Jang Julie K, Khawli Leslie A, Canter David C, Hu Peisheng, Zhu Tian H, Wu Brian W, Angell Trevor E, Li Zhongjun, Epstein Alan L
Department of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, HMR 205, Los Angeles, CA, 90033, USA.
Department of Endocrinology, Metabolism, and Hypertension, Thyroid Section, Brigham and Women's Hospital, Boston, MA, USA.
Cancer Immunol Immunother. 2016 May;65(5):511-23. doi: 10.1007/s00262-016-1813-x. Epub 2016 Mar 9.
CpG oligodeoxynucleotides (CpG) potently activate the immune system by mimicking microbial DNA. Conjugation of CpG to chTNT-3, an antibody targeting the necrotic centers of tumors, enabled CpG to accumulate in tumors after systemic delivery, where it can activate the immune system in the presence of tumor antigens. CpG chemically conjugated to chTNT-3 (chTNT-3/CpG) were compared to free CpG in their ability to stimulate the immune system in vitro and reduce tumor burden in vivo. In subcutaneous Colon 26 adenocarcinoma and B16-F10 melanoma models in BALB/c and C57BL/6 mice, respectively, chTNT-3/CpG, free CpG, or several different control constructs were administered systemically. Intraperitoneal injections of chTNT-3/CpG delayed tumor growth and improved survival and were comparable to intratumorally administered CpG. Compared to saline-treated mice, chTNT-3/CpG-treated mice had smaller average tumor volumes by as much as 72% in Colon 26-bearing mice and 79% in B16-bearing mice. Systemically delivered free CpG and CpG conjugated to an isotype control antibody did not reduce tumor burden or improve survival. In this study, chTNT-3/CpG retained immunostimulatory activity of the CpG moiety and enabled delivery to tumors. Because systemically administered CpG rapidly clear the body and do not accumulate into tumors, chTNT-3/CpG provide a solution to the limitations observed in preclinical and clinical trials.
CpG寡脱氧核苷酸（CpG）通过模拟微生物DNA来有效激活免疫系统。将CpG与靶向肿瘤坏死中心的抗体chTNT-3偶联，能使CpG在全身给药后在肿瘤中积聚，在肿瘤抗原存在的情况下激活免疫系统。将化学偶联至chTNT-3的CpG（chTNT-3/CpG）与游离CpG在体外刺激免疫系统和体内减轻肿瘤负担的能力方面进行了比较。分别在BALB/c和C57BL/6小鼠的皮下结肠26腺癌和B16-F10黑色素瘤模型中，对chTNT-3/CpG、游离CpG或几种不同的对照构建体进行全身给药。腹腔注射chTNT-3/CpG可延缓肿瘤生长并提高生存率，与瘤内注射CpG效果相当。与生理盐水处理的小鼠相比，chTNT-3/CpG处理的小鼠在携带结肠26肿瘤的小鼠中平均肿瘤体积小多达72%，在携带B16肿瘤的小鼠中平均肿瘤体积小多达79%。全身给药的游离CpG和与同型对照抗体偶联的CpG均未减轻肿瘤负担或提高生存率。在本研究中，chTNT-3/CpG保留了CpG部分的免疫刺激活性，并能够递送至肿瘤。由于全身给药的CpG会迅速从体内清除且不会在肿瘤中积聚，chTNT-3/CpG为临床前和临床试验中观察到的局限性提供了解决方案。
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