An engineered superantigen SEC2 exhibits promising antitumor activity and low toxicity

Abstract

Recent studies suggested that the histidine residues at 118 and 122 play an important role for the toxicity of staphylococcal enterotoxin C subtype 2 (SEC2),

and the substitutions of both histidines with alanine can severely impair the fever activity of SEC2. We hypothesized that promising SEC2 antitumor agent with low toxicity and enhanced superantigen activity can be constructed by introducing related mutations at protein functional sites of SEC2. We showed that the SEC2 mutants H122A and H118A/H122A exhibited improved superantigen activity after introducing the point mutations at Thr20 and Gly22. A resultant mutant, named as SAM-3, has considerable abilities to inhibit the growth of H22 and Hepa1-6 tumor

cells in vitro and colon 26 solid tumor in vivo. Furthermore, SAM-3 also exhibits significantly reduced toxicity compared with native SEC2. The study provides a novel

strategy for designing promising superantigen immunotherapeutic agent. The constructed SEC2 mutant SAM-3 can be used as a powerful candidate for cancer immunotherapy and could compensate the deficiency caused by toxicity of native SEC2 in clinic.

超抗原SEC2突变蛋白抗肿瘤活性和低毒性研究

近期研究表明118位和122位的组氨酸残基在金葡菌肠毒素C亚型SEC2的毒性方面起着重要的作用。用丙氨酸取代上述2个位点的组氨酸可显着降低SEC2的致热性。 据此推测，通过在SEC2的蛋白功能位点造成相应的突变可构建毒性降低及超抗原活性增强的SEC2抗肿瘤药物。Thr20 和Gly22定点突变后SEC2突变蛋白H122A和H118A/H122A的超抗原活性增强。命名为SAM-3的突变蛋白有显着的抑制性，可体外抑制H22和Hepa1-6肿瘤细胞，体内抑制colon 26实体瘤。此外，与野生型SEC2相比，SAM-3的毒性也显着降低。本研究为设计有效的超抗原免疫治疗药物提供了一种新策略。构建的SEC2突变体SAM-3可用作癌症免疫治疗的有效候选药物，并可弥补野生型SEC2临床毒性的缺陷。

An engineered superantigen SEC2 exhibits promising antitumor activity and low toxicity