IASO207 Injection for Active Refractory Systemic Lupus Erythematosus (SLE)

This study is a single-arm, single-center, open-label, first-in-human (FIH) clinical trial designed to preliminarily evaluate the safety and efficacy of IASO207 injection, an in vivo chimeric antigen receptor T-cell (CAR-T) therapy, in patients with active, refractory systemic lupus erythematosus (SLE), and to determine the recommended dose for subsequent clinical development.

A standard "3+3" dose-escalation design will be employed during the dose-escalation phase, with three predefined dose levels: 5.0 × 10⁸ TU, 1.0 × 10⁹ TU, and 2.0 × 10⁹ TU. Each dose cohort will enroll 3-6 subjects, with a single administration of IASO207 injection.

The primary objective is to assess the safety and tolerability of IASO207 across different dose levels. Secondary and exploratory objectives include the characterization of pharmacokinetics, pharmacodynamics, and immunogenicity, as well as the preliminary evaluation of clinical efficacy in patients with active refractory SLE. The results of this study are expected to inform dose selection and support subsequent clinical trials.

Inclusion criteria

• Subjects aged 18-75 years old, regardless of gender.
• Subjects diagnosed with active refractory SLE: a) Confirmed by the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria or the 2012 Systemic Lupus Erythematosus Collaborative Clinic (SLICC) criteria for at least 24 weeks; b) SLE Disease Activity Index 2000 (SLEDAI-2K) score ≥ 8, with at least 1 organ system having a BILAG-2004 A-class activity score at screening, or 2 organ systems having a BILAG-2004 B-class activity score; c) Previously treated with standardized glucocorticoids and at least two immunosuppressants/adjusters, antimalarial drugs or biologics for at least 3 months.
• Positive for disease-related pathogenic antibodies: Anti-nuclear antibody (ANA) positive and/or anti-dsDNA positive and/or anti-Smith positive.
• Allowed to use ≤ 20mg/d prednisone or equivalent dose of corticosteroids at screening, and use at a stable dose for at least 2 weeks. Note: Local or inhaled corticosteroids (or its immunomodulators) can be used concurrently;
• If antimalarial treatment has been initiated for ≥ 12 weeks before screening and is used at a stable dose for at least 8 weeks, it is allowed to continue in the study (maximum hydroxychloroquine dose ≤ 400mg/d).
• If immunosuppressants have been used before screening, they must be used at a stable dose for at least 4 weeks.
• Laboratory tests must meet the following conditions: a) Blood routine: Absolute neutrophil count (ANC) ≥ 1.0×10^9/L; Absolute lymphocyte count (ALC) ≥ 0.3×10^9/L; Hemoglobin ≥ 60 g/L; Platelets ≥ 50×10^9/L b) Liver function: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5× upper limit of normal (ULN); Serum total bilirubin ≤ 1.5×ULN (Gilbert's syndrome ≤ 3.0×ULN).
• The subject and their spouse agree to take effective contraceptive measures (excluding safe period contraception) from the time of signing the informed consent form by the subject until one year after IASO207 injection treatment.
• The subject must agree to sign or personally write and present the signed informed consent form approved by the ethics committee before starting any screening procedure.

Exclusion criteria

Disease-related:

• Diagnosed with drug-induced SLE.
• Complicated with other autoimmune diseases that may affect the assessment of the study, including but not limited to Sjögren's syndrome, psoriasis, rheumatoid arthritis.
• Had a catastrophic antiphospholipid syndrome or developed a severe antiphospholipid syndrome within 1 year before screening.
• The study disease involved neurological symptoms with a BILAG-2004 activity score of class A.

Other medical history-related:

• Known primary immunodeficiency (congenital or acquired).
• The subject has uncontrollable active fungal, viral, bacterial or other infections (existing persistent infection-related signs/symptoms, not improved after appropriate anti-infection treatment) or requires intravenous anti-infection drug treatment for infection.
• Positive hepatitis B surface antigen (HBsAg), or positive hepatitis B core antibody (HBcAb) and abnormal peripheral blood hepatitis B virus (HBV) DNA detection (defined as HBV DNA quantification above the normal reference range of the testing center or positive HBV DNA qualitative detection); positive hepatitis C virus (HCV) antibody and positive peripheral blood hepatitis C virus (HCV) RNA; positive Human Immunodeficiency Virus (HIV) antibody; positive cytomegalovirus (CMV) DNA detection; positive Treponema pallidum specific antibody and positive rapid plasma reagin test for syphilis.
• Severe heart disease: including but not limited to unstable angina pectoris and/or myocardial infarction within 12 months of screening, any congestive heart failure (NYHA classification ≥ III), and a history of severe arrhythmia; or left ventricular ejection fraction (LVEF) < 45%.
• Severe asthma or chronic obstructive pulmonary disease (COPD), with stable treatment considered for mild or moderate asthma or COPD by the investigator and sponsor; or resting arterial blood oxygen saturation < 91%.
• Evaluated by the investigator as having a severe bleeding risk.
• Evaluated by the investigator as having severe liver dysfunction.
• History of severe kidney disease; or eGFR < 30 mL/min/1.73m2 calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula.
• Acute cerebrovascular disease events occurred within 6 months before enrollment, including transient ischemic attack or stroke history.
• Any severe and/or uncontrolled comorbid diseases as assessed by the investigator.
• Had a malignant tumor within 5 years before screening, excluding cured cervical carcinoma in situ, basal cell or squamous cell skin cancer, locally advanced prostate cancer after radical surgery, breast duct carcinoma in situ after radical surgery, or papillary thyroid carcinoma after radical surgery.
• Had a clear history of mental disorder or a history of substance abuse for mental disorders that cannot be quit.
• Known allergy to the components of IASO207 injection or to the supportive drugs required for the toxicity management of CAR-T cell therapy (such as tocilizumab).

Previous and concurrent treatments:

• History of organ transplantation.
• History of autologous or allogeneic stem cell transplantation.
• History of cell therapy or CD19-targeted drug treatment.
• Received targeted CD20 biologic therapy within 12 weeks before screening, such as rituximab, obinutuzumab.
• Received plasma exchange or immunoadsorption treatment within 12 weeks before screening.
• Had or planned to have major surgery or surgical treatment caused by any reason within 12 weeks before screening.
• Have participated in the treatment of other investigational drugs (except for placebo) within the previous 4 weeks or 5 half-lives (whichever is longer);
• Have received a BAFF antagonist, such as belimumab or tixagevimab, within the previous 4 weeks;
• Have received live attenuated vaccine within the previous 4 weeks;
• Pregnant or lactating women;
• Other situations deemed unsuitable for inclusion by the investigators.