the Safety and Efficacy of Targeted BCMA In Vivo LV Injection for Recurrent or Refractory Autoimmune Diseases

Clinical Study on the Safety and Efficacy of Targeted BCMA In Vivo LV Injection in the Treatment of Recurrent or Refractory Autoimmune Diseases

This study is designed as a single arm, open label, single center clinical trial to evaluate the safety, tolerability, efficacy, pharmacokinetic or pharmacodynamic characteristics of the investigational drug V001-BCMA in autoimmune disease.

Inclusion Criteria:

• 1. The age at the time of signing the informed consent form is ≥18 years old and ≤65 years old;

• 2. For cohort 1: recurrent or refractory systemic lupus erythematosus (all of the following four items must be met simultaneously)

  1. Diagnosed with SLE according to the 2012 SLICC or 2019 EULAR/ACR revised criteria.
  2. During screening, the patient exhibits positive anti-nuclear antibodies, and/or positive anti-ds-DNA antibodies, and/or positive anti-Smith antibodies.
  3. Before screening, patients must have received treatment with glucocorticoids combined with immunosuppressants and/or biologics for at least 3 months, with a stable dose for more than 2 weeks, and the disease remains active or the patient is intolerant to the medication.
  4. During the screening period, the SLEDAI-2K score is ≥8 points

• 3. For cohort 2: recurrent or refractory IgG4-related disease (all three of the following criteria must be met simultaneously)

  1. Meet the American College of Rheumatology (ACR)/EULAR 2019 classification criteria for IgG4-RD.
  2. Patients with clinical manifestations of recurrent or refractory IgG4-RD and ineffective conventional treatment
  3. Meet the clinical phenotype of "Mikulicz-system involvement"

• 4. For cohort 3: relapsed or refractory systemic sclerosis (all of the following 5 items must be met simultaneously)

  1. Meet the 2013 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) classification criteria for SSc.
  2. Anti-Scl 70 antibody positive, or anti-centromere protein antibody positive, or anti-RNA polymerase III antibody positive
  3. Patients with a modified Rodnan skin score (mRSS) of ≥10 at screening
  4. Before screening, patients must have received treatment with glucocorticoids combined with immunosuppressants and/or biologics for at least 3 months, with a stable dose for more than 2 weeks, and the disease remains active or intolerable.

• 5. For cohort 4: relapsed or refractory idiopathic inflammatory myopathies (all of the following 5 criteria must be met)

  1. Meet the 2017 EULAR/ACR classification criteria for inflammatory myopathies (including dermatomyositis DM, polymyositis PM, anti-synthetase syndrome ASS, and necrotizing myositis NM).
  2. At least one myositis-specific antibody (MSA) or myositis-associated antibody (MAA) positive (+ or above)
  3. During the screening period, the patient meets 2 of the following criteria: PGA(VAS)≥2cm (VAS-10cm scale); PtGA(VAS)≥2cm (VAS-10cm scale); HAQ>0.25; one or more muscle enzymes are elevated (CK, LDH, AST, ALT) ≥1.5×ULN; overall muscle extrinsic assessment (MDAAT) ≥2.0cm (VAS-10cm scale)
  4. After at least 3 months of treatment with glucocorticoids and immunosuppressants and/or biologics, with stable doses for more than 2 weeks, the disease remains active or the patient is intolerant to the medication.
  5. Active myositis is present in muscle biopsy or muscle MRI during the screening period or within the first 6 months before the screening period.

• 6. For cohort 5: relapsed or refractory AAV (all three of the following conditions must be met simultaneously)

  1. According to the 2022 ACR/EULAR criteria, the patient is diagnosed with AAV (GPA or MPA subtype). According to the KDIGO guidelines, after 3 months of treatment with glucocorticoids combined with immunosuppressants such as cyclophosphamide or biologics such as rituximab, and the dose is stable for more than 2 weeks, the disease is still active or the patient is intolerant to the drug;
  2. The patient is currently or has been in the course of AAV related antibodies positive;
  3. Severe disease requiring treatment (BVAS score ≥3.0).

• 7. Possess sufficient organ function

• 8. Men with fertility and women of childbearing age must agree to use effective contraception from the time they sign the informed consent form until 1 year after the study drug is administered. Blood pregnancy tests for women of childbearing age must be negative at screening and before infusion;

• 9. The subject or his/her guardian agrees to participate in this clinical study and signs the informed consent form (ICF), indicating that he/she understands the purpose and procedures of this clinical study and is willing to participate in the study.

Exclusion Criteria:

• 1. For cohort 1: relapsed or refractory systemic lupus erythematosus

  1. Subjects with uncontrolled lupus crisis within 8 weeks before screening were assessed by the investigator as unsuitable for participation in this study.
  2. Before screening, patients with clinically significant central nervous system diseases or pathological changes not caused by lupus, including but not limited to cerebrovascular accident, aneurysm, epilepsy, convulsion/convulsion, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, brain organic syndrome, or mental illness, should be excluded.

• 2. For cohort 3: relapsed or refractory systemic sclerosis. High-risk pulmonary arterial hypertension, according to the "Risk Stratification of Arterial Pulmonary Arterial Hypertension (PAH)" in the "Guidelines for the Diagnosis and Treatment of Pulmonary Arterial Hypertension in China (2021 Edition)".

• 3. History of major organ transplantation (such as heart, lung, kidney, liver) or hematopoietic stem cell/bone marrow transplantation.

• 4. Subjects with a history of ≥ Grade 2 bleeding within 30 days prior to screening, as assessed by the investigator, were deemed unsuitable for enrollment.

• 5. Use of any live vaccines against infectious diseases within 8 weeks before infusion.

• 6. Received any treatment using vesicular stomatitis virus G (VSVG) pseudotype virus.

• 7. The subject has a history or evidence of suicidal thoughts within 6 months before signing the ICF, or any suicidal behavior within 12 months before signing the ICF, and the researcher believes that there is a significant risk of suicide.

• 8. Pregnant or lactating women;

• 9. The patient has a history of severe and/or uncontrolled liver, gastrointestinal, kidney, lung, cardiovascular, psychiatric, neurological, or musculoskeletal diseases, hypertension, or any other medical condition that, in the opinion of the investigator, may affect the integrity of the patient's participation in the study, or may endanger the safety of the subject or affect the validity of the study results.

• 10. Suffered from malignant tumor within 3 years before screening, except for the following conditions: received radical treatment for malignant tumor and had no known active disease within ≥3 years before enrollment; or had fully treated non-melanoma skin cancer and currently had no evidence of disease;

• 11. Received any B-cell depleting biologic therapy (e.g., rituximab, ocrelizumab, obinutuzumab, ofatumumab, inebilizumab, etc.) within 3 months prior to infusion, unless B-cell recovery is proven.

• 12. Received immunosuppressants and other small molecule drugs within 3 days before infusion.

• 13. Use of any other clinical research drugs within 4 weeks before infusion. However, if the study treatment is ineffective or the disease progresses during the study period, and at least 3 half-lives have elapsed before screening, enrollment is allowed.

• 14. The patient has received live vaccines or live therapeutic infectious pathogens within 2 weeks before infusion.

• 15. The presence of chronic and active hepatitis B (excluding HBV-DNA levels below 500IU/ml), hepatitis C (HCV), human immunodeficiency virus (HIV) infection, or syphilis infection;

• 16. Active infection exists, requiring intravenous antibiotic therapy or hospitalization;

• 17. Patients who have undergone major surgery other than diagnosis or biopsy within 4 weeks before infusion, or are expected to undergo major surgery during the study period; note: patients who plan to undergo surgical procedures under local anesthesia can participate in the study.

Kyphoplasty or vertebroplasty are not considered major surgery;

• 18. Obvious evidence of cardiovascular disease as follows: a. N-terminal pro-B-type natriuretic peptide (NT-proBNP) > 8500ng/L; b. New York Heart Association (NYHA) classification of heart failure as III or IV; c. Patients who have received inpatient treatment for unstable angina or myocardial infarction within 6 months before the first dose, or who have received percutaneous coronary intervention and have received the latest stent placement within 6 months, or who have received coronary artery bypass grafting within 6 months;
• 19. Individuals who have known allergies, hypersensitivity reactions, intolerances, or contraindications to any component of V001-BCMA, or who have previously experienced severe allergic reactions.
• 20. Those who were deemed unsuitable for infusion or otherwise unsuitable for participation in the study by the researchers.