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：
10671669
负责人：
MARK W. GRINSTAFF
金额：
$ 22.68万
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/10671669
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 Harvest Hour Human Immunotherapy In Vitro Individual Injections Lung Neoplasms Macrophage 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 Treatment-related toxicity Tumor Antigens United States United States National Institutes of Health anti-cancer therapeutic antigen binding aqueous cancer therapy chemotherapy cytokine cytotoxic cytotoxicity design drug efficacy experimental study fluorophore immunogenicity improved inhibitor innovation lung cancer cell new therapeutic target novel organizational structure 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治疗的新型抗体 - 药物结合物项目摘要肺鳞状细胞癌（SCC）几乎没有可用的治疗方法，只有5年的生存率为21％。这提案概述了一种新型抗体 - 药物结合物（ADC）肺SCC疗法，该疗法针对并提供了高度有效的化学疗法单甲基极氨酸E（MMAE）至G蛋白偶联受体87（GPR87） - 过表达的SCC肿瘤。 ADC结合了靶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效率和降低脱靶毒性。我们将采用一种使用新的可靠方法来利用毒品共轭盘绕线圈肽的超分子组装。这种方法允许特定于现场的两种药物均匀加载每种抗体的FC区域的分子，并保持FAB区域的靶向特异性。强大的结合盘绕线圈的亲和力增强了ADC的稳定性，并防止了该药物的过早释放。而且，方法允许在轻度水性条件下轻松搭配抗体和药物。提议实验将检验以下假设：αGPR87抗体 - mmae结合物将靶向肺部肿瘤，与常规ADC和MMAE相比，降低MMAE的全身毒性并延长生存率单独使用SCC患者衍生的异种移植（PDX）模型。重要的是，特征良好的材料和在本提案中建立了严格的实验设计，并通过基本的跨学科合作建立和专家。该探索性和发展提案的目的如下。 AIM 1确定 ADC成分的免疫原性以及血浆稳定性，肿瘤结合和细胞毒性的性质人类肺癌和正常细胞系中的ADC。 AIM 2评估生物分布，PK，全身毒性并在SCC PDX模型中易于ADC。该ADC交付平台的成功开发将产生一种新型的靶向疗法，对SCC的脱靶毒性最小。我们的超分子自组装共轭方法还提供了适用于其他抗体 - 药物对的多功能共轭策略治疗其他癌症和疾病。