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.

拟议的发育活性将导致人性化的单克隆抗体Tiptuhumab，Tiptuhumab，充当放射性调节剂/免疫治疗剂。该抗体靶向癌症新抗原，税收相互作用蛋白1（TIP-1），对非小细胞肺癌细胞具有细胞毒性， NSCLC。对于NSCLC患者，5年总生存率为14.9％，中位生存率为时间为4个月。治疗结果的挑战部分是由于肿瘤遗传异质性，患者异质性，肿瘤诱导的免疫抑制和有限的药物癌细胞的生物利用度。当前细胞毒性化学疗法对NSCLC的影响有限通过抵抗治疗和疾病复发。除了有限的生存率外，一些 NSCLC当前治疗方式的主要问题包括它们缺乏特异性以及对正常细胞的随之而来的细胞毒性。拟议的研究是我们的铅抗体的开发，以促进研究。我们通过使用噬菌体显示肽库和随后从肺癌中对表面蛋白的亲和力纯化。 Tip-1是脚手架蛋白结合调节癌细胞活力和侵入性的细胞蛋白。 TIP-1表达在包括NSCLC在内的癌细胞中升高并定位在细胞表面。提示1 在总体生存和无进展生存。我们的抗TIP-1抗体与NSCLC细胞结合并敏感辐射。抗TIP-1 mAb被内在化并触发凋亡。此外，我们还有证明了这种抗体对动物肿瘤模型中植入的NSCLC细胞的特异性。我们将人性化小鼠单克隆抗体并测量tiptuhumab的功效作为临床前 / PDX /人性化模型系统的有效免疫治疗剂 NSCLC。此外，我们将使用使用药代动力学和药效学在大鼠和猴子中建立的方法，并确定人类的剂量首先人类临床试验。这项研究的目的是开发和证明 tiptuhumab并为与FDA举行的预定会议做准备。