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.

项目摘要 /摘要 该项目的目的是开发一种针对非小细胞肺的新型肿瘤糖果明靶向剂 癌症（NSCLC）。 NSCLC占所有肺部肿瘤的大部分，并且经常被诊断为高级 阶段不良预后。当前的疗法，包括新型靶向药物和免疫疗法，已导致 结果改善，但在晚期疾病中的有效性较小，其中一些药物导致 反抗。鉴于可能需要采用多种治疗策略来产生最佳治疗策略 治疗结果，针对NSCLC独特生物标志物的新型治疗剂的开发是 有必要。特别是，可以促进抗抗菌免疫响应的肿瘤靶向免疫疗法可能 提高免疫切除剂抑制剂的效率。越来越多的证据表明增加 癌细胞的高甘露糖糖（包括NSCLC）中的高甘露糖。为了瞄准这种糖斑点， 申请人的实验室已经开发了Avaren-FC（AVFC），这是一种重组抗体样分子“束” 识别恶性细胞表面上的高臭糖。 AVFC的抗肿瘤潜力和安全性 在人类A549和H460 NSCLC Xenographic挑战模型中已证明了使用免疫缺陷型 小鼠以及合成性B16F10黑色素瘤使用免疫能力的C57BL/6小鼠挑战模型。在 后一种模型AVFC处理增加了非经典单核细胞和其他髓样细胞的浸润 以及CD4/CD8 T淋巴细胞。此外，免疫组织化学分析表明，AVFC可以选择性地 在相邻的非肿瘤肺组织上识别的原代人NSCLC肿瘤。基于这些发现，我们 假设AVFC可以用作针对肿瘤相关的高甘露糖的新型免疫治疗剂 NSCLC中的Glycans。为了证实在更临床相关的NSCLC模型中的可能性，目的 R21项目揭示条件下AVFC的免疫治疗效率和涉及肿瘤的特征 KRAS/p53突变驱动的NSCLC小鼠模型。在特定的目标1中，我们将确定并表征 AVFC的治疗作用基于总体生存，肺肿瘤的免疫组织化学和 肺浸润的免疫细胞的免疫表型。此外，我们将评估AVFC的效率 与免疫切除剂阻滞剂抗PD-1抗体的结合。在特定目标2中，我们将分析 NSCLC小鼠中AVFC的生物分布和肿瘤检测曲线，使用放射性标记的AVFC衍生物 微型/CT成像分析。在我们的初步数据的基础上，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敏感性。特别是，我们会 评估放射性标记的AVFC检测肿瘤进展和转移的能力。集体， 拟议的研究将提供关键信息，以解决AVFC是否可以可行的问题 针对NSCLC的免疫治疗和/或诊断剂。如果答案是积极的，结果将 明显利用AVFC对I期临床试验的进一步临床前开发。