An engineered superantigen SEC2 exhibits promising antitumor activity and low toxicity

• Published in: Cancer Immunology, Immunotherapy Vol. 60; no. 5; pp. 705 - 713
• Main Authors: Xu, Mingkai, Wang, Xiaogang, Cai, Yongming, Zhang, Huiwen, Yang, Hongli, Liu, Changxiao, Zhang, Chenggang
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.05.2011; Springer; Springer Nature B.V
• Subjects: Animals; Antigens; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - immunology; Antineoplastic Agents - toxicity; Bacterial diseases; Biological and medical sciences; Cancer; Cancer Research; Cell Line, Tumor; E coli; Enterotoxins - chemistry; Enterotoxins - genetics; Enterotoxins - immunology; Enterotoxins - toxicity; Enzymes; Female; Human bacterial diseases; Immunology; Immunotherapy; Infectious diseases; Laboratory animals; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Mutagenesis; Mutagenesis, Site-Directed; Mutation; Neoplasms - therapy; Oncology; Original; Original Article; Pets; Pharmacology. Drug treatments; Plasmids; Point Mutation; Protein Engineering; Rabbits; Staphylococcal infections, streptococcal infections, pneumococcal infections; Superantigens - genetics; Superantigens - immunology; Superantigens - toxicity; Toxicity; China; Superantigen; Site-directed mutagenesis; Immunotherapy; Staphylococcal enterotoxin C2; Antineoplastic agent; Toxicity; Site directed mutagenesis; Biological activity; Staphylococcus; Infection; Toxin; Treatment; Bacteriosis; Enterotoxin; Bacteria; Micrococcales; Micrococcaceae; Staphylococcal infection
• DOI: 10.1007/s00262-011-0986-6
• ISSN: 0340-7004; 1432-0851

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.