Design and modification of EGF4KDEL 7Mut, a novel bispecific ligand-directed toxin, with decreased immunogenicity and potent anti-mesothelioma activity.
Design and modification of EGF4KDEL 7Mut, a novel bispecific ligand-directed toxin, with decreased immunogenicity and potent anti-mesothelioma activity.
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DOI：
10.1038/sj.bjc.6605297
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发表时间：
2009-10-06
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
效力、免疫原性和毒性是限制靶向毒素在实体肿瘤治疗中使用的三个问题。为了解决这个问题，我们利用基因工程技术开发了一种新的双特异性配体导向毒素（BLT），称为EGF4KDEL，这是一种新的重组抗间皮瘤药物，通过将人表皮生长因子（EGF）和白细胞介素-4 （IL-4）与截断的假单胞菌外毒素（PE38）在同一单链分子上连接而成。通过突变PE38分子上的7个免疫显性b细胞表位来产生一种新的药物EGF4KDEL 7Mut，从而降低了免疫原性。在体外，与单特异性EGF4KDEL相比，双特异性EGF4KDEL显示出更好的抗间皮瘤活性。将两种配体放在同一分子上，可以降低小鼠的毒性，使BLT的剂量比单体IL4KDEL和EGFKDEL的混合物大10倍。EGF4KDEL 7Mut保留了其所有的功能活性，并诱导的抗毒素抗体比给予亲本未突变形式的小鼠少87%。在体内，当肿瘤接种后14-16天开始治疗时，腹腔注射BLT对两种侵袭性恶性IP间皮瘤模型显示显著（P<0.01）和令人印象深刻的效果。这些数据表明，EGF4KDEL 7Mut是一种有前景的新型抗间皮瘤药物，专门用于解决靶向毒素在临床应用中面临的障碍。
Potency, immunogenicity, and toxicity are three problems that limit the use of targeted toxins in solid tumour therapy. To address potency, we used genetic engineering to develop a novel bispecific ligand-directed toxin (BLT) called EGF4KDEL, a novel recombinant anti-mesothelioma agent created by linking human epidermal growth factor (EGF) and interleukin-4 (IL-4) to truncated pseudomonas exotoxin (PE38) on the same single-chain molecule. Immunogenicity was reduced by mutating seven immunodominant B-cell epitopes on the PE38 molecule to create a new agent, EGF4KDEL 7Mut. In vitro, bispecific EGF4KDEL showed superior anti-mesothelioma activity compared with its monospecific counterparts. Toxicity in mice was diminished by having both ligands on the same molecule, allowing administration of a 10-fold greater dose of BLT than a mixture of monomeric IL4KDEL and EGFKDEL. EGF4KDEL 7Mut, retained all of its functional activity and induced about 87% fewer anti-toxin antibodies than mice given the parental, non-mutated form. In vivo, intraperitoneal (IP) injection of the BLT showed significant (P<0.01) and impressive effects against two aggressive, malignant IP mesothelioma models when treatment was begun 14–16 days post tumour innoculation. These data show that EGF4KDEL 7Mut is a promising new anti-mesothelioma agent that was developed to specifically address the obstacles facing clinical utility of targeted toxins.
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影响因子：
11.2
作者：
Shimamura, Takeshi;Royal, Richard E.;Puri, Raj K.
通讯作者：
Puri, Raj K.
影响因子：
45.3
作者：
Garland, Linda L.;Rankin, Cathryn;Borden, Ernest C.
通讯作者：
Borden, Ernest C.
影响因子：
3.9
作者：
Garland, L;Gitlitz, B;Figlin, R
通讯作者：
Figlin, R
DOI：
10.1073/pnas.91.15.6889
发表时间：
1994-07-19
影响因子：
11.1
作者：
KREITMAN, RJ;PURI, RK;PASTAN, I
通讯作者：
PASTAN, I
影响因子：
6.4
作者：
Frizelle, SP;Rubins, JB;Kratzke, RA
通讯作者：
Kratzke, RA