Anti-CD19/BCMA CAR-NK Cells in Patients With B Cell Mediated Autoimmune Disease

Inclusion Criteria:

1. Patients or their legal guardians must acknowledge the risks and procedures involvedand subsequently provide informed consent to participate in the clinical trial.

2. Predicted survival time ≥ 12 weeks;

3. ECOG: 0~2;

4. Cardiac function: Left ventricular ejection fraction (LVEF) ≥55% ;

5. Renal function: eGFR≥30ML/min/1.73m2； (For patients with an eGFR < 30 mL/min/1.73 m²or those receiving renal replacement therapy, inclusion or exclusion in the study isdetermined at the discretion of the investigators. )

6. Liver function: Asparagus cochinchinensis transase (AST) and AlanineAminotransferase (ALT)≤3.0 ULN, Total Bilirubin (TBIL) in serum ≤2.0×ULN;

7. Lung function: No serious lung lesions, SpO2≥92%;

8. Negative pregnancy test for female Subjects of childbearing age, agree to takeeffective contraceptive measures the first year after CAR-NK infusion;

SLE:

1. Age:≥5 years old;

2. Diagnosed with SLE according to the 2019 EULAR/ACR SLE classification criteria；

3. Still in moderate to severe disease activity despite ≥3M of high doseglucocorticoids(prednisone≥1mg/kg/d or other equivalent amount of other steriod ),hydroxychloroquine and at least 2 of the following treatments(cyclophosphamide, MMF,azathioprine, methotrexate, cyclosporin, tacrolimus, sirolimus, leflunomide,telitacicept, Beliumab, and rituximab,etc,al); or Intolerant to standard treatments;or the dosage of steroid can not be reduced to 5mg/d after 6-month of routinetreatment.

4. SLEDAI 2K score>6 points;

5. No history of Central nervous system (CNS) disease within 60 days prior toscreening;

6. No history of macrophage activation syndrome (MAS) within one month prior toscreening.

MDR-SRNS

1. Age ≥3 years old, gender unlimited;

2. Diagnosed with SRNS according to the 2021 Kidney Disease: Improving Global Outcomes （KDIGO） Guidelines and have not achieved a complete response after 12 months oftreatment with two standard doses of hormone replacement drugs with differentmechanisms of action or relapse of disease activity after remission (at least one ofthe two drugs is a calcineurin inhibitor such as cyclosporine or tacrolimus; Otherhormone replacement drugs include Mycophenolate Mofetil, cyclophosphamide, Taitaceptor rituximab); Or if no remission has been achieved after 3 to 6 months of adequatetreatment with one calcineurin inhibitor, if the researcher judges that the benefitsoutweigh the risks and the patient or guardian has fully informed consent, thepatient can be considered for inclusion.Patients with other diseases, such assystemic lupus erythematosus, requiring long-term systemic treatment withglucocorticoids or immunosuppressants, may be considered for inclusion after theinvestigator determines that the benefits outweigh the risks and the patient orguardian has fully informed consent;

3. Renal biopsy was performed and the pathological type was determined to be minimallesion nephropathy(MCD) or focal segmental glomerulosclerosis (FSGS);

IgA nephropathy

1. Age: ≥ 5 years old, male or female;

2. IgA nephropathy pathologically confirmed by renal biopsy;

3. Angiotensin-Converting Enzyme Inhibitors (ACE) or angiotensin receptor blocker (ARB)treated for at least 3 months and meet at least one of the following requirements:

4. Combination or sequential treatment with steroids and at least oneimmunosuppressant or biologic for ≥ 3 months; and 24-hour urine proteinquantification ≥500mg or UPCR≥0.5mg/mg;

5. >50% decline in eGFR within 3 months;

6. Patients who are unable to tolerate conventional treatment and for whom theinvestigator determines the benefits outweigh the risks and who have obtainedfully informed consent from the patient or guardian may be considered forinclusion;

7. Exclude subjects with other secondary causes; exclude patients with uncontrolledblood pressure.

Exclusion Criteria:

1. Subjects with known severe allergic reactions, hypersensitivity, contraindication toany medications during the trial (cyclophosphamide, fludarabine, obinutuzumab), orsubjects with a history of severe allergic reactions

2. Uncontrollable infection, or active infection that requires systemic treatmentwithin 1 week prior to screening；

3. Subjects with grade III or IV heart failure (NYHA classification)

4. Have a history of congenital heart disease or acute myocardial infarction within 6months prior to screening; Or severe arrhythmias (including multisource frequentsupraventricular tachycardia, ventricular tachycardia, etc.); Or combined withmoderate to massive pericardial effusion, serious myocarditis, etc; Or patients withunstable vital signs who need hypertensive drugs；

5. Renal replacement therapy has been or is being performed within 3 months prior totransfusion;

6. Hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positiveand peripheral blood hepatitis B virus (HBV) DNA titer greater than the normalreference value range; Or hepatitis C virus (HCV) antibody positive and peripheralblood hepatitis C virus (HCV) RNA titer greater than the normal reference valuerange; Or positive for human immunodeficiency virus (HIV) antibodies; Or syphilistest positive; Or cytomegalovirus (CMV) DNA test positive;

7. Signs of herpes or varicella-zoster virus infection (especially chickenpox,shingles) within 12 weeks prior to screening;

8. Patients had seizure, or other active central nervous system disease;

9. Patients with malignant diseases such as tumors before screening, or with otherserious life-threatening diseases;

10. Secondary or congenital immunodeficiency.

11. History of any cardiac, endocrine, hematologic, hepatic, immunologic, metabolic,urologic, pulmonary, neurologic, dermatologic, psychiatric, and renal disease orother major medical condition that would prevent the administration of KN5601,except for lupus (determined by the investigator)

12. Received solid organ transplantation or hematopoietic stem cell transplantationwithin 3 months prior to screening; Acute graft-versus-host disease (GVHD) of grade 2 or above was present within 2 weeks prior to screening;

13. Received live vaccine within 4 weeks before screening;

14. Subjects who have received B cell-targeted drug therapy within 1 month beforeenrollment

15. Tested positive in Blood pregnancy test；

16. Patients who participated in other clinical study within 3 months prior toenrollment;

17. Any abnormal laboratory test results judged by the investigator to be clinicallysignificant and prevent the subject from participating in the study. Laboratory testvalues that are out of range and not of clinical significance will not be consideredas exclusion criteria

18. Any situation judged by the investigators that may increase the risk of the subjectsor interfere with the clinical trial outcome