causing cancer-related death among all human cancers with very poor prognosis and horrendous survival rate. Despite the use of gemcitabine/nab- paclitaxel and FOLFIRINOX, the median survival rates for patients with metastatic PDAC are still less than one year. Immune checkpoint inhibitor had little responses against PDAC in clinical trials. Currently, there is an urgent unmet need to develop precision medicine that can be used for more effective treatment of PDAC. One exciting strategy to specifically kill solid tumors is by using antibody-drug conjugate (ADC), which has achieved remarkable success both clinically and commercially. Unfortunately, the development of ADC for a specific cancer type such as PDAC is significantly limited by the lack of tumor surface antigens that bind only to cancer cells of interest but not normal cells. In this SBIR Phase I project, we propose to develop an Aptamer- directed IgG-Fc Drug Conjugate (AFDC) platform by integrating the unique aptamer highly specific to PDAC cells with the Fc fragment of human IgG1 that is well-known to have prolonged circulating time and exposable cysteine residues for efficient conjugation with cytotoxic warhead. Two specific aims will be pursued. The first aim is to validation of APTPDAC-mediated killing of PDAC cells and development of a potent Aptamer-directed IgG1-Fc Drug Conjugate (AFDC) highly specifically against human PDAC cells. The second aim is to perform in vivo evaluation, assess anti-tumor efficacy of AFDC in orthotopic PDAC mouse models, and identify the putative cell surface receptor(s) on PDAC cells that is recognized by APTPDAC. The success of this proof-of-concept Phase I project will result in an innovative drug conjugate platform with unique features and a drug candidate that can be further developed for the treatment of PDAC. In the Phase II studies, we will perform extensive mechanistic studies on the identified target(s) for tissue specificity and possible side toxicities. We will more accurately determine the drug conjugation sites, the ratios of aptamer, Fc and vcMMAE in the final product by trypsin digest/MOTI-TOF, and trypsin digest/HPLC. The in vivo stability of aptamer can be further enhanced by using the 2’-fully modified RNA aptamer technology the Liu lab reported. We will further engineer additional cysteine residues to the N-terminal region of IgG1-Fc and test the upper limit of drug-to-Fc ratios that can be achieved, to evaluate the consequences in terms of toxicity and therapeutic efficacy in human PDAC PDX mouse models. When we have generated sufficient data in CMC and preclinical studies, we will seek for CRO to generate materials under the GMP regulations and get ready for PK and toxicity studies in dogs and in primates. These studies will pave the road for an IND application for a phase I human clinical trial.

抽象的 胰腺导管腺癌（PDAC）在所有人中造成癌症相关死亡的第七位 预后较差和可怕生存率的人类癌症。尽管使用了吉西他滨/nab-- 紫杉醇和FOLFIRINOX，转移性PDAC患者的中位存活率仍然少于1 年。在临床试验中，免疫检查点抑制剂对PDAC的反应很小。目前，有一个紧急的 未满足的需要开发可用于更有效治疗PDAC的精确药物。 专门杀死实体瘤的一种令人兴奋的策略是使用抗体 - 药物缀合物（ADC），该抗体 - 在临床和商业上取得了巨大的成功。不幸的是，ADC的发展 由于缺乏仅结合的肿瘤表面抗原，例如PDAC等特定的癌症类型受到明显的限制 感兴趣的癌细胞，但不是正常细胞。在这个SBIR阶段项目中，我们建议开发一个apamer- 通过集成高度特定于PDAC细胞的独特座位，定向IgG-FC药物共轭（AFDC）平台 众所周知的人类IgG1的FC片段长时间循环时间和可暴露的半胱氨酸 与细胞毒性弹头有效结合的残留物。将追求两个具体的目标。第一个目的是 验证APTPDAC介导的PDAC细胞杀死和潜在的稳固指导的IgG1-FC的开发 药物结合物（AFDC）高度特别针对人PDAC细胞。第二个目的是在体内执行 AFDC在原位PDAC小鼠模型中的评估，评估抗肿瘤效率，并识别推定的细胞 由APTPDAC识别的PDAC细胞上的表面受体。概念验证阶段的成功 项目将导致具有独特功能的创新药物共轭平台，并且可以是候选药物 进一步开发用于治疗PDAC。 在第二阶段研究中，我们将对鉴定的组织进行广泛的机械研究 特异性和可能的​​侧面毒性。我们将更准确地确定药物结合位点，比率 最终产品中的Atamer，FC和VCMMAE的作品，由胰蛋白酶摘要/Moti-TOF以及胰蛋白酶摘要/HPLC。 in 通过使用2'经过修改的RNA座垫技术，可以进一步增强磷的体内稳定性 实验室报告。我们将进一步设计额外的半胱氨酸保留到IgG1-FC的N末端区域并进行测试 可以实现的药物与FC比率的上限，以评估毒性和 人PDAC PDX小鼠模型中的治疗效率。当我们在CMC和 临床前研究，我们将寻求CRO根据GMP法规生成材料并为PK做好准备 以及狗和私人的毒性研究。这些研究将为一个阶段的IND申请铺平道路 我人类的临床试验。