开发用于B细胞淋巴瘤的靶向IL-12免疫疗法平台
Development of a targeted IL-12 immunotherapy platform for B-cell lymphomas
影响因子:4.70000
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
摘要
免疫疗法已成为一种有希望的癌症治疗方法，它利用免疫系统的潜力精确地识别和消除了癌细胞。尽管免疫疗法取得了重大进展，但仍需要创新的方法来增强这些疗法的有效性和安全性。白介素12（IL-12）因其在免疫反应中的基本功能而被广泛认可，已被探讨为治疗癌症的潜在候选者。但是，涉及系统性给药IL-12的早期尝试无效，有重大的不利影响，因此突显了创新的需求。为了应对这些挑战，我们开发了一种治疗性分子，该分子利用与靶向肿瘤靶向组相关的单链IL-12突变体（IL-12MUT）。在这里，我们通过采用B细胞淋巴瘤模型（称为CD20-IL-12MUT）来描述高效的基于IL-12的TMEKINE™平台的开发。 CD20-IL-12MUT将IL-12的衰减活性与靶向输送到肿瘤相结合，从而最大程度地发挥了治疗潜力，同时最大程度地减少了脱靶效应。我们的结果表明，CD20-IL-12MUT通过诱导完全回归并为肿瘤抗原产生免疫记忆而表现出有效的抗癌活性。总的来说，我们的数据为CD20-IL-12MUT作为对B细胞淋巴瘤患者（如非霍奇金淋巴瘤）的潜在治疗选择提供了基础。
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.