An Exploratory Clinical Study of Anti-CD19 CAR NK Cell (KN5501) in the Treatment of Relapsed/Refractory Immune Nephropathy

Common Inclusion Criteria:

1. Age: ≥ 18 years old and ≤ 70 years old, male or female;

2. Positive CD19 expression in peripheral blood B cells as determined by flowcytometry;

3. The functions of important organs meet the following requirements:

4. Bone marrow hematopoietic function: a. White blood cell count ≥ 3 x 10^9/L b.Neutrophil count ≥ 1 x 10^9/L (no colony-stimulating factor treatment within 2weeks before examination); c. Hemoglobin ≥60g/L.

5. Liver function: ALT ≤ 3 x ULN,AST≤3 x ULN, TBIL≤1.5 x ULN(excluding Gilbertsyndrome, total bilirubin ≤ 3.0 x ULN)

6. Coagulation function: International standardized ratio (INR) ≤ 1.5 x ULN,prothrombin time (PT) ≤1.5 x ULN.

7. Cardiac function: good hemodynamic stability, left ventricular ejectionfraction (LVEF) ≥55%.

8. Female subjects of childbearing potential and male subjects whose partner is afemale of childbearing potential are required to use medically approvedcontraception or abstain from sex for at least 6 months during and at least 6 monthsafter the end of the study treatment period; female subjects of childbearingpotential have had a negative serum HCG test within 7 days prior to study enrollmentand are not lactating;

9. Voluntarily participate in this clinical study, sign an informed consent form, havegood compliance, and cooperate with follow-up.

Criteria for Recurrent/refractory primary membranous nephropathy

1. Primary membranous nephropathy diagnosed pathologically by renal biopsy;

2. Screening period 24-hour urine protein quantification ≥3.5 g;

3. Individuals who have not achieved partial remission (PR) after more than 6 months oftreatment with hormonal and/or cytotoxic drugs, immunosuppressive therapy, and/orbiologics (including but not limited to anti-CD20 monoclonal antibody); orindividuals who have relapsed again after achieving complete remission/partialremission (CR/PR) with treatment (24h urine protein quantification ≥3.5g);

4. Glomerular filtration rate (eGFR, CKD-EPI formula) ≥45 ml/min/1.73m2 during thescreening period.

Criteria for Relapsed/refractory IgA nephropathy

1. Primary IgA nephropathy pathologically confirmed by renal biopsy;

2. Treated (ACEI/ARB analogs) for at least 3 months;

3. Treatment with hormonal and/or cytotoxic drugs, immunosuppressive therapy, and/orbiologics (including, but not limited to anti-CD20 monoclonal antibody) for morethan 6 months, 24-hour urine protein quantification ≥ 1.0 g; or rapid progression ofrenal function (≥ 50% decrease in eGFR within 3 months); or relapse after treatmentto achieve complete remission/partial remission (CR/PR) (24-hour urine proteinquantification ≥ 1.0 g);

4. Glomerular filtration rate (eGFR, CKD-EPI formula) ≥30 ml/min/1.73m2 during thescreening period.

Criteria for Relapsed/refractory ANCA-associated vasculitis

1. Meets 2022 ACR/EULAR diagnostic criteria for ANCA vasculitis, including microscopicpolyangiitis, granulomatous polyangiitis, eosinophilic granulomatous polyangiitis;

2. Positive ANCA related antibodies (MPO-ANCA or PR3-ANCA positive);

3. Renal biopsy pathology consistent with renal damage in ANCA-associated vasculitis;

4. The Birmingham Vasculitis Activity Scale (BVAS) is ≥ 15 points (a total score of 63points), indicating the activity of the vasculitis condition;

5. BVAS score includes at least 2 abnormalities in the renal program;

6. Definition of relapse/refractory : ineffective conventional treatment or relapse ofdisease activity after remission. Definition of routine treatment: use ofglucocorticoids (more than 1 mg/kg/d) and cyclophosphamide for ≥3 months, and any ofthe following immunomodulatory drugs: antimalarial drugs, azathioprine,mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, as wellas biological agents such as rituximab and belimumab;

7. Glomerular filtration rate (eGFR, CKD-EPI formula) ≥15 ml/min/1.73m2 during thescreening period.

Common exclusion Criteria:

1. Individuals with known severe allergic reactions, hypersensitivity, contraindicationto any medications during the trial (cyclophosphamide, fludarabine, tozumabs), orsubjects with a history of severe allergic reactions;

2. Existence or suspicion of uncontrollable or treatable fungal, bacterial, viral orother infections;

3. Individuals with central nervous system disorders caused by ADs or not caused by ADs (including epilepsy, psychiatric disorders, organic encephalopathy syndromes,cerebrovascular accidents, encephalitis, central nervous system vasculitis);

4. Individuals with relatively serious heart diseases, such as angina pectoris,myocardial infarction, heart failure, and arrhythmia;

5. Subjects with congenital immunoglobulin deficiency;

6. Subjects with malignant tumors (except for non-melanoma skin cancer and in situcervical, bladder, and breast cancers that have been disease-free for more than 5years);

7. Subjects with end-stage renal failure;

8. Subjects with positive hepatitis B surface antigen (HBsAg) or hepatitis B coreantibody (HBcAb) and HBV DNA titer in peripheral blood higher than the upper limitof detection; Patients with positive hepatitis C virus (HCV) antibodies and positiveperipheral blood HCV RNA; People who are positive for human immunodeficiency virus (HIV) antibodies; Those who have tested positive for syphilis;

9. Subjects with mental illness and severe cognitive impairment;

10. Subjects who have received other clinical trial treatment within 3 months;

11. Pregnant or intending to conceive women;

12. In the opinion of the investigator, there are other reasons why subjects cannot beincluded in this study.

Exclusion Criteria for Recurrent/refractory primary membranous nephropathy

1. Secondary membranous nephropathy (e.g., hepatitis B, systemic lupus erythematosus,drug-associated, malignancy-associated, etc.), or in combination with other renaldiseases confirmed by renal biopsy;

2. Type 1 or type 2 diabetes.

Exclusion Criteria for Relapsed/refractory IgA nephropathy

1. Exclude secondary IgA nephropathy, including but not limited to: anaphylacticpurpura, ankylosing spondylitis, systemic lupus erythematosus, desiccation syndrome,viral hepatitis, cirrhosis of the liver, rheumatoid arthritis, and mixed connectivetissue disease; or in combination with other renal diseases confirmed by renalbiopsy;

2. Crescentic nephritis (pathologic diagnosis of >50% crescentic bodies), micrognathicnephropathy with IgA deposition, and other specific types of pathologic or clinicalrenal disease.

Exclusion Criteria for Relapsed/refractory ANCA-associated vasculitis

1. Estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2;

2. If the patient has alveolar hemorrhage invasive lung ventilation is required,estimated to last longer than the screening period.