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.

摘要 胰腺导管腺癌（PDAC）在所有癌症相关死亡中排名第七 人类癌症预后极差，存活率极高。尽管使用吉西他滨/NAB- 紫杉醇和FOLFIRINOX，转移性PDAC患者的中位生存率仍低于1 年免疫检查点抑制剂在临床试验中对PDAC几乎没有反应。目前，紧急 因此，开发可用于更有效治疗PDAC的精准医学的需求尚未得到满足。 特异性杀死实体瘤的一种令人兴奋的策略是通过使用抗体-药物缀合物（ADC）， 在临床和商业上都取得了显著的成功。不幸的是，ADC的发展 一种特定的癌症类型如PDAC由于缺乏肿瘤表面抗原而受到显著限制， 而不是正常细胞。在SBIR第一阶段项目中，我们建议开发一种适体- 定向IgG-Fc药物偶联物（AFDC）平台，通过整合对PDAC细胞高度特异性的独特适体 与人IgG 1的Fc片段结合，该Fc片段众所周知具有延长的循环时间和可降解的半胱氨酸 用于与细胞毒性弹头有效缀合的残基。将追求两个具体目标。第一个目标是 APTPDAC介导的PDAC细胞杀伤的验证和有效适体指导的IgG 1-Fc的开发 药物偶联物（AFDC）对人PDAC细胞具有高度特异性。第二个目标是在体内进行 评价，评估AFDC在原位PDAC小鼠模型中的抗肿瘤功效，并鉴定推定的细胞 PDAC细胞上由APTPDAC识别的表面受体。这一概念验证阶段I的成功 该项目将产生一个具有独特功能的创新药物偶联物平台和一种可以 进一步开发用于治疗PDAC。 在II期研究中，我们将对已确定的组织靶点进行广泛的机制研究， 特异性和可能的副作用。我们将更准确地确定药物结合位点， 通过胰蛋白酶消化/MOTI-TOF和胰蛋白酶消化/HPLC测定最终产物中的适体、Fc和vcMMAE。的in 通过使用2 '-完全修饰的RNA适体技术，可以进一步增强适体的体内稳定性， 实验室报告我们将进一步工程化额外的半胱氨酸残基到IgG 1-Fc的N-末端区域，并测试 可以达到的药物-Fc比率的上限，以评价毒性方面的后果， 在人PDAC PDX小鼠模型中的治疗功效。当我们在CMC中生成足够的数据并 临床前研究，我们将寻求CRO根据GMP法规生成材料，并准备PK 以及对狗和灵长类动物的毒性研究这些研究将为IND申请阶段铺平道路 我的人体临床试验。