Humanization, Production, and PK/PD Characterization of anti-TIP1 antibody against Non-Small Cell Lung Cancer

抗非小细胞肺癌抗 TIP1 抗体的人源化、生产和 PK/PD 表征

基本信息

批准号：
10020906
负责人：
Sapna Deore
金额：
$ 97.82万
依托单位：
MEDICAL GUIDANCE SYSTEMS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-19 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10020906
关键词：
Affect Affinity Affinity Chromatography Agreement Animal Model Animals Antibodies Antibody Specificity Antigens Apoptosis Bacteriophages Binding Binding Proteins Biological Biological Availability Biological Models Blocking Antibodies Blood Circulation Cell Death Cell Survival Cell surface Characteristics Clinical Trials Collaborations Combination Drug Therapy Communication Cytotoxic Chemotherapy Development Disease Dose Drug Kinetics Effector Cell Endocytosis Genetic Heterogeneity Goals Grant Heterogeneity Human Immune Immunoassay Immunosuppression Immunotherapeutic agent Immunotherapy Implant Lead Licensing Malignant Neoplasms Malignant neoplasm of lung Measures Medical Membrane Proteins Methods Modality Modeling Molecular Target Monkeys Monoclonal Antibodies Mus Non-Small-Cell Lung Carcinoma Normal Cell Oncology Outcome Patients Peptide Library Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Phase Post-Translational Protein Processing Production Progression-Free Survivals Property Proteins Radiation Radiation therapy Radiosensitization Rattus Recurrence Research Rodent Scaffolding Protein Small Business Innovation Research Grant Specificity Survival Rate System Taxes Testing Therapeutic Therapeutic antibodies Time Tissue Microarray Treatment Efficacy Treatment outcome Tumor Antigens Unresectable Variant Work Xenograft procedure cancer cell commercial application commercialization cytotoxic cytotoxicity de-immunization design dosage efficacy study first-in-human humanized antibody humanized monoclonal antibodies humanized mouse immunogenicity improved in silico in vivo meetings molecular targeted therapies mouse model neoantigens nonhuman primate outcome forecast overexpression pharmacokinetics and pharmacodynamics pre-clinical preclinical efficacy standard of care targeted treatment therapy resistant tumor tumor heterogeneity

项目摘要

The proposed developmental activity will result in a humanized monoclonal antibody, Tiptuhumab, which acts as a radiomodulator/immunotherapeutic. This antibody targets the cancer neoantigen, Tax Interacting Protein-1 (TIP-1), and is cytotoxic to non-small-cell lung cancer cells, NSCLC. For patients with NSCLC, the 5-year overall survival rate is 14.9% with a median survival time of 4 months. The challenge in treatment outcomes is partly due to tumor genetic heterogeneity, patient heterogeneity, tumor-induced immunosuppression, and limited drug bioavailability to cancer cells. The impact of current cytotoxic chemotherapies on NSCLC is limited by resistance to therapy and disease recurrence. In addition to the limited survival rates, some of the major problems with the current treatment modalities of NSCLC include their lack of specificity and the attendant cytotoxicity to normal cells. The proposed research is the development of our lead antibody, towards IND enabling studies. We identified TIP-1 through the use of bacteriophage displayed peptide libraries and subsequent affinity purification of surface proteins from lung cancer. TIP-1 is a scaffold protein that binds to cellular proteins that regulate cancer cell viability and invasiveness. TIP-1 expression is elevated in cancer cells including NSCLC and localizes to the cell surface. TIP-1 overexpression correlates with the poor outcomes in terms of both overall survival and progression-free survival. Our anti-TIP-1 antibody binds to and sensitizes NSCLC cells to radiation. Anti-TIP-1 mAbs are internalized and trigger apoptosis. In addition, we have demonstrated the specificity of this antibody to implanted NSCLC cells in animal tumor models. We will humanize our lead mouse monoclonal antibody and measure the efficacy of Tiptuhumab as an effective immunotherapeutic agent in preclinical / PDX / humanized model systems of NSCLC. Furthermore, we will study the pharmacokinetics and pharmacodynamics using established methods in rats and monkey, and determine the human dosage for planned first in human clinical trials. The goal of this research is to develop and demonstrate the efficacy of Tiptuhumab and prepare for a pre-IND meeting with FDA.

拟议的开发活动将产生人源化单克隆抗体 Tiptuhumab，作为放射调节剂/免疫治疗剂。该抗体针对癌症新抗原，Tax Interacting Protein-1 (TIP-1)，对非小细胞肺癌细胞具有细胞毒性，非小细胞肺癌。对于 NSCLC 患者，5 年总生存率为 14.9%，中位生存期 4个月的时间。治疗结果的挑战部分归因于肿瘤遗传异质性、患者异质性、肿瘤诱导的免疫抑制和有限药物癌细胞的生物利用度。目前细胞毒化疗对非小细胞肺癌的影响有限由于对治疗的抵抗和疾病复发。除了有限的生存率之外，一些目前非小细胞肺癌治疗方式的主要问题是缺乏特异性以及随之而来的对正常细胞的细胞毒性。拟议的研究是开发我们的先导抗体，以实现 IND 研究。我们通过使用噬菌体展示肽文库鉴定了 TIP-1 随后对肺癌表面蛋白进行亲和纯化。 TIP-1是一种支架蛋白与调节癌细胞活力和侵袭性的细胞蛋白结合。 TIP-1表达在包括 NSCLC 在内的癌细胞中升高，并定位于细胞表面。提示-1 过度表达与总体生存率和生存率方面的不良结果相关无进展生存期。我们的抗 TIP-1 抗体与 NSCLC 细胞结合并使其敏感辐射。抗 TIP-1 mAb 被内化并引发细胞凋亡。此外，我们还有在动物肿瘤模型中证明了该抗体对植入的 NSCLC 细胞的特异性。我们将人源化我们的主要小鼠单克隆抗体并测量 Tiptuhumab 的功效作为临床前/PDX/人源化模型系统中的有效免疫治疗剂非小细胞肺癌。此外，我们将使用以下方法研究药代动力学和药效学：在大鼠和猴子中建立方法，并确定首先计划的人体剂量人体临床试验。这项研究的目标是开发并证明其功效 Tiptuhumab 并准备与 FDA 举行的 IND 前会议。