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.

The construction of a bifunctional fusion protein consisting of SEC2 and EGFP

“…Although SEC2 can lead to devastating illness, it has also been proposed that if SEC2‐induced response could be specifically directed toward pathogens and tumors, then SEC2 could prove to be a highly effective therapeutic agent. In fact, in China, its clinical application for malignant tumors dates back to 1999 . Therefore, it is necessary to clarify the distribution pattern and metabolic pathways of SEC2 in associated cells to maximize its clinical application value and to minimize side effects.…”

Evaluation of a Recombinant Double Mutant of Staphylococcal Enterotoxin B (SEB-H32Q/K173E) with Enhanced Antitumor Activity Effects and Decreased Pyrexia

“…Therefore, the search for a feasible solution to this problem forms a significant focus of research. Recently, it has been reported that the purified SEC protein exhibits elevated SAg activity and/or reduced toxicity [12], [13], [14], [15]. In addition, previous studies have shown that SEB stimulates more potent activation of T lymphocytes than SEC3 [16].…”

Superantigen staphylococcal enterotoxin C1 inhibits the growth of bladder cancer

“…10) Due to this attribute, SEs are believed to be exploited in immunotherapy of a variety of malignant tumors. [11][12][13][14] Recently, some types of SEs have been widely studied for their tumor-therapeutic applications. A mutant staphylococcal enterotoxin A (SEA) conjugated with an antibody Fab fragment has been used in Phase II clinical trial for colorectal cancer-targeted immunotherapy.…”

“…15) SEC2, a mild superantigen with decreased toxicity, has been intensively evaluated for its tumor inhibition potential in vitro and in vivo. 12) As a closely related homolog of SEC2, SEC1 has a stronger immunostimulatory activity than SEC2. 16) Therefore, we believe that SEC1 may also show immunotherapy role in cancers.…”