基于IL-12的靶向免疫治疗平台开发，用于B细胞淋巴瘤
Development of a targeted IL-12 immunotherapy platform for B-cell lymphomas
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影响因子:4.7
分区:医学2区 / 药学2区 免疫学3区
发表日期:2024 Sep 30
作者:
Dahea Lee, Dongsu Kim, Donggeon Kim, Nahmju Kim, Young Woo Nam, Byoung Chul Lee, Jaewhan Song, Jihoon Chang
DOI:
10.1016/j.intimp.2024.112600
摘要
免疫治疗已成为一种利用免疫系统精准识别和消灭癌细胞的有潜力的治疗策略。尽管免疫治疗取得了显著进展，但仍需创新方法以提升疗效和安全性。白细胞介素-12（IL-12）因其在免疫反应中的关键作用，被探索作为癌症治疗的潜在候选。然而，早期系统性给药的尝试效果不佳，并伴有严重不良反应，突显了创新的必要性。为此，我们开发了一种利用单链IL-12突变体（IL-12mut）与肿瘤靶向臂结合的治疗分子。我们描述了一种高效的IL-12平台——TMEkine™，采用B细胞淋巴瘤模型（称为CD20-IL-12mut）。该平台结合了IL-12的减弱活性与靶向递送，最大化治疗潜力同时减少非靶向副作用。结果显示，CD20-IL-12mut具有强效抗癌活性，能诱导完全消退并产生针对肿瘤抗原的免疫记忆。总之，我们的研究为CD20-IL-12mut作为非霍奇金淋巴瘤等B细胞淋巴瘤患者的潜在治疗方案提供了基础。
Abstract
Immunotherapy has emerged as a promising approach to cancer treatment that utilizes the potential of the immune system to precisely identify and eradicate cancerous cells. Despite significant progress in immunotherapy, innovative approaches are required to enhance the effectiveness and safety of these treatments. Interleukin-12 (IL-12), widely recognized for its essential function in immune responses, has been explored as a potential candidate for treating cancer. However, early attempts involving the systemic administration of IL-12 were ineffective, with significant adverse effects, thus underscoring the need for innovation. To address these challenges, we developed a therapeutic molecule that utilizes a single-chain IL-12 mutant (IL-12mut) linked to a tumor-targeting arm. Here, we describe the development of a highly effective IL-12-based TMEkine™ platform by employing a B-cell lymphoma model (termed CD20-IL-12mut). CD20-IL-12mut combined the attenuated activities of IL-12 with targeted delivery to the tumor, thereby maximizing therapeutic potential while minimizing off-target effects. Our results revealed that CD20-IL-12mut exhibited potent anticancer activity by inducing complete regression and generating immunological memory for tumor antigens. Collectively, our data provide a basis for additional research on CD20-IL-12mut as a potential treatment choice for patients with B-cell lymphomas such as non-Hodgkin's lymphoma.