R21: A novel antibody-drug conjugate for treatment of squamous cell lung carcinoma

R21：一种用于治疗鳞状细胞肺癌的新型抗体药物偶联物

基本信息

批准号：
10510002
负责人：
MARK W. GRINSTAFF
金额：
$ 19.28万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10510002
关键词：
Address Adenocarcinoma Affinity Antibodies Antibody-drug conjugates Binding Binding Proteins Biodistribution Biological Assay Biological Products Blood C-terminal Cancer Etiology Cancer Patient Cancer cell line Cell Line Cessation of life Chemotherapy-Oncologic Procedure Cisplatin Collaborations Cysteine Cytotoxic agent Data Development Disease Distant Metastasis Docking Enzyme-Linked Immunosorbent Assay Experimental Designs FDA approved Fibroblasts G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Harvest Hour Human Immunotherapy In Vitro Individual Injections Lead Lung Neoplasms Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of lung Methods Microtubules Mission Molecular Target Monoclonal Antibodies Mus Non-Small-Cell Lung Carcinoma Normal Cell Organ Patients Peptides Pharmaceutical Preparations Plasma Primary Neoplasm Prognosis Research Saline Site Specificity Squamous Cell Lung Carcinoma Squamous cell carcinoma Stains Structure Structure of parenchyma of lung Survival Rate Tail Testing Tissues Toxic effect Treatment-Related Cancer Tumor Antigens United States United States National Institutes of Health anti-cancer therapeutic antigen binding aqueous base cancer therapy chemotherapy cytokine cytotoxic cytotoxicity design drug efficacy experimental study fluorophore immunogenicity improved inhibitor innovation lung cancer cell macrophage new therapeutic target novel overexpression patient derived xenograft model pharmacokinetics and pharmacodynamics premature prevent self assembly systemic toxicity targeted agent targeted treatment tumor

项目摘要

A novel antibody-drug conjugate for treatment of squamous cell lung carcinoma Project Summary With few available treatments, lung squamous cell carcinoma (SCC) has a 5-year survival of only 21%. This proposal outlines a novel antibody-drug conjugate (ADC) therapy for lung SCC, which targets and delivers a highly potent chemotherapy monomethyl auristatin E (MMAE) to G protein-coupled receptor 87 (GPR87)- overexpressing SCC tumors. ADCs combine the advantages of the high specificity of a targeting antibody and the high potency of a cytotoxic drug, and therefore, have the potential to improve the efficacy of the drug and reduce off-target toxicity. We will employ a new reliable approach for drug conjugation that utilizes supramolecular assembly of coiled coil peptides. This method allows site-specific, uniform loading of two drug molecules at the Fc region per antibody and maintains targeting specificity of the Fab region. The strong binding affinity of the coiled coils enhances ADC stability and prevents premature release of the drug. Moreover, the approach allows facile pairing of antibodies and drugs under mild aqueous conditions. The proposed experiments will test the hypothesis that an αGPR87 antibody-MMAE conjugate will target lung tumors, reduce systemic toxicity of MMAE, and extend survival, compared to a conventional ADC and MMAE alone in a SCC patient-derived xenograft (PDX) model. Importantly, well-characterized materials and rigorous experimental designs are established in this proposal with essential cross-disciplinary collaborations and expertise. The aims of this exploratory and developmental proposal are as follow. Aim 1 determines immunogenicity of the ADC components, and plasma stability, tumor binding and cytotoxicity of the ADC in human lung cancer and normal cell lines. Aim 2 evaluates biodistribution, PK, systemic toxicity and efficacy of the ADC in a SCC PDX model. Successful development of this ADC delivery platform will generate a novel targeted therapy with minimal off-target toxicity for SCC. Our supramolecular self-assembly conjugation approach also provides a versatile conjugation strategy applicable to other antibody-drug pairs for treatment of other cancers and diseases.

一种用于治疗鳞状细胞肺癌的新型抗体-药物偶联物项目概要由于可用的治疗方法很少，肺鳞状细胞癌 (SCC) 的 5 年生存率仅为 21%。该提案概述了一种针对肺 SCC 的新型抗体药物偶联物 (ADC) 疗法，该疗法针对并提供针对 G 蛋白偶联受体 87 (GPR87) 的高效化疗单甲基奥瑞他汀 E (MMAE)- 过度表达的 SCC 肿瘤结合了靶向抗体的高特异性和细胞毒性药物的高效力，因此有可能提高药物的功效和我们将采用一种新的可靠的药物偶联方法来减少脱靶毒性。卷曲螺旋肽的超分子组装允许两种药物的位点特异性、均匀负载。每个抗体的 Fc 区分子，并保持 Fab 区的强结合的靶向特异性。卷绕线圈的亲和力增强了 ADC 稳定性并防止药物过早释放。该方法允许在温和的水性条件下轻松配对抗体和药物。实验将检验αGPR87抗体-MMAE缀合物将靶向肺部肿瘤的假设，与传统 ADC 和 MMAE 相比，降低 MMAE 的全身毒性并延长生存期重要的是，在 SCC 患者来源的异种移植（PDX）模型中单独进行。该提案建立了严格的实验设计以及必要的跨学科合作该探索性和发展性提案的目标如下。 ADC 成分的免疫原性，以及血浆稳定性、肿瘤结合和细胞毒性 ADC 在人肺癌和正常细胞系中的作用目标 2 评估生物分布、PK、全身毒性。该 ADC 交付平台的成功开发将有助于评估 SCC PDX 模型中 ADC 的功效。我们的超分子自组装产生了一种具有最小脱靶毒性的新型靶向疗法。缀合方法还提供了适用于其他抗体-药物对的通用缀合策略治疗其他癌症和疾病。