Anti-PD-L1 F(ab) Conjugated PEG-PLGA Nanoparticle Enhances Immune Checkpoint Therapy.
Anti-PD-L1 F(ab) Conjugated PEG-PLGA Nanoparticle Enhances Immune Checkpoint Therapy.
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DOI：
10.7150/ntno.65544
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Felsher DW
中科院分区：
文献类型：
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作者：
Lee CK;Atibalentja DF;Yao LE;Park J;Kuruvilla S;Felsher DW
背景：免疫检查点疗法对于治疗许多不同癌症的一部分患者是有效的。免疫疗法的疗效有限，部分原因是药物清除速度快和脱靶相关毒性。 PEG-PLGA 是 FDA 批准的、安全的、可生物降解的聚合物，具有灵活的尺寸控制。通过 PEG-PLGA 聚合物递送免疫检查点抑制剂，例如抗 PD-L1 (α-PD-L1)，有可能提高生物利用度并减少免疫清除，从而增强临床疗效并降低毒性。方法：将 α-PD-L1 单克隆抗体 (α-PD-L1 mAb) 的 Fc 截短 F(ab) 部分连接至 PEG-PLGA 聚合物。 α-PD-L1 F(ab)-PEG-PLGA 聚合物在水包油乳液中孵育，形成 α-PD-L1 F(ab)-PEG-PLGA 纳米颗粒 (α-PD-L1 NP)。对 α-PD-L1 NP 的大小、极性、毒性和稳定性进行了表征。在皮下小鼠结肠癌模型 (MC38) 中腹膜内 (IP) 或静脉内 (IV) 给药时，测量了 α-PD-L1 NP 与 α-PD-L1 mAb 的相对功效。使用荧光成像测量抗体保留。通过流式细胞术和免疫组织化学检查小鼠的免疫特征。结果：发现工程化 α-PD-L1 NP 具有比 α-PD-L1 mAb 潜在优势的药理学特性。 α-PD-L1 NP 的表面电荷对于肿瘤细胞摄取和减少自聚集都是最佳的。 α-PD-L1 NP 大小的改变减少了肾脏排泄和单核吞噬细胞的摄取，这使得 NP 在宿主系统中保留更长时间。 α-PD-L1 NP 在体外和体内均无毒性。 α-PD-L1 NP 相对抑制 MC38 肿瘤生长。通过脾脏生发中心面积的增加和肿瘤中先天免疫细胞的激活来测量，α-PD-L1 NP 似乎引发了增强的免疫反应。最后，我们观察到，一般来说，对于 α-PD-L1 NP 和 α-PD-L1 mAb，腹腔注射途径比静脉注射途径更能有效减少肿瘤。结论：α-PD-L1 NP 是一种无毒、生物相容性合成聚合物，可以延长 α-PD-L1 抗体循环并降低肾脏清除率，同时保留抗癌活性并可能增强免疫激活。
Background: Immune checkpoint therapies are effective in the treatment of a subset of patients in many different cancers. Immunotherapy offers limited efficacy in part because of rapid drug clearance and off-target associated toxicity. PEG-PLGA is a FDA approved, safe, biodegradable polymer with flexible size control. The delivery of immune checkpoint inhibitors such as anti-PD-L1 (α-PD-L1) via PEG-PLGA polymer has the potential to increase bioavailability and reduce immune clearance to enhance clinical efficacy and reduce toxicity. Methods: The Fc truncated F(ab) portion of α-PD-L1 monoclonal antibody (α-PD-L1 mAb) was attached to a PEG-PLGA polymer. α-PD-L1 F(ab)-PEG-PLGA polymers were incubated in oil-in-water emulsion to form a α-PD-L1 F(ab)-PEG-PLGA nanoparticle (α-PD-L1 NP). α-PD-L1 NP was characterized for size, polarity, toxicity and stability. The relative efficacy of α-PD-L1 NP to α-PD-L1 mAb was measured when delivered either intraperitoneally (IP) or intravenously (IV) in a subcutaneous mouse colon cancer model (MC38). Antibody retention was measured using fluorescence imaging. Immune profile in mice was examined by flow cytometry and immunohistochemistry. Results: Engineered α-PD-L1 NP was found to have pharmacological properties that are potentially advantageous compared to α-PD-L1 mAb. The surface charge of α-PD-L1 NP was optimal for both tumor cell uptake and reduced self-aggregation. The modified size of α-PD-L1 NP reduced renal excretion and mononuclear phagocyte uptake, which allowed the NP to be retained in the host system longer. α-PD-L1 NP was non-toxic in vitro and in vivo. α-PD-L1 NP comparably suppressed MC38 tumor growth. α-PD-L1 NP appeared to elicit an increased immune response as measured by increase in germinal center area in the spleen and in innate immune cell activation in the tumor. Finally, we observed that generally, for both α-PD-L1 NP and α-PD-L1 mAb, the IP route was more effective than IV route for tumor reduction. Conclusion: α-PD-L1 NP is a non-toxic, biocompatible synthetic polymer that can extend α-PD-L1 antibody circulation and reduce renal clearance while retaining anti-cancer activity and potentially enhancing immune activation.