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

一种治疗肺鳞癌的新型抗体-药物偶联物 项目摘要 肺鳞状细胞癌（SCC）的5年生存率仅为21%。这 该提案概述了一种用于肺SCC的新型抗体-药物偶联物（ADC）疗法，该疗法靶向并递送 高效化疗单甲基澳瑞他汀E（MMAE）对G蛋白偶联受体87（GPR 87）- 过度表达SCC肿瘤。ADC联合收割机了靶向抗体的高特异性的优点， 细胞毒性药物的高效力，因此具有改善药物功效的潜力， 降低脱靶毒性。我们将采用一种新的可靠的药物偶联方法， 卷曲螺旋肽的超分子组装。该方法允许两种药物的位点特异性、均匀负载 在一些实施方案中，Fab区在每个抗体的Fc区处具有靶向分子，并且维持Fab区的靶向特异性。的强结合 卷曲螺旋的亲和力增强ADC稳定性并防止药物的过早释放。而且 该方法允许在温和的水性条件下容易地配对抗体和药物。拟议 实验将检验α GPR 87抗体-MMAE偶联物将靶向肺肿瘤的假设， 与常规ADC和MMAE相比，降低MMAE的全身毒性，并延长生存期 单独在SCC患者来源的异种移植物（PDX）模型中。重要的是，良好表征的材料和 在这个建议中，通过必要的跨学科合作，建立了严格的实验设计 和专业知识。这一探索性和发展性建议的目的如下。目标1确定 ADC组分的免疫原性，以及ADC组分的血浆稳定性、肿瘤结合和细胞毒性。 人肺癌和正常细胞系中的ADC。目的2评价生物分布、PK、全身毒性 和ADC在SCC PDX模型中的功效。ADC交付平台的成功开发将 产生一种新的靶向治疗，对SCC的脱靶毒性最小。我们的超分子自组装 缀合方法还提供了适用于其它抗体-药物对的通用缀合策略， 治疗其他癌症和疾病。

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.