<br>基于假单胞菌外毒素 A 的针对表达 CCK2R 的结直肠恶性肿瘤的免疫疗法：体外和体内评估,Molecular Pharmaceutics

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基于假单胞菌外毒素 A 的针对表达 CCK2R 的结直肠恶性肿瘤的免疫疗法：体外和体内评估
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2021-05-17 , DOI: 10.1021/acs.molpharmaceut.1c00095
Jiang Chang ₁ , Xilin Liu ₁ , Honglin Ren ₁ , Shiying Lu ₁ , Meng Li ₁ , Song Zhang ₂ , Ke Zhao ₁ , Hanxiao Li ₁ , Xiaoshi Zhou ₁ , Lixiong Peng ₁ , Zengshan Liu ₁ , Pan Hu ₁

Affiliation

胆囊收缩素-2 受体 (CCK2R) 已被证明是结直肠恶性肿瘤的特异性生物标志物。免疫毒素是一类有价值的免疫治疗剂，由靶向元件和细菌或植物毒素组成。先前的工作表明，靶向CCK2R是治疗结直肠癌（CRC）的良好治疗策略。在本研究中，我们开发了一种新版本的 CCK2R 靶向免疫毒素 GD9P，使用靶向肽 GD9 作为结合基序，并使用截短的假单胞菌外毒素 A (PE38) 作为细胞杀伤剂。 BALB/c裸鼠接受不同剂量的GD9P治疗，并在整个研究过程中获得了药效学、药代动力学和毒理学数据。与亲本免疫毒素rCCK8PE38相比，GD9P在体外和体内表现出约1.5倍的产率、更高的荧光强度以及增强的针对人CRC的抗肿瘤活性。 GD9P的体外IC ₅₀值范围为1.61至4.55 nM。在小鼠中进行药代动力学研究， T _1/2为 69.315 分钟。当荷瘤裸鼠接受剂量≥2mg/kg的GD9P治疗五次时，观察到肿瘤体积迅速缩小，在某些情况下观察到完全缓解。初步安全性评估表明，GD9P 作为基于假单胞菌外毒素 A 的免疫疗法具有良好的安全性。与奥沙利铂联合治疗可增加抗肿瘤疗效并减少化疗引起的毒副作用。总之，数据支持使用 GD9P 作为一种有前途的针对表达 CCK2R 的结直肠恶性肿瘤的免疫疗法。

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Pseudomonas Exotoxin A-Based Immunotherapy Targeting CCK2R-Expressing Colorectal Malignancies: An In Vitro and In Vivo Evaluation

Cholecystokinin-2 receptor (CCK2R) has been proven to be a specific biomarker for colorectal malignancies. Immunotoxins are a valuable class of immunotherapy agents consisting of a targeting element and a bacterial or plant toxin. Previous work demonstrated that targeting CCK2R is a good therapeutic strategy for the treatment of colorectal cancer (CRC). In the present study, we developed a new version of CCK2R-targeting immunotoxin GD9P using a targeted peptide, GD9, as the binding motif and a truncated Pseudomonas exotoxin A (PE38) as the cytokiller. BALB/c nude mice were treated with different doses of GD9P, and pharmacodynamics, pharmacokinetic, and toxicological data were obtained throughout this study. Compared to the parental immunotoxin rCCK8PE38, GD9P exhibited about 1.5-fold yield, higher fluorescence intensity, and increased antitumor activity against human CRC in vitro and in vivo. The IC₅₀ values of GD9P in vitro ranged from 1.61 to 4.55 nM. Pharmacokinetic studies were conducted in mice with a T_1/2 of 69.315 min. When tumor-bearing nude mice were treated with GD9P at doses ≥2 mg/kg for five doses, a rapid shrinkage in tumor volume and, in some cases, complete remission was observed. A preliminary safety evaluation demonstrated a good safety profile of GD9P as a Pseudomonas exotoxin A-based immunotherapy. The therapy in combination with oxaliplatin can increase the antitumor efficacy and reduce the toxic side effects caused by chemotherapy. In conclusion, the data support the use of GD9P as a promising immunotherapy targeting CCK2R-expressing colorectal malignancies.

更新日期：2021-06-07

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