An immunotoxin with greatly reduced immunogenicity by identification and removal of B cell epitopes
An immunotoxin with greatly reduced immunogenicity by identification and removal of B cell epitopes
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DOI：
10.1073/pnas.0804851105
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发表时间：
2008-08-12
影响因子：
11.1
通讯作者：
Pastan, Ira
中科院分区：
文献类型：
--
作者：
Onda, Masanori;Beers, Richard;Pastan, Ira
重组免疫毒素是由结合肿瘤抗原的Fv与细菌或植物毒素融合而成的杂合蛋白。免疫毒素BL 22靶向CD 22阳性恶性肿瘤，由融合至假单胞菌外毒素A（PE 38）的38-kDa片段的抗-CD 22 Fv组成。BL 22在耐药毛细胞白血病中产生了许多完全缓解，其中可以给予许多治疗周期，因为中和抗体不会形成。与此形成鲜明对比的是，在针对实体瘤的免疫毒素试验中只观察到轻微的反应，因为在抗体产生之前只能给予一个治疗周期。为了允许更多的治疗周期和提高疗效，我们通过鉴定和消除PE 38上的大多数B细胞表位来产生免疫原性较低的免疫毒素。这是通过将特定的大亲水性氨基酸（Arg、Gln、Glu、Lys）突变为Ala、Ser或Gly来实现的。新的免疫毒素（HA 22 -8X）在三种小鼠品系中的免疫原性显著降低，但保留了完整的细胞毒性和抗肿瘤活性。消除B细胞表位是生产用于治疗目的的免疫原性较低的蛋白质的有前途的方法。
Recombinant immunotoxins are hybrid proteins composed of an Fv that binds to a tumor antigen fused to a bacterial or plant toxin. Immunotoxin BL22 targets CD22 positive malignancies and is composed of an anti-CD22 Fv fused to a 38-kDa fragment of Pseudomonas exotoxin A (PE38). BL22 has produced many complete remissions in drug-resistant Hairy cell leukemia, where many treatment cycles can be given, because neutralizing antibodies do not form. In marked contrast, only minor responses have been observed in trials with immunotoxins targeting solid tumors, because only a single treatment cycle can be given before antibodies develop. To allow more treatment cycles and increase efficacy, we have produced a less immunogenic immunotoxin by identifying and eliminating most of the B cell epitopes on PE38. This was accomplished by mutation of specific large hydrophilic amino acids (Arg, Gln, Glu, Lys) to Ala, Ser, or Gly. The new immunotoxin (HA22-8X) is significantly less immunogenic in three strains of mice, yet retains full cytotoxic and anti-tumor activities. Elimination of B-cell epitopes is a promising approach to the production of less immunogenic proteins for therapeutic purposes.