Antitumor potential of AvFc lectibody in non-small cell lung cancer

AvFc 凝集体在非小细胞肺癌中的抗肿瘤潜力

• 批准号: 10717195
• 负责人: Haixun Guo
• 金额: $ 40.24万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10717195
• 关键词: A549; Address; Affect; Antibodies; Apoptosis; Binding; Biodistribution; Biological Markers; C57BL/6 Mouse; CD8-Positive T-Lymphocytes; Cancer Model; Cancer cell line; Cell surface; Cells; Chimeric Proteins; Collaborations; Cytometry; Data; Detection; Development; Diagnosis; Diagnostic; Drug Kinetics; Drug Targeting; E-Cadherin; Endoplasmic Reticulum; Flow Cytometry; Glycocalyx; Glycoconjugates; Goals; Histopathology; Human; IgG1; Immune; Immune checkpoint inhibitor; Immunocompetent; Immunodeficient Mouse; Immunohistochemistry; Immunophenotyping; Immunotherapeutic agent; Immunotherapy; In Vitro; Infiltration; Investigational Drugs; Lectin; Link; Lung; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Mannose; Melanoma Cell; Modeling; Monitor; Mus; Mutate; Mutation; Myeloid Cells; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Normal Cell; Oligosaccharides; Pharmaceutical Preparations; Phase I Clinical Trials; Polysaccharides; Population; Prognosis; Proteins; Radiolabeled; Recombinant Antibody; Recombinant Fusion Proteins; Research; Resistance; SCID Mice; Safety; Structure of parenchyma of lung; Surface; TP53 gene; Therapeutic; Therapeutic Effect; Time; Treatment Efficacy; Tumor Markers; Variant; Vascularization; Visualization; X-Ray Computed Tomography; Xenograft procedure; advanced disease; anti-PD-1; anti-PD1 antibodies; anti-tumor immune response; antibody mimetics; antibody-dependent cell cytotoxicity; antitumor effect; cancer cell; cancer diagnosis; cancer immunotherapeutics; cancer immunotherapy; cancer therapy; clinically relevant; design; detection sensitivity; efficacy evaluation; immune cell infiltrate; immune checkpoint; immune checkpoint blockers; improved outcome; lung cancer cell; melanoma; microPET/CT; monocyte; mouse model; mutant; new therapeutic target; novel; novel therapeutics; preclinical development; response; targeted agent; targeted treatment; therapy outcome; tool; tumor; tumor growth; tumor progression; tumor xenograft

PROJECT SUMMARY / ABSTRACT The goal of this project is to develop a novel tumor glycobiomarker-targeting agent against non-small cell lung cancer (NSCLC). NSCLC accounts for the majority of all lung tumors and is frequently diagnosed at an advanced stage with poor prognosis. Current therapies, including novel targeted drugs and immunotherapies, have led to improved outcomes but have had less efficacy in advanced disease, and several of these agents result in resistance. Given that a combination of multiple therapeutic strategies may be necessary to produce an optimal therapeutic outcome, development of novel therapeutic agents targeting a unique biomarker of NSCLC is warranted. Particularly, tumor-targeted immunotherapy that can boost an antitumor immune response might enhance the efficacy of immune checkpoint inhibitors. There is growing evidence for an aberrant increase of high-mannose glycans in the glycome of cancer cells, including those of NSCLC. To target this glycobiomarker, the applicant’s lab has developed Avaren-Fc (AvFc), a recombinant antibody-like molecule “lectibody” efficiently recognizing high-mannose glycans on the surface of malignant cells. The antitumor potential and safety of AvFc has been demonstrated in human A549 and H460 NSCLC xenograft challenge models using immunodeficient mice as well as in syngeneic B16F10 melanoma challenge models using immunocompetent C57bl/6 mice. In the latter model, AvFc treatment increased the infiltration of non-classical monocytes and other myeloid cells as well as CD4/CD8 T lymphocytes. Furthermore, immunohistochemical analysis revealed that AvFc can selectively recognize primary human NSCLC tumors over adjacent non-tumor lung tissues. Based on these findings, we hypothesize that AvFc may serve as a novel immunotherapeutic agent targeting tumor-associated high-mannose glycans in NSCLC. To substantiate the possibility in a more clinically relevant NSCLC model, the goal of this R21 project is to reveal the immunotherapeutic efficacy and tumor-targeting profile of AvFc in a conditional Kras/p53 mutation-driven NSCLC mouse model. In Specific Aim 1, we will determine and characterize the therapeutic effects of AvFc based on overall survival, immunohistochemistry of lung tumors, and immunophenotyping of lung-infiltrated immune cells. Additionally, we will assess the efficacy of AvFc in combination with the immune checkpoint blocker anti-PD-1 antibody. In Specific Aim 2, we will analyze biodistribution and tumor detection profiles of AvFc in the NSCLC mice, using a radiolabeled AvFc derivative in a microPET/CT imaging analysis. Building on our preliminary data, we will design and optimize radiolabeled AvFc derivatives to have an optimal pharmacokinetic profile and tumor-detection sensitivity. In particular, we will assess the capability of radiolabeled AvFc to detect tumor progression and metastasis. Collectively, the proposed research will provide critical information addressing the question of whether AvFc could be a viable immunotherapeutic and/or diagnostic agent against NSCLC. Should the answer be positive, the results will significantly facilitate further preclinical development of AvFc towards a Phase I clinical trial.

项目总结/摘要 本项目的目的是开发一种新型的针对非小细胞肺癌的肿瘤糖基化因子靶向药物， 癌症（NSCLC）。NSCLC占所有肺肿瘤的大多数，并且经常在晚期被诊断为NSCLC。 预后差的阶段。目前的疗法，包括新型靶向药物和免疫疗法，已经导致 改善的结果，但在晚期疾病中的疗效较低，其中几种药物导致 阻力考虑到多种治疗策略的组合可能是产生最佳治疗效果所必需的， 治疗结果，开发靶向NSCLC独特生物标志物的新型治疗药物， 有正当理由特别是，可以增强抗肿瘤免疫反应的肿瘤靶向免疫疗法可能 增强免疫检查点抑制剂的功效。越来越多的证据表明， 癌细胞糖组中的高甘露糖聚糖，包括NSCLC的糖组。为了靶向这种糖生物标志物， 本申请人实验室已经开发了Avaren-Fc（AvFc），一种重组抗体样分子“lectibody 识别恶性细胞表面的高甘露糖聚糖。AvFc的抗肿瘤潜力和安全性 已在使用免疫缺陷的人A549和H460 NSCLC异种移植物激发模型中得到证实 小鼠以及使用免疫活性C57 bl/6小鼠的同基因B16 F10黑素瘤攻击模型中。在 在后一种模型中，AvFc处理增加了非经典单核细胞和其他骨髓细胞的浸润， 以及CD 4/CD 8 T淋巴细胞。此外，免疫组织化学分析显示，AvFc可以选择性地 与相邻的非肿瘤肺组织相比，识别原发性人NSCLC肿瘤。基于这些发现，我们 推测AvFc可作为靶向肿瘤相关高甘露糖的新型免疫抑制剂 非小细胞肺癌中的聚糖。为了证实在更临床相关的NSCLC模型中的可能性，本研究的目标是 R21项目旨在揭示AvFc在条件性免疫应答中的免疫功效和肿瘤靶向性。 Kras/p53突变驱动的NSCLC小鼠模型。在具体目标1中，我们将确定和表征 基于总生存期、肺肿瘤免疫组织化学和 肺浸润免疫细胞的免疫表型分析。此外，我们将评估AvFc在以下方面的疗效： 与免疫检查点阻断剂抗PD-1抗体组合。在第二章中，我们将分析 在NSCLC小鼠中使用放射性标记的AvFc衍生物， microPET/CT成像分析。基于我们的初步数据，我们将设计和优化放射性标记的 AvFc衍生物具有最佳的药代动力学特征和肿瘤检测灵敏度。特别是要 评估放射性标记的AvFc检测肿瘤进展和转移的能力。统称 拟议的研究将提供关键信息，解决AvFc是否可行的问题。 免疫抑制剂和/或诊断剂。如果答案是肯定的，结果将 显著地促进AvFc进一步临床前开发朝向I期临床试验。