基于生理学的药物动力学框架用于量化从肿瘤到肿瘤引流淋巴结的抗体分布梯度

IF 3 Q3 IMMUNOLOGY Antibodies Pub Date : 2022-04-14 DOI:10.3390/antib11020028
Eric Salgado, Yanguang Cao
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引用次数: 0

摘要

在新佐剂环境中开出的免疫检查点阻断剂目前正在对许多类型的肿瘤进行积极研究,许多肿瘤已显示出早期成功。原发性肿瘤(PT)和肿瘤引流淋巴结(TDLN)免疫因子,以及PT和TDLN的足够治疗性抗体分布,对于新辅助免疫疗法中的最佳免疫激活和抗肿瘤疗效至关重要。然而,在不同的临床情况下,有多少抗体可以分布到PT-TDLN轴中,这在很大程度上仍然是未知的。当前工作的目标是建立一个基于生理学的药代动力学(PBPK)模型框架,该框架能够在各种临床和病理生理场景中表征PT-TDLN轴上的抗体分布梯度。该模型使用免疫PET抗体成像研究的临床数据进行校准,这些研究量化了血液、PT和TDLNs中的抗体药代动力学(PK)。表征了转移性病变位置、肿瘤诱导的压迫、炎症以及手术对PT-TDLN轴上抗体浓度梯度的影响。PBPK模型是预测各种类型肿瘤、转移和相关淋巴结中抗体暴露的有价值工具,支持有效的免疫治疗。
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A Physiologically Based Pharmacokinetic Framework for Quantifying Antibody Distribution Gradients from Tumors to Tumor-Draining Lymph Nodes
Immune checkpoint blockades prescribed in the neoadjuvant setting are now under active investigation for many types of tumors, and many have shown early success. The primary tumor (PT) and tumor-draining lymph node (TDLN) immune factors, along with adequate therapeutic antibody distributions to the PT and TDLN, are critical for optimal immune activation and anti-tumor efficacy in neoadjuvant immunotherapy. However, it remains largely unknown how much of the antibody can be distributed into the PT-TDLN axis at different clinical scenarios. The goal of the current work is to build a physiologically based pharmacokinetic (PBPK) model framework capable of characterizing antibody distribution gradients in the PT-TDLN axis across various clinical and pathophysiological scenarios. The model was calibrated using clinical data from immuno-PET antibody-imaging studies quantifying antibody pharmacokinetics (PK) in the blood, PTs, and TDLNs. The effects of metastatic lesion location, tumor-induced compression, and inflammation, as well as surgery, on antibody concentration gradients in the PT-TDLN axis were characterized. The PBPK model serves as a valuable tool to predict antibody exposures in various types of tumors, metastases, and the associated lymph node, supporting effective immunotherapy.
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来源期刊
Antibodies
Antibodies IMMUNOLOGY-
CiteScore
7.10
自引率
6.40%
发文量
68
审稿时长
11 weeks
期刊介绍: Antibodies (ISSN 2073-4468), an international, peer-reviewed open access journal which provides an advanced forum for studies related to antibodies and antigens. It publishes reviews, research articles, communications and short notes. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. Full experimental and/or methodical details must be provided. Electronic files or software regarding the full details of the calculation and experimental procedure - if unable to be published in a normal way - can be deposited as supplementary material. This journal covers all topics related to antibodies and antigens, topics of interest include (but are not limited to): antibody-producing cells (including B cells), antibody structure and function, antibody-antigen interactions, Fc receptors, antibody manufacturing antibody engineering, antibody therapy, immunoassays, antibody diagnosis, tissue antigens, exogenous antigens, endogenous antigens, autoantigens, monoclonal antibodies, natural antibodies, humoral immune responses, immunoregulatory molecules.
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