SNC116 Therapy for Refractory Systemic Lupus Erythematosus

This study is a investigator-initiated exploratory clinical trials, mainly evaluating the safety and tolerability of SNC116 in treating subjects with refractory systemic lupus erythematosus, and determining the MTD and/or RD. This study is divided into dose escalation and dose expansion phases. It is planned to enroll 14 to 28 subjects. The first phase adopts the standard "3+3" design, with 3 dose groups pre-set for dose escalation, and 9 to 18 subjects are enrolled. After completing the first phase of the study, SRC will determine the MTD and/or RD of SNC116, and then proceed to the second phase of dose expansion study. In the second phase, SRC will decide to continue enrolling a total of 5 to 10 subjects to further evaluate the safety and efficacy of SNC116.

Inclusion criteria

• Age ≥ 18 years, ≤ 65 years, gender not restricted.
• For refractory systemic lupus erythematosus (SLE), the following criteria must be met:

• Conform to the classification criteria of SLE of the European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) in 2019
• Disease activity score SLEDAI-2000 ≥ 6, and at least one BILAG-2004 index of the British Isles Lupus Activity Group (severe manifestations) or two B-class (moderate manifestations) organ scores, or both; or disease activity score SLEDAI-2000 ≥ 8
• Definition of recurrence/refractory: After receiving conventional treatment for at least 6 months, the disease remains active. Conventional treatment is defined as using glucocorticoids and/or antimalarial drugs, and any one or more of the following immunomodulatory drugs: cyclophosphamide, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biological agents/molecular targeted drugs, including CD20 monoclonal antibodies, belimumab, tepredipine, tofacitinib, baricitinib, upadacitinib, etc.
• Refractory lupus nephritis (LN) requires simultaneous satisfaction of: According to the classification of the International Society of Nephrology (ISN)/Renal Pathology Society (RPS), biopsy-proven type III, IV, or V, or type III/IV combined with type V, activity index (AI) ≥ 1, diagnosed as active LN; Renal biopsy must be conducted within one year before screening or during the screening period; Urine protein to creatinine ratio (UPCR) ≥ 1.0 g/g, or 24-hour urine protein ≥ 1.0 g, with or without red blood cell casts in active urinary sediment;
• Within 7 days before SNC116 administration, the blood routine test results must meet the following requirements (excluding SLE activity caused by surgery and assessed by the investigator):

• Absolute neutrophil count (ANC) ≥ 1.5×10^9/L;
• Absolute lymphocyte count (ALC) ≥ 0.5×10^9/L (or lymphocyte subpopulation detection CD3+ T cells ≥ 300 cells/μL);
• Hemoglobin (Hb) ≥ 80 g/L;
• Platelet count (PLT) ≥ 50×10^9/L.
• During the screening period, serum pregnancy test results of fertile female subjects must be negative (women who have undergone surgical sterilization or have been menopausal for at least 2 years are considered to have no fertility). Fertile female subjects and male subjects must use highly effective contraceptive methods throughout the clinical study and within 2 years after the last study treatment.
• Subjects must agree not to donate blood, organs, tissues, sperm/spirit and/or egg cells for at least 2 years after SNC116 treatment.
• Voluntarily participate in the clinical trial and sign the informed consent form.

Exclusion criteria

• Individuals who have had any allergic reaction, hypersensitivity reaction, intolerance or contraindication to the components of SNC116 or the drugs that may be used in the study (such as tocilizumab), or who have previously experienced severe allergic reactions.
• Subjects who had uncontrolled active infections requiring intravenous antibiotics, antiviral or antifungal drugs, etc. within 7 days before the administration of SNC116.
• Subjects with a primary immunodeficiency disorder.
• Subjects who had malignant tumors requiring treatment or evidence of recurrence within 2 years before screening (excluding: non-melanoma skin cancer that has been fully cured, cervical carcinoma in situ, localized prostate cancer, superficial bladder cancer, breast duct carcinoma, thyroid cancer, and other localized carcinomas).
• Subjects who have previously received any treatment using vesicular virus G glycoprotein pseudotyped viruses.
• Subjects who have previously received CD19 CAR-T cell therapy or other genetically modified T cell therapy.
• Subjects with organ dysfunction, meeting any of the following criteria:

• Serum ALT and AST > 2.5 times the upper limit of normal;
• Total bilirubin > 1.5 times the upper limit of normal, for those with Gilbert syndrome, total bilirubin > 3.0 times the upper limit of normal;
• Creatinine clearance rate (estimated by the Cockcroft-Gault formula) < 30 ml/min;
• Blood oxygen saturation ≤ 91% under indoor ventilation conditions without oxygen inhalation;
• Left ventricular ejection fraction < 45%.
• Subjects with clinically significant major cardiovascular diseases, including any of the following:

• Had myocardial infarction within 6 months before screening;
• Had unstable angina pectoris within 3 months before screening, or had evidence of active ischemic heart disease indicated by electrocardiogram and other examinations;
• Uncontrolled and clinically significant arrhythmias (such as persistent ventricular tachycardia, ventricular fibrillation, torsades de pointes, severe atrioventricular block, etc.);
• For male subjects, QTcF ≥ 450 milliseconds, for female subjects, QTcF ≥ 470 milliseconds and the investigator judges it to be clinically significant;
• Congestive heart failure of NYHA classification ≥ 3;
• Poorly controlled hypertension (systolic pressure > 160 mmHg and/or diastolic pressure > 100 mmHg) or with hypertensive crisis or hypertensive encephalopathy;
• Had deep vein thrombosis or pulmonary embolism within 6 months before screening;
• Other cardiovascular diseases assessed by the investigator as being significantly high risk and not suitable for enrollment.
• Meet any of the following criteria:

• Human immunodeficiency virus (HIV) antibody positive;
• Positive for hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody (HBcAb) and HBV-DNA above the detection limit of the testing method;
• Positive for hepatitis C virus (HCV) antibody and HCV RNA above the detection limit;
• Active syphilis (excluding false positives caused by the disease);
• Subjects with positive plasma cytomegalovirus (CMV) DNA or plasma Epstein-Barr virus (EBV) DNA detection (virus active);
• Subjects who had active tuberculosis or latent tuberculosis that was not properly treated within 6 months before screening.
• Subjects who had a history of or symptoms of severe central nervous system diseases within 6 months before screening (excluding simple trigeminal nerve disease; except for those caused by SLE activity, as assessed by the investigator). These include but are not limited to mental disorders, cerebrovascular diseases, encephalitis, brain injury, epilepsy, convulsions, aphasia, dementia, suicidal tendencies, etc. 11. Before receiving SNC116, the following drugs/treatments were administered:

• Within 1 week, preventive treatment with short-acting oral antiretroviral drugs was received.
• Within 1 week, small molecule drugs (such as JAK inhibitors) or iltiazumab were received.
• Within 2 weeks or 3 half-lives (as determined by the investigator) received immunosuppressants, such as azathioprine (AZA), mycophenolate mofetil (MMF), methotrexate (MTX), cyclosporine (CsA), tacrolimus (FK506), cyclophosphamide (CYC), leflunomide (LEF).
• Within 4 weeks received biologics (such as belimumab, tixagevimab, anifrolumab), experimental drugs/treatments (except for clear placebo-controlled groups), or plasma exchange treatment; for belimumab and tixagevimab, baseline B cell levels need to be recorded.
• Within 6 months received anti-CD20 monoclonal antibodies (such as rituximab, obinutuzumab), and the peripheral blood CD19+ B cell count at screening needs to be ≥ 50 cells/μL.
• Experienced major surgery within 4 weeks.
• Received live vaccines within 4 weeks.

• Had other active autoimmune diseases and the investigator determined that they were not suitable to participate in this study.

• Pregnant, or lactating, or planning to become pregnant. 14. Had other serious or diagnosed medical conditions within 3 months before screening (such as severe pulmonary disease or oxygen-dependent dependence, or progressive renal function deterioration requiring dialysis treatment, or active gastrointestinal bleeding/ulcer/perforation, or uncontrolled serous cavity effusion, etc.), and the investigator believed that these conditions might affect the safety or study compliance of the subjects, and were not suitable to participate in this study.

• Exclusion criteria for SLE:

a) Diagnosed as drug-induced lupus; b) At screening, had lupus crisis, or severe central nervous system involvement (neuro-psychiatric lupus) of the subjects.

• Other situations that the investigator believed might affect the safety or study compliance of the subjects and were not suitable to participate in the study.