Safety and Efficacy of PRG-2311 for Refractory Lupus Nephritis and IgG4-Related Disease

Safety and Efficacy of PRG-2311 (CD19/BCMA-targeting CAR-T Cells) for Refractory Lupus Nephritis and IgG4-Related Disease

A Clinical Study on the Safety and Effectiveness of CD19/BCMA Chimeric Antigen Receptor T Cells in the Treatment of Refractory Lupus Nephritis and IgG4-Related Disease.

Inclusion Criteria:

1. Age ≥ 18 years old;

2. If the kidneys are involved, estimate the glomerular filtration rate (eGFR) to be ≥ 15 mL/minute/1.73 m2;

3. The following test values within 3 days before the collection of mononuclear cells meet the following standards:

   1. Absolute lymphocyte count: ≥ 0.5 × 10 ^ 9/L [The use of granulocyte colony-stimulating factor (G CSF) is allowed, but subjects are not allowed to receive this supportive treatment within 7 days before the screening period laboratory examination];
   2. Absolute neutrophil count: ≥ 1.0 × 10 ^ 9/L [The use of granulocyte colony-stimulating factor (G-CSF) is allowed, but subjects are not allowed to receive this supportive treatment within 7 days before the screening period laboratory examination];
   3. Platelets: Subject platelet count ≥ 50 × 10 ^ 9/L (subjects are not allowed to receive blood transfusion support within 7 days before the screening period laboratory examination);
   4. Hemoglobin: ≥ 8.0 g/dL (allowing the use of recombinant human erythropoietin) [subjects have not received red blood cell (RBC) infusion within 7 days prior to the screening period laboratory examination];
   5. Creatinine clearance rate: (CrCl) or glomerular filtration rate (GFR) (Cockcroft Gault formula) ≥ 30 mL/min;
   6. Total bilirubin (serum): Total bilirubin (serum) ≤ 1.5 × ULN; Blood bilirubin>1.5 × Gilbert subjects from ULN can be enrolled with the consent of the sponsor AST and ALT: ≤ 3.0 × ULN;
   7. Plasma prothrombin time (PT), international standardized ratio (INR), partial prothrombin time (APTT): PT ≤ 1.5 × ULN, APTT ≤ 1.5 × ULN, INR ≤ 1.5 × ULN Willing to sign an informed consent form.

4. Fertile men and women of childbearing age must agree to use effective contraception from the time they sign an informed consent and up to 1 year after the study drug is used. Blood pregnancy tests for women of reproductive age at the time of screening and before cell infusion must be negative.

5. The patients or their guardians agree to participate in the clinical study and sign the informed consent, indicating that they understand the purpose and procedure of the clinical study and are willing to participate in the study.

   • for refractory LN

     1. According to the 2019 American Society of Rheumatology (ACR) criteria, diagnosed with systemic lupus erythematosus, within 6 months prior to infusion, confirmed by renal tissue biopsy according to the 2003 International Society of Nephrology (ISN)/Society of Nephropathology (RPS) criteria as active, proliferative lupus nephritis (LN), type III or IV, or type III/IV combined with type V, or type V. And have received standard treatment that is ineffective or relapses after disease remission.
     2. Positive anti-nuclear antibodies (ANA) and/or anti-dsDNA antibodies during the screening period.
     3. The SLE Disease Activity Index (SLEDAI-2000) score during the screening period is ≥ 8. SLEDAI-2000 clinical score ≥ 6 points, but low complement and/or anti ds-DNA positivity can be selected.

   • for refractory IgG4-RD

     1. According to the 2019 ACR/EULAR criteria, diagnosed with IgG4-RD;
     2. The clinical manifestations were recurrent or refractory IgG4-RD;
     3. IgG4-RD response index (RI) ≥2, the disease is in the active stage;
     4. meet the clinical phenotype of Mikulitz/systemic

Exclusion Criteria:

Subjects who meet any of the following criteria should be excluded from this study:

1. Pregnant or lactating women;
2. A history of malignant tumors within 5 years （①Carcinoma in situ of the cervix that has undergone curative treatment for more than 12 months prior to screening, ②Basal cell or squamous cell carcinoma of the skin that has been treated therapeutically, ③ Prostate cancer that has been treated with radical prostatectomy or curative radiation therapy for more than 3 years prior to screening has no known recurrence and is not currently receiving treatment；④have had surgery for thyroid cancer, and have not evidence of active disease）;
3. Received any B-cell depletion biologic therapy (for example, rituximab, ocrelizumab, obinutuzumab, ofatumumab, inebilizumab, etc) in the 6 months prior to CAR-T reinfusion, unless B-cell recovery was demonstrated;
4. Received immunosuppressant therapy within 3 days prior to CAR-T reinfusion, or systemic corticosteroid therapy (>10 mg/ day of prednisone or equivalent doses of other corticosteroids) within 3 days prior to CAR-T reinfusion;
5. Received live vaccine or live therapeutic STDS within 2 weeks prior to screening;
6. The presence of chronic and active hepatitis B (except for HBV DNA testing below 500IU/ml), hepatitis C (HCV), human immunodeficiency virus (HIV) infection, or syphilis infection;
7. With an active infection that requires intravenous antibiotics or hospitalization;
8. Obvious evidence of cardiovascular disease as follows: a N-terminal B-type natriuretic peptide (NT proBNP)>8500ng/L; b. The New York Heart Association (NYHA) classifies heart failure as Grade IV; c. Patients who received hospitalization for unstable angina or myocardial infarction within 6 months prior to the first administration, or patients who received percutaneous cardiac intervention and received the most recent stent placement within 6 months or coronary artery bypass grafting within 6 months;
9. People who have a known allergy, hypersensitivity, intolerance, or contraindication to any component of PRG-2311 or the drugs that may be used in the study, including fludarabine, cyclophosphamide, tolumab, or albumin, or who have had a prior severe allergic reaction;
10. Patients with other conditions determined by the investigator to be unsuitable for lymphocyte clearance or cell infusion, or who are otherwise unsuitable for study participation.