Institute of Biotherapeutics Convergence Technology, Lemonex Inc., Seoul, 06683, Republic of Korea.
Department of Chemistry, Seoul National University, Seoul, 08826, Republic of Korea.
Biomaterials. 2022 Jan;280:121257. doi: 10.1016/j.biomaterials.2021.121257. Epub 2021 Nov 19.
Recent strategies in cancer immunotherapy based on interleukin-2 (IL-2) are generally focused on reducing regulatory T cell (Treg) development by modifying IL-2 receptor alpha (IL-2Rα) domain. However, the clinical utility of high-dose IL-2 treatment is mainly limited by severe systemic toxicity. We find that peritumorally injectable 'BALLkine-2', recombinant human IL-2 (rIL-2) loaded porous nanoparticle, dramatically reduces systemic side effects of rIL-2 by minimizing systemic IL-2 exposure. Notably, in cynomolgus monkeys, subcutaneous (SC)-injection of BALLkine-2 not only dramatically reduces systemic circulation of rIL-2 in the blood, but also increases half-life of IL-2 compared to IV- or SC-injection of free rIL-2. Peritumorally-injected BALLkine-2 enhances intratumoral lymphocyte infiltration without inducing Treg development and more effectively synergizes with PD-1 blockade than high-dose rIL-2 administration in B16F10 melanoma model. BALLkine-2 could be a highly potent therapeutic option due to higher anti-tumor efficacy with lower and fewer doses and reduced systemic toxicity compared to systemic rIL-2.
基于白细胞介素-2（IL-2）的癌症免疫治疗的最新策略通常侧重于通过修饰 IL-2 受体α（IL-2Rα）结构域来减少调节性 T 细胞（Treg）的发育。然而，高剂量 IL-2 治疗的临床应用主要受到严重的全身毒性的限制。我们发现，局部注射的“BALLkine-2”，即负载重组人白细胞介素-2（rIL-2）的多孔纳米颗粒，通过最小化全身 IL-2 暴露，显著降低了 rIL-2 的全身副作用。值得注意的是，在食蟹猴中，BALLkine-2 的皮下（SC）注射不仅显著降低了血液中 rIL-2 的全身循环，而且与 IV 或 SC 注射游离 rIL-2 相比，增加了 IL-2 的半衰期。局部注射的 BALLkine-2 增强了肿瘤内淋巴细胞浸润，而不会诱导 Treg 发育，并且在 B16F10 黑色素瘤模型中比高剂量 rIL-2 给药更有效地与 PD-1 阻断协同作用。与全身 rIL-2 相比，BALLkine-2 具有更高的抗肿瘤疗效、更低和更少的剂量以及降低的全身毒性，因此可能成为一种非常有效的治疗选择。
