Targeted Delivery of Endosomal Escape Peptides to Enhance Immunotoxin Potency and Anti-cancer Efficacy.
Targeted Delivery of Endosomal Escape Peptides to Enhance Immunotoxin Potency and Anti-cancer Efficacy.
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DOI：
10.1208/s12248-022-00698-x
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发表时间：
2022-03-25
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--
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这项工作描述了使用抗癌胚抗原抗体（10 H6，T84.66）靶向递送内体逃逸肽（H6 CM 18）和白树蛋白，一种I型核糖体失活蛋白。在用白树毒素或白树毒素免疫毒素处理后，在有或没有用T84.66-H6 CM 18共处理的情况下，评估结肠直肠癌细胞（LS 174 T，LoVo）的活力。使用荧光显微镜观察免疫缀合物从经处理细胞的内体的逃逸，并在单次和多次给药方案后在异种移植荷瘤小鼠中体内评估功效和毒性。应用25 pM T84.66-H6 CM 18与T84.66-白树素的组合在LS 174 T和LoVo细胞中使白树素效力增加约1，000倍和约6，000倍。1.0 mg/kg的静脉注射10 H6-白树毒素在LS 174 T荷瘤小鼠中耐受良好，而10和25 mg/kg剂量导致毒性体征。评价PBS、与T84.66或10 H6缀合的白树毒素、T84.66-H6 CM 18或与T84.66-H6 CM 18共同施用的白树毒素免疫毒素的单剂量施用。T84.66-白树毒素+1.0 mg/kg T84.66-H6 CM 18和10 H6-白树毒素+0.1 mg/kg T84.66-H6 CM 18的组合导致LS 174 T生长的显著延迟。多剂量方案的使用允许进一步的抗肿瘤作用，对于接受lmg/kg 10 H6-白树素+0.lmg/kg T84.66-H6 CM 18（p = 0.0072）和lmg/kg 10 H6-白树素+1mg/kg T84.66-H6 CM 18（p = 0.0017）的小鼠，中值存活时间显著延长33%和69%。白树毒素免疫缀合物与抗体靶向的内体逃逸肽的组合施用增加了白树毒素向靶细胞的细胞质的递送，使白树毒素体外细胞杀伤增加了1，000 - 6，000倍，并且显著增加了体内功效。
This work describes use of anti-carcinoembryonic antigen antibodies (10H6, T84.66) for targeted delivery of an endosomal escape peptide (H6CM18) and gelonin, a type I ribosome inactivating protein. The viability of colorectal cancer cells (LS174T, LoVo) was assessed following treatment with gelonin or gelonin immunotoxins, with or without co-treatment with T84.66-H6CM18. Fluorescent microscopy was used to visualize the escape of immunoconjugates from endosomes of treated cells, and efficacy and toxicity were assessed in vivo in xenograft tumor-bearing mice following single and multiple-dose regimens. Application of 25 pM T84.66-H6CM18 combined with T84.66-gelonin increased gelonin potency by ~1,000-fold and by ~6,000-fold in LS174T and LoVo cells. Intravenous 10H6-gelonin at 1.0 mg/kg was well tolerated by LS174T tumor-bearing mice, while 10 and 25 mg/kg doses led to signs of toxicity. Single dose administration of PBS, gelonin conjugated to T84.66 or 10H6, T84.66-H6CM18, or gelonin immunotoxins co-administered with T84.66-H6CM18 were evaluated. The combinations of T84.66-gelonin + 1.0 mg/kg T84.66-H6CM18 and 10H6-gelonin + 0.1 mg/kg T84.66-H6CM18 led to significant delays in LS174T growth. Use of a multiple dose regimen allowed further anti-tumor effects, significantly extending median survival time by 33% and by 69%, for mice receiving 1 mg/kg 10H6-gelonin + 0.1 mg/kg T84.66-H6CM18 (p = 0.0072) and 1 mg/kg 10H6-gelonin + 1 mg/kg T84.66-H6CM18 (p = 0.0017). Combined administration of gelonin immunoconjugates with antibody-targeted endosomal escape peptides increased the delivery of gelonin to the cytoplasm of targeted cells, increased gelonin cell killing in vitro by 1,000–6,000 fold, and significantly increased in vivo efficacy.
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影响因子：
4.2
作者：
de Virgilio M;Lombardi A;Caliandro R;Fabbrini MS
通讯作者：
Fabbrini MS
影响因子：
5.8
作者：
Alewine, Christine;Hassan, Raffit;Pastan, Ira
通讯作者：
Pastan, Ira
影响因子：
3.7
作者：
EIKLID, K;OLSNES, S;PIHL, A
通讯作者：
PIHL, A
影响因子：
4.7
作者：
Dubowchik, GM;Firestone, RA;Trail, PA
通讯作者：
Trail, PA
影响因子：
--
作者：
Engler, Frank A;Balthasar, Joseph P
通讯作者：
Balthasar, Joseph P