Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, United States.
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
Front Immunol. 2023 Feb 23;14:1072810. doi: 10.3389/fimmu.2023.1072810. eCollection 2023.
Cancer immunotherapy has demonstrated great promise with several checkpoint inhibitors being approved as the first-line therapy for some types of cancer, and new engineered cytokines such as Neo2/15 now being evaluated in many studies. In this work, we designed antibody-cytokine chimera (ACC) scaffolding cytokine mimetics on a full-length tumor-specific antibody. We characterized the pharmacokinetic (PK) and pharmacodynamic (PD) properties of first-generation ACC TA99-Neo2/15, which synergized with DLnano-vaccines to suppress melanoma proliferation and induced significant systemic cytokine activation. A novel second-generation ACC TA99-HL2-KOA1, with retained IL-2Rβ/γ binding and attenuated but preserved IL-2Rα binding, induced lower systemic cytokine activation with non-inferior protection in murine tumor studies. Transcriptomic analyses demonstrated an upregulation of Type I interferon responsive genes, particularly ISG15, in dendritic cells, macrophages and monocytes following TA99-HL2-KOA1 treatment. Characterization of additional ACCs in combination with cancer vaccines will likely be an important area of research for treating melanoma and other types of cancer.
癌症免疫疗法已经展现出巨大的潜力，几种检查点抑制剂已被批准作为某些类型癌症的一线治疗药物，而新型工程细胞因子如 Neo2/15 目前正在许多研究中进行评估。在这项工作中，我们在全长肿瘤特异性抗体上设计了抗体-细胞因子嵌合体 (ACC) 支架细胞因子模拟物。我们对第一代 ACC TA99-Neo2/15 的药代动力学 (PK) 和药效动力学 (PD) 特性进行了表征，该药物与 DLnano 疫苗协同作用，抑制黑色素瘤增殖并诱导显著的全身细胞因子激活。一种新型的第二代 ACC TA99-HL2-KOA1，保留了 IL-2Rβ/γ 结合，减弱但保留了 IL-2Rα 结合，在小鼠肿瘤研究中诱导较低的全身细胞因子激活和非劣效保护。转录组分析表明，TA99-HL2-KOA1 治疗后，树突状细胞、巨噬细胞和单核细胞中 I 型干扰素反应基因，特别是 ISG15，上调。与癌症疫苗联合使用的其他 ACC 的表征可能是治疗黑色素瘤和其他类型癌症的重要研究领域。
