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European Review for Medical and Pharmacological Sciences 2021; 25: 1622-1630 Superantigens, superantigen-like and superantigen derivatives for treatment

J.-Y. CHEN

Xiehe Biology Group, Nobel Institute of Medicine, Shenzhen, Guangdong Province, China

Abstract. – OBJECTIVE: Bacterial superanti- gesting a more complex mechanism of immune gens (SAgs) are proteins produced by few types response6. Indeed, the current view is that SAgs of bacteria that have been linked to several hu- bind to multiple coreceptors forming a costimu- man diseases. Due to their potent in vitro and in latory axis between coreceptors critical for T-cell vivo tumoricidal effects, they are extensively in- 7 vestigated for oncological applications either activation . CD28 is a homodimer expressed alone or in combination with classical antican- constitutively on T cells that interacts with its cer drugs. However, the intrinsic toxicity of nat- B7 coligands expressed on -presenting ural SAgs stimulated the development of more cells, transducing the signal essential for effective and less toxic SAg-based immunother- activation. The staphylococcal superantigen-like apy. This review summarizes our current knowl- 1 (SSL1) specifically binds to human edge on SAg-based including extracellular signal-regulated kinase 2 (hERK2), SAg-like proteins and SAg derivatives, as well as their potential alone or with other therapeu- an important stress-activated kinase in mito- 8 tic modalities including and ra- gen-activated protein kinase signaling pathways . diotherapy. It is now clearer that SAgs induce the release of and chemokines through multiple Key Words: pathways as it was recently observed in in vitro Superantigen, Superantigen derivative, Superanti- 9 gen-like, Cancer, Combination therapy experiments . SAgs can cause severe poisoning and several serious human diseases. For instance, Staphylo- coccus aureus have potent super- Introduction antigenic activity associated with frequent food poisoning outbreaks10, toxic syndrome11,12, Bacterial Superantigens (SAgs), also common- pneumonia13, Kawasaki disease14-17, nasopha- ly known as erythrogenic or streptococcal ryngeal infections18, atopic (AD), and pyrogenic exotoxins1, are the most potent types chronic rhinosinusitis (CRS) and -related of T cell mitogens. SAgs are produced by only a infections. few bacterial , including Staphylococ- SAgs can induce the production of cytokines cus aureus2. The majority are produced by the leading to the hypothesis that viral proteins with Gram-positive organisms a possible superantigen activity may be responsi- and Streptococcus pyogenes3,4. Bacterial SAgs at ble for the systemic shock, acute respiratory syn- a very low concentration (typically < 0.1 pg/ml) drome, multiorgan failure and consequently death are sufficient to stimulate the T lymphocytes5. In observed in patients with COVID-1919. A recent vitro femtomolar concentrations of SAgs are able finding from in silico studies suggests that small to stimulate profound proliferation and insertions unique to SARS-CoV-2 (SARS-CoV-2 production in up to 20% of all peripheral T cells6. Spike) can display SAg activity and support this It was initially thought that the powerful immune hypothesis20. It is relatively well established that response generated by SAgs was due to its bind- at least one of the mechanisms by which SAgs ing to Major Histocompatibility Complex class II contribute to systemic multiorgan failure is the molecules on antigen-presenting cells and T cell production of a cytokine storm by enhancing receptors on T cells. Later, it was found that the the B7-2/CD28 costimulatory receptor interac- staphylococcal B (SEB) SAg, also tion21,22. The formation of the B7-2/CD28 costim- binds the co-stimulatory molecule CD28 sug- ulatory axis is critical for full T-cell activation21.

1622 Corresponding Author: Juyu Chen, MD; e-mail: [email protected] Superantigens, superantigen-like proteins and superantigen derivatives for cancer treatment

Picomolar amounts of staphylococcal entero- at very low dosage but of limited use due to A (SEA) SAg rapidly induced cytotoxic ac- toxic effects27. Natural superantigens have been tivity against K562 and Raji cells, as well as some used for cancer immunotherapy but at the cost of natural-killer (NK)-resistant tumour cell lines23 severe side effects due to their ability to induce which could be of value in therapeutic applica- high systemic levels of a large panel of inflam- tions. Therefore, despite the serious toxic and matory cytokines that may lead to a toxic shock adverse effects, SAgs are actively investigated as syndrome and therefore attempts to translate the therapeutic tools for cancer treatment. The aim of in vitro antitumor effect into clinical trials have this article is to provide a concise review of the been limited. To increase the effect of the SAgs, potential application of SAgs, SAg-like proteins the concept of tumor-targeted SAgs (TTS) was and SAg derivatives for cancer treatment. established with the aim of recruiting a large number of T cells (Figure 1). In addition, be- SAgs for Cancer Treatment cause of the differential species susceptibilities, For their ability to potentially activate T lym- predicting the toxicity of SAgs in humans is phocytes, SAgs have been used clinically as difficult. For instance, mice are not valid human an immunomodifier in the treatment of tumors. disease models because they are significantly The SAg Staphylococcal enterotoxin A (SEA) less sensitive to toxic shock induced by bacterial when co-cultured with human peripheral blood SAgs when compared with primates and rab- mononuclear cells (PBMCs) inhibited the pro- bits28. These limitations triggered the evaluation liferation and induced the death of human lung of other SAg alternatives such as SAg-like pro- carcinoma A549 cells24. The Staphylococcal en- teins and derivatives. terotoxin B (SEB) is an efficient activator of the antitumor immune response that leads to the SAg-Like Proteins eradication of tumor growth and inhibition of The common structure and function of the metastasis25. SEB-Superantigen-activated PBMC SAgs are also shared by another group of staph- (peripheral blood mononuclear cells) significantly ylococcal virulence factors called the superanti- induced in transitional cell carcinoma gen-like proteins (SAg-like proteins)4. Staphylo- cells (TCC)26. The Staphylococcal enterotoxin coccal enterotoxin-like toxins (SEls) are proteins C2 (SEC2) is another classical SAg with potent with similar amino acid sequences to those of antitumor activity by activating T classical SAgs but they exhibit low or no emetic

Figure 1. Potential immunotherapy using Tumor-Targeted Superantigen (SAg) (Modified from61). A SAg or SAg-based ligand can be linked to a tumor-specific or ligand. The tumor-specific antibody/ligand binds to the tumor antigen whereas the superantigen/ligand crosslink between the major histocompatibility complex class II molecule (MHC-II) and the T cell receptor (TCR) induces T-cell hyperactivation of a T (shown in this figure) and / and results in the release of huge amounts of cytokines and chemokines, such as α (TNF-α), interleukin 1 (IL-1), IL-2, interferon γ (IFN-γ). and many others. This leads to T-cell dependent tumor killing likely by apoptosis. APC = Antigen Presenting cell.

1623 J.-Y. Chen

Figure 2. Potential mechanism of action of ABR-217620 (Naptumomab estafenatox; 5T4Fab-SEA/E-120). Modified from55. T lymphocyte activation occurs through its T-cell receptor (TCR) upon binding of the ABR-217620 to the 5T4 tumor-associated antigen. The T cell kills tumoral cells directly by its cytotoxic T lymphocyte (CTL) activity and indirectly by producing cytokines (tumor necrosis factor [TNFa] – and interferon [IFNg ). activity and have anticancer effects by activat- SAg Derivatives ing lymphocytes particularly CD4+ and CD8+ T SAg derivatives have been created to reduce cells29. Treatment with a low concentration of systemic toxicity while maintaining profound an- Staphylococcal enterotoxin-like Q (SElQ) (30 µg/ titumor effects. SAg side-effects may be caused mouse) could inhibit the growth of tumors by by nonspecific binding to class II positive cells. approximately 30% without significant toxicity29. To overcome this, several authors created mutat- Staphylococcal SAg-like protein 6 (SSL6) inhibit- ed staphylococcal enterotoxin A (SEA). In partic- ed CD47 and promoted Sorafenib-induced apop- ular, Hansson et al35 created a tumor-reactive SAg tosis of hepatocellular carcinoma cells Huh-7 and by engineering a fusion protein composed of a MHCC97H30 that are widely used as liver cancer tumor-reactive mAb (C215Fab) and the bacterial models. Other staphylococcal SAg-like protein SAg staphylococcal enterotoxin A (SEA) (SEA), such as staphylococcal SAg-like protein 7 (SSL7) a well-known SAg. They introduced a point mu- have been shown to inhibit the formation of the tation (D227A) at the major MHC class II binding complement membrane attack complex (MAC) site. The Fab–SEA D227A fusion protein showed and can be useful for treating complement-me- profound antitumor effects with a markedly re- diated hemolysis31. Recombinant staphylococcus duced toxicity as compared with the wild-type aureus SAg-like protein 7 -that inhibits the com- Fab–SEA fusion protein. Kodama et al36, generat- plement- decreased the rate of tumor growth in a ed mutated SEA by changing Asp at position 227 transplantable murine colon cancer model32. Hu- of native SEA to Ala (mSEA-D227A), which has manized single-domain antibody (sdAb) mimick- reduced affinity to MHC class II molecules, but ing the C-terminal domain of SSL7 may also be retains the potential for T cell activation. mSEA- efficient in inhibiting complement-mediated he- D227A was 500 times more tolerated compared molysis of erythrocytes from patients with parox- to native SEA and had enhanced antitumor activ- ysmal nocturnal hemoglobinuria33. Staphylococ- ity when conjugated to anti-MUC1 mAb. cal SAg-like 10 was found to bind the chemokine SEA, when genetically conjugated to epider- receptor CXCR4 expressed on human T acute mal growth factor inhibited the proliferation lymphoblastic leukemia, lymphoma, and cervical of human nasopharyngeal carcinoma cell line carcinoma cell lines inhibiting CXCL12-induced CNE2 by promoting the proliferation of hu- cell migration34. man peripheral blood mononuclear cells and

1624 Superantigens, superantigen-like proteins and superantigen derivatives for cancer treatment enhancing the secretion of several cytokines mum tolerated dose sing a Bayesian model of -such as interferon-γ, tumor necrosis factor-α, Escalation with Overdose Control (EWOC)49. and interleukin-2 -that have broad antitumor Intratumoural injection of superantigen staph- activities37. Highly agglutinative staphylococcin ylococcal enterotoxin C (SEC) in patients with (HAS) SAg, a derivative from Staphylococcus hepatocellular carcinoma (HCC) after percuta- aureus, can inhibit and kill a variety of tumors neous microwave ablation (PMWA) was found cells as reviewed by Tian et al38. His-tagged to be safe and to achieve longer overall survival SEC2 (SEC2-His) a derivative of the Staphy- as well as disease free survival50. ABR-214936, a lococcal enterotoxin C2 (SEC2) inhibited the fusion of a Fab recognizing the antigen 5T4, and growth of human colon adenocarcinoma (Ca- Staphylococcal enterotoxin was tested in renal co-2) cells in vivo27. TGFαL3-SEB is anoth- cell carcinoma patients. Patients who received er derivative created by fusing the third loop higher drug exposure had greater disease control of transforming growth factor α (TGFαL3) to and lived almost twice as long as expected51. staphylococcal (SEB) that ABR-217620 (Naptumomab estafenatox; 5T4Fab- significantly increased the tumor volume in mice SEA/E-120) is an engineered antibody-superanti- bearing breast cancer without systemic toxici- gen fusion protein52 that induces T-cell mediated ty39,40. Bio-products made up of proteins produced killing of tumor cells at concentrations around by Staphylococcus aureus potently inhibit tu- 10 pM with low toxicity and reduced antigenic- mour growth in a murine model of mesothelio- ity53. Naptumomab estafenatox was created by 41 ma . The SpeCD203A-based TTS fusion protein, an fusing a superantigen (SAg) to the Fab moiety engineered human scFv that specifically targets of a tumor-reactive . Nap- human 5T4 (scFv5T4), was able to control the tumomab estafenatox targets a 72-kDa oncofe- growth and spread of large tumors in an in vivo tal trophoblast protein (the 5T4 tumor antigen) humanized mouse model of colon cancer42. The expressed on many carcinomas, including renal Mutant Staphylococcal enterotoxin C2 with low- cell carcinoma and has shown anticancer activity er toxic activity, named 2M-118 (H118A/T20L/ in these cells54. Fab targeting of ABR-217620 to G22E) engineered by site-directed mutagenesis tumor cells where the SAg portion of the fusion effectively inhibited the growth of S180 sarcoma protein elicits a potent tumoricidal cytotoxic T with acceptable toxicity in the BALB/c mice43. response and production of cytokines (TNF-al- The iRGD peptide fused superantigen mutant ex- pha and IFN-gamma) are the main proposed hibited enhanced anti-solid tumor characteristics mechanism of action55. At present there are 4 and induced improved lymphocyte infiltration in registered clinical trials (www.clinicaltrials.gov: mouse B16F10 cells44. SAg derivatives NCT00420888, NCT03983954, NCT00056537, for cancer immunotherapy can be also created NCT00132379) evaluating the anticancer effects by splitting into fragments, individually inactive, of Naptumomab estafenatox in human . until both fragments came into close proximity Despite the drug was well tolerated55 in phase I and reassembled into a biologically active form studies, a phase II/III study to determine the ef- capable of activating T cell response45. ficacy of naptumomab estafenatox (Nap) + IFNα vs. IFN in metastatic (RCC) SAg-Based Treatments in Clinical Trials did not meet its primary endpoint56. Few SAg-based therapies have been tested in Despite the scarcity of published clinical trials clinical trials for cancer. The Fab-SEA fusion on SAg-based treatment in cancer patients, this protein (PNU-214565) made by fusing the super- therapeutic modality seems to be safe, well toler- antigen staphylococcal enterotoxin A (SEA) with ated and more importantly they showed promis- the Fab fragment of the monoclonal antibody ing antitumor effects as reported in Phase I and C242 recognizing human colorectal (CRC) and II clinical trials. pancreatic carcinomas (PC) was tested in patients with the aim to determine the maximum tolerat- Combination Therapy ed dose and it was found to be safe46,47. Similar Tumors are complex and genetically and phe- results were reported in a cohort of patients with notypically heterogeneous and some cancers may advanced gastrointestinal malignancies48. A dif- not be treatable with just one strategy. A combi- ferent SEA-based fusion protein, PNU-214936, nation of traditional anticancer drugs with SAg- was evaluated in patients with advanced non- based therapies can help to overcome the drug small-cell lung cancer to establish the maxi- resistance, lessen the symptoms and improve

1625 J.-Y. Chen overall survival. Thus, effectiveness of SAgs, Conclusions SAg-like proteins and SAg derivatives can be increased by combination therapy with tradi- Although SAgs have been associated with sev- tional FDA-approved anticancer drugs that have eral diseases and serious adverse effects, they are been proven to give superior results when used extensively investigated for oncological applica- in combination57. Additionally, this combination tions either alone or in combination with classical therapy can be added to tumors that are routinely anticancer drugs. The potent antitumor activity treated with radiotherapy such as gliomas58 and of natural SAgs is limited by their high intrinsic esophageal cancer59. Table I shows examples of toxicity. However, a plethora of SAg-like proteins combinations therapy using SAg-based therapies and derivatives with lower toxicity are already with traditional chemotherapy +/- radiotherapy. available and new ones are under development.

Table I. Combination therapy using SAg-based therapy. SAg Adjuvant Cell type/tumor model Effect Ref.

SAg Doxorubicin Urothelial urinary Iincreased CD4+ T cell 62 bladder cancer activation Tumor-targeted Tasquinimod Melanoma cells Increased Tumor-specific 63 superantigen CD8(+) Microbiota-derived Sorafenib (SFN) Hepatocellular Carcinoma Enhances SFN sensitivity 30 Staphylococcal superantigen-like protein 6 (SSL6) Staphylococcal Chimeric antigen Mice bearing established Tumor-growth inhibition 64 enterotoxin-B receptor (CAR) E0771-Her2 tumors T cell Superantigen and Mouse MC38 and CT26 Increased anti-Tumor activity 65 staphylococcal colorectal tumor models enterotoxin B Staphylococcal Surgery + Glioma patients Increased “effective rate” 58 enterotoxin C Chemotherapy + (SEC) Radiotherapy ABR-217620 Docetaxel Patients with non-small-cell Evidence of immunological 55 lung cancer (NSCLC), and antitumor activity. pancreatic cancer (PC), and renal cell cancer (RCC) Staphylococcal Docetaxel B16-C215 tumors growing in Prolonged long term survival 66 enterotoxin A the lung of C57Bl/6 mice (SEA) in fusion with an anti-tumor Fab-fragment C215Fab-SEA Linomide Syngenic B16 melanoma cells > 99% reduction of liver 67 fusion protein transfected with GA733-2 metastasis in C57/Bl6 mice. (a human colon cancer cell surface antigen) Staphylococcal Interferon alpha B16-C215 tumors growing in the Synergistic anti-tumor effects, 68 enterotoxin A lung of C57Bl/6 mice prolonged survival (SEA) in fusion with an anti-tumor Fab-fragment Staphylococcal Staphylococcal Animals carrying the Long-term survival as 69 enterotoxin-A protein-A (PA) Ehrlich ascites tumor. compared with PA or (SEA), SEA alone Fab-SEA Fab-IL-2 B16 melanoma Cure in 90% of tumo -bearing 70 animals

1626 Superantigens, superantigen-like proteins and superantigen derivatives for cancer treatment

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