Evaluation of Safety, Pharmacokinetics and Pharmacodynamics of Arnovie101, an mRNA-LNP-Based In Vivo CAR-T Therapy, for the Treatment of B Cell-Mediated Autoimmune Diseases (SLE and AIHA)

Evaluation of Safety, Pharmacokinetics and Pharmacodynamics of Arnovie101, an mRNA-LNP-Based In Vivo CAR-T Therapy, for the Treatment of B Cell-Mediated Autoimmune Diseases (Systemic Lupus Erythematosus and Autoimmune Hemolytic Anemia)

This is an open lable and single arm study designed to evaluate the safety, PK and PD of Arnovie101 in B cell-mediated Autoimmune Disease

This is a prospective, exploratory clinical trial of Arnovie101 injection, an mRNA-LNP-based in vivo CAR-T therapy, in subjects with B cell-mediated autoimmune diseases (SLE, AIHA). The objective is to evaluate its safety, PK, and PD in these conditions.

Inclusion Criteria:

1. Ability to voluntarily sign informed consent, including compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and this protocol.

2. Male or female, aged 18 to 60 years (inclusive) at screening.

3. Participants with relapsed/refractory SLE with at least 6 months of disease history and meeting the following criteria:

   A. Confirmed diagnosis of SLE according to the 2012 SLICC or 2019 EULAR/ACR revised criteria. SLEDAI-2K score ≥6 at screening. If the score includes low complement and/or anti-dsDNA antibodies, the clinical symptom score of SLEDAI-2K (excluding low complement and/or anti-dsDNA antibodies) should be ≥4. Poor response to standard therapy (at least two first-line treatments, including corticosteroids and immunosuppressants) and disease relapse after treatment.

   B. SLE: Stable standard therapy (including non-steroidal anti-inflammatory drugs, immunosuppressants, biologics, and glucocorticoids; oral glucocorticoid dose of prednisone or equivalent ≥7.5 mg/day and ≤30 mg/day; if combined with an immunosuppressant, no minimum daily dose requirement) for at least 8 weeks before screening, with current dose stable for at least 2 weeks and expected to remain stable during the study. Prior use of at least two immunosuppressants including hydroxychloroquine.

   C. Life expectancy >6 months.

4. Participants with AIHA meeting the following criteria:

   A. Participants with AIHA or Evans syndrome who have failed ≥3 lines of therapy.

   B. Failure of ≥3 lines of therapy must meet all of the following: hemoglobin <10 g/dL with symptoms of anemia; failure of first-line corticosteroid therapy; failure of second-line rituximab therapy; failure of any one or more third-line regimens (splenectomy, cyclosporine, cyclophosphamide, azathioprine, mycophenolate mofetil, fludarabine, bortezomib, etc.).

   C. Life expectancy >3 months.

5. Adequate organ function:

   A. Renal function: Calculated creatinine clearance (Cockcroft-Gault) ≥30 mL/min without hydration support.

   B. Bone marrow function: Absolute neutrophil count (ANC) ≥1.0×10⁹/L, absolute lymphocyte count (ALC) ≥0.1×10⁹/L, hemoglobin (Hb) ≥60 g/L, platelet count (PLT) ≥20×10⁹/L. Coagulation: International normalized ratio (INR) or activated partial thromboplastin time (APTT) ≤1.5×ULN. Note: No blood transfusion, white blood cell growth factors (e.g., colony-stimulating factors), erythropoietin, or thrombopoietin within 7 days before the laboratory assessment.

   C. Hepatic function: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN, total bilirubin <2.0 mg/dL (for participants with Gilbert's syndrome, total bilirubin <3.0 mg/dL; except when caused by SLE itself).

   D. Pulmonary function: Dyspnea ≤CTCAE grade 1 and oxygen saturation (SpO₂) ≥92% on room air (measured by pulse oximeter).

6. Female participants must meet the following criteria: 1) Not pregnant or breastfeeding; 2) Surgically sterile or postmenopausal for ≥2 years, or if of childbearing potential (including those postmenopausal <2 years), have a negative serum pregnancy test (β-hCG) and agree to use effective contraception (e.g., condom, spermicide, or intrauterine device) during the study and for at least 12 months after the last dose. Use of progesterone-only contraceptives is not permitted; 3) Agree not to breastfeed during the study and for at least 12 months after the last dose.

7. Male participants must meet the following criteria: If not surgically sterile and engaging in sexual activity that could lead to pregnancy, agree to use effective contraception (e.g., condom, spermicide) during the study and for at least 12 months after the last dose, and refrain from donating semen or sperm during the study and for 12 months after the last dose.

Exclusion Criteria:

1. Presence of an unresected thymoma.
2. Pregnant or lactating women.
3. History of active severe or unstable neuropsychiatric SLE, including but not limited to poorly controlled seizures, psychosis, acute confusional state, cerebrovascular accident, demyelinating syndrome, cranial neuropathy, or active central nervous system vasculitis.
4. Presence of clinically significant central nervous system disease or pathology before screening, including but not limited to: cerebrovascular accident, aneurysm, epilepsy, convulsions/seizures, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis.
5. History of major organ transplantation (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/bone marrow transplantation.
6. Presence of known active infection at screening, including active tuberculosis, active or infectious pneumonia, or recurrent peptic ulcer; requiring hospitalization, intravenous antibiotics within 4 weeks before screening, or oral antibiotics within 2 weeks before screening; history of herpes zoster within 12 weeks before screening; history of human immunodeficiency virus (HIV) or positive HIV antibody test; positive hepatitis B surface antigen (HBsAg) and/or positive anti-hepatitis B core antibody (HBcAb) with detectable hepatitis B virus (HBV) DNA above the lower limit of detection; positive hepatitis C virus (HCV) antibody with detectable HCV RNA above the lower limit of detection; positive syphilis antibody with active infection.
7. History of any of the following cardiovascular diseases within 6 months before screening: New York Heart Association (NYHA) class II or higher heart failure, myocardial infarction, unstable angina, uncontrolled or symptomatic atrial arrhythmias (e.g., second-degree type II atrioventricular block, third-degree atrioventricular block, symptomatic bradycardia with ventricular rate <50 bpm), any ventricular arrhythmia, or other clinically significant heart disease. QTcF >480 ms (Fridericia's formula), left ventricular ejection fraction (LVEF) <50% by echocardiography at screening, or other significant electrocardiogram abnormalities.
8. Malignancy within 5 years before signing the ICF, except for: curatively treated basal cell carcinoma of the skin, superficial bladder cancer, localized prostate cancer, biopsy-proven cervical carcinoma in situ or cervical squamous intraepithelial lesion detected by Pap smear, and completely resected ductal carcinoma in situ of the breast.
9. Previous treatment with B-cell targeted therapies such as belimumab, rituximab, telitacicept; anti-CD22 agents (e.g., epratuzumab); anti-CD52 agents (e.g., alemtuzumab), or other similar biologics; TNF-α antagonists, IL-6 antagonists, IL-1 antagonists, selective T-cell costimulation modulators, etc., with less than 5 half-lives before screening.
10. Use of any other investigational drug for SLE in a clinical trial within 4 weeks before screening.
11. Presence of other serious diseases, including liver disease, neurological/psychiatric disorders, endocrine system disorders, hematological disorders (including moderate-to-severe dyslipidemia and related conditions), which in the investigator's judgment would affect participation in this study.
12. Receipt of non-biologic investigational drugs (e.g., BTK inhibitors, JAK inhibitors), intravenous immunoglobulin, or plasma exchange within 4 weeks or 5 half-lives (whichever is shorter) before screening.
13. Vaccination within 30 days before the first dose of study drug.
14. Prior treatment with mRNA-LNP or other LNP-based drugs within 2 years before the first dose of study drug.
15. History of asthma, severe allergic reactions, or known allergy to any active or inactive ingredient of the study drug (including background therapy).
16. Prior CAR-T cell therapy.
17. Major surgery within 4 weeks before the first dose of study drug, or minor surgery within 2 weeks before the first dose.
18. Severe mental disorder or suicidal tendency.
19. Any other condition that, in the investigator's judgment, makes the participant unsuitable for this study.