A Clinical Study Evaluating the Safety and Efficacy of GT719 Universal Cell Injection in the Treatment of Immune-mediated Kidney Diseases

A Clinical Study Evaluating the Safety and Efficacy of GT719 Universal Cell Injection in the Treatment of Immune-mediated Kidney Diseases

This study is a single-arm, open-label, dose-escalation and dose-expansion clinical trial, divided into two phases: the first phase is the dose-escalation phase, and the second phase is the dose-expansion phase. In the dose-escalation phase, approximately 9-18 adult participants with immune-mediated kidney diseases are planned to be enrolled and treated with GT719 universal cell injection. The objectives of this phase are to evaluate the safety and tolerability of the product, determine the recommended dose (RD) for subsequent studies, conduct a preliminary assessment of its clinical efficacy, and investigate the pharmacokinetic and pharmacodynamic characteristics. Upon completion of the dose-escalation phase, after evaluation by investigators and collaborators, an appropriate dose will be selected for the dose-expansion phase. An additional 12 participants will be enrolled to fully assess the safety and efficacy of the product.

Inclusion Criteria:

• 1. The participant or their legal representative voluntarily signs a written informed consent form, and is willing and able to comply with the procedures of this study.

• 2. Aged 18 to 75 years (inclusive) at the time of signing the informed consent, regardless of gender.

• 3. Positive expression of CD19 on B cells in peripheral blood is confirmed by flow cytometry.

• 4. Participants with IgA nephropathy (IgAN) at high risk of progression:

  ① A definite pathological diagnosis of IgAN confirmed by renal biopsy (renal biopsy must be performed within 2 years prior to screening or during the screening period).

  • Meet at least one of the following requirements:

    1. Prior treatment with glucocorticoids, budesonide enteric-coated capsules, immunosuppressants (including mycophenolate mofetil, cyclophosphamide, cyclosporine, tacrolimus, Tripterygium wilfordii, leflunomide, azathioprine), or biological agents (including but not limited to anti-CD20 monoclonal antibodies, telitacicept, daratumumab) for a cumulative duration of at least 3 months, with persistent 24-hour urinary protein ≥ 0.75 g or UPCR ≥ 0.75 g/g.
    2. The predicted probability of a 50% decline in eGFR or end-stage renal disease (ESRD) within 5 years calculated by the international IgAN prediction tool is ≥ 20%.
    3. A ≥ 20% decline in eGFR within 3 months.
    4. Renal biopsy performed within 6 months indicating Oxford classification C2 lesion.
    5. Patients who are intolerant to conventional treatment and for whom the investigator determines that the benefits outweigh the risks, with adequate informed consent obtained, may be considered for inclusion.

• 5. Participants with ANCA-associated vasculitis (AAV)/ANCA-associated glomerulonephritis (AAGN) must meet the following criteria:

  ① Diagnosis of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) according to the 2022 ACR/EULAR classification criteria for ANCA-associated vasculitis.

  ② Positive anti-myeloperoxidase (MPO-ANCA) antibody or anti-proteinase 3 (PR3-ANCA) antibody detected during screening or in previous tests.

  ③ AAGN: Availability of a renal biopsy pathological report within 2 years; if eGFR < 30 mL/min/1.73 m², a renal biopsy pathological report obtained during the screening period is required. Presence of active lesions according to the 2010 Berden classification criteria for AAGN.

  ④ Renal-uninvolved AAV: Birmingham Vasculitis Activity Score (BVAS) version 3.0 ≥ 3 points, indicating active vasculitis.

  ⑤ Failure of standard of care (SOC), defined as any of the following:

  a) Failure to achieve remission after at least 3 months of treatment with glucocorticoids combined with cyclophosphamide or rituximab.

  b) Disease relapse after achieving remission. c) Persistent disease activity despite receiving SOC for at least 6 months, including glucocorticoids, cyclophosphamide, rituximab, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, as well as other biological agents (including but not limited to mepolizumab) or avacopan.

• 6. Participants with membranous nephropathy (MN) must meet the following criteria:

  • Definite pathological diagnosis of primary (idiopathic) MN confirmed by renal biopsy (renal biopsy must be performed within 2 years prior to screening or during the screening period).

    ② Elevated serum anti-PLA2R antibody titer detected during screening or in previous tests, or positive PLA2R antigen staining in renal tissue.

    ③ eGFR ≥ 30 mL/min/1.73 m².

    ④ Meeting the criteria for high-risk or relapsed/refractory MN: c) High-risk patients, defined as meeting any of the following: Normal eGFR, urinary protein > 3.5 g/24h, < 50% reduction in urinary protein after 6 months of ACEI/ARB treatment, and serum albumin < 25 g/L or anti-PLA2R antibody > 50 RU/mL.

eGFR < 60 mL/min/1.73 m² and/or urinary protein > 8 g/24h for more than 6 months.

d) Relapsed/refractory patients: Relapsed patients: Defined as achieving complete or partial remission with previous SOC treatment, followed by recurrence of urinary protein ≥ 3.5 g/24h.

Refractory patients: Defined as refractory to previous SOC treatment (persistent urinary protein ≥ 3.5 g/24h with < 50% reduction compared to baseline).

• 7. Participants with refractory podocytopathy:

  ① Pathological diagnosis of minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS) confirmed by renal biopsy (renal biopsy must be performed within 2 years prior to screening or during the screening period).

  ② Meet at least one of the following requirements:

  1. Previous diagnosis of steroid-resistant nephrotic syndrome (SRNS): 24-hour urinary protein > 3 g or UPCR ≥ 3.5 g/g, serum albumin < 30 g/L, failure to achieve complete remission after 4 weeks of standard-dose glucocorticoid treatment.
  2. Previous diagnosis of steroid-dependent nephrotic syndrome (SDNS): Remission achievable with glucocorticoid treatment, but relapse within 2 weeks of glucocorticoid tapering or discontinuation, or two consecutive relapses during glucocorticoid tapering.
  3. Previous diagnosis of frequently relapsing nephrotic syndrome (FRNS): ≥ 3 relapses within 1 year or ≥ 2 relapses within 6 months after achieving complete remission with glucocorticoid treatment.
  4. Previous treatment with one immunosuppressant (including cyclosporine A, tacrolimus, mycophenolate mofetil, cyclophosphamide) or biological agent (including but not limited to anti-CD20 monoclonal antibodies, telitacicept, daratumumab) for ≥ 6 months without achieving remission or with intolerance.
  5. Failure to achieve remission within 6 months of adequate treatment with one immunosuppressant or biological agent, but the investigator judges that the benefits outweigh the risks and the patient has provided full informed consent, the patient may be considered for inclusion.

• 8. Participants with proliferative glomerulonephritis with monoclonal immunoglobulin deposition (PGNMID):

  • Definite pathological diagnosis of PGNMID confirmed by renal biopsy (renal biopsy must be performed within 3 years prior to screening or during the screening period).

    • Meet at least one of the following requirements:

Persistent 24-hour urinary protein ≥ 1 g or UPCR ≥ 1 g/g despite treatment with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) for at least 4 weeks.

eGFR ≥ 30 mL/min/1.73 m² with progressive decline (≥ 20% decrease in eGFR) within the recent 6-12 months.

Development of nephrotic syndrome or nephrotic-range proteinuria (24-hour urinary protein ≥ 3 g or UPCR ≥ 3 g/g) without stable remission with short-term glucocorticoid treatment.

③ Exclusion of hematological malignancies (leukemia, lymphoma, multiple myeloma, systemic light chain amyloidosis) by bone marrow aspiration and biopsy (bone marrow aspiration must be performed within 6 months prior to screening or during the screening period).

• 9. Screening laboratory test results must meet the following criteria (excluding indicators related to the study disease):

  1. Neutrophil count ≥ 1.5 × 10⁹/L;
  2. Hemoglobin ≥ 80 g/L; Platelet count ≥ 50 × 10⁹/L;
  3. Alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN); Aspartate aminotransferase (AST) ≤ 3 × ULN; Total bilirubin (TBIL) < 2 × ULN (for participants with Gilbert syndrome, direct bilirubin (DBIL) ≤ 1.5 × ULN);
  4. Creatinine clearance rate ≥ 30 mL/min; (except for anti-GBM glomerulonephritis, AAV/ANCA-associated glomerulonephritis);
  5. Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN; Prothrombin time (PT) ≤ 1.5 × ULN;
  6. Left ventricular ejection fraction (LVEF) ≥ 50% diagnosed by echocardiography.
  7. Pulmonary function: Defined as dyspnea ≤ CTCAE Grade 1 and oxygen saturation (SpO₂) ≥ 92% at rest while breathing room air (measured by pulse oximetry).

• 10. Female participants of childbearing potential must:

  a. Have a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test result at screening, confirmed by the investigator; b. Agree to avoid breastfeeding during study participation until at least 1 year after GT719 cell infusion or until GT719 cells are no longer detected by two consecutive flow cytometry tests, whichever is later.

• 11. Male participants with sexual partners and female participants of childbearing potential must agree to use highly effective contraceptive methods (e.g., contraceptive pills, intrauterine devices, or condoms) starting from screening until at least 1 year after GT719 cell infusion or until GT719 cells are no longer detected by two consecutive flow cytometry tests, whichever is later. Male participants must agree to use condoms during sexual contact with pregnant women or women of childbearing potential for at least 1 year after GT719 cell infusion, even after successful vasectomy.

Exclusion Criteria:

• 1. Participants with IgA nephropathy (IgAN) at high risk of progression:

  a. Secondary IgAN (e.g., associated with active hepatitis B/hepatitis C infection, HIV, etc.).

• 2. Participants with ANCA-associated vasculitis (AAV)/ANCA-associated glomerulonephritis (AAGN):

  1. Drug-induced or secondary AAV/AAGN.
  2. Alveolar hemorrhage requiring invasive mechanical ventilation support at screening.

• 3. Participants with membranous nephropathy (MN):

  a. Secondary membranous nephropathy.

• 4. Participants with refractory podocytopathy:

  a. Hereditary podocytopathy and secondary focal segmental glomerulosclerosis (FSGS).

• 5. Participants with proliferative glomerulonephritis with monoclonal immunoglobulin deposition (PGNMID):

  1. Monoclonal deposition caused by secondary nephropathy (e.g., those diagnosed with multiple myeloma or severe systemic lymphoplasmacytic disease requiring immediate oncological treatment).

For all participants:

• 6. History of severe hypersensitivity reaction or allergy.

• 7. Contraindication or hypersensitivity to fludarabine, cyclophosphamide, or any component of the investigational product.

• 8. Currently receiving renal replacement therapy or expected to require renal replacement therapy during the study period.

• 9. Rapidly progressive glomerulonephritis unrelated to AAV/AAGN, anti-GBM disease, MN, acute post-streptococcal nephritis (APSN), or IgG4-related kidney disease (IgG4-RKD), defined as a ≥ 50% decrease in eGFR within 3 months of diagnosis.

• 10. History of other uncontrolled severe conditions not directly related to the study disease prior to screening, such as severe hemolytic anemia, severe immune thrombocytopenic purpura, severe agranulocytosis, severe myocardial damage, severe pneumonia or pulmonary hemorrhage, severe hepatitis, severe vasculitis, active central nervous system (CNS) symptoms including cerebrovascular accident, aneurysm, epilepsy, convulsion, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis.

• 11. History of the following cardiac diseases or conditions:

  1. New York Heart Association (NYHA) Class III or IV congestive heart failure within 12 months prior to screening;
  2. Myocardial infarction or coronary artery bypass grafting within 6 months prior to screening;
  3. History of clinically significant ventricular arrhythmia or unexplained syncope not caused by vasovagal response or dehydration, or corrected QT interval (QTc) > 480 ms at screening;
  4. History of severe non-ischemic cardiomyopathy;
  5. Pulmonary arterial hypertension, including secondary pulmonary arterial hypertension, with WHO functional class > 2;
  6. QTcF > 450 msec in males and QTcF > 470 msec in females, based on the average QTcF (QT interval corrected by Fridericia's formula) value from a single ECG or three repeated ECGs performed at intervals of more than 3 minutes.

• 12. Presence of significant pulmonary or cardiac manifestations (e.g., pericarditis, pleural effusion) at screening, which the investigator assesses may affect the participant's ability to receive treatment safely or tolerate treatment.

• 13. Evidence of advanced fibrotic interstitial lung disease on chest CT, with the latest pulmonary function test showing forced vital capacity (FVC) < 40% of predicted value or diffusing capacity of the lung for carbon monoxide (DLCO) < 30% of predicted value.

• 14. History of any active malignancy or malignant tumor within 5 years prior to screening. Exceptions include: early-stage tumors treated with radical therapy (carcinoma in situ or Stage I tumor, non-ulcerative primary melanoma with depth < 1 mm and no lymph node involvement), cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma, cervical carcinoma in situ, or ductal carcinoma in situ of the breast that has received potentially curative treatment.

• 15. Clinically significant bleeding symptoms or definite bleeding tendency within 6 months prior to screening, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, etc.; hereditary or acquired bleeding and thrombotic tendency (e.g., hemophilia, coagulation dysfunction, hypersplenism, etc.); occurrence of arteriovenous thrombotic events within 6 months prior to screening, such as cerebrovascular disease (including cerebral hemorrhage, cerebral infarction, etc.), deep vein thrombosis, and/or pulmonary embolism.

• 16. Presence of severe underlying medical conditions at screening, such as:

  1. Evidence of uncontrolled viral, bacterial, fungal, or other infections requiring systemic intravenous treatment;
  2. Obvious clinical evidence of dementia or altered mental status;
  3. History of any other CNS disease or neurodegenerative disease, such as epilepsy, convulsion, paralysis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, or psychosis.

• 17. Positive results for any of the following tests:

  1. Human immunodeficiency virus (HIV) antibody positive;
  2. Hepatitis B surface antigen (HBsAg) positive; or hepatitis B core antibody (HBcAb) positive with hepatitis B virus (HBV)-DNA level above the lower limit of quantification (LLOQ) of the assay;
  3. Hepatitis C virus (HCV) antibody positive with HCV RNA level above the LLOQ of the assay;
  4. Syphilis antibody positive (excluding false-positive results caused by underlying diseases).

• 18. H Positive results for cytomegalovirus (CMV) DNA or Epstein-Barr virus (EBV) DNA test.

• 19. Active tuberculosis prior to screening or latent tuberculosis not receiving appropriate treatment.

• 20. Receipt of other investigational drugs within 4 weeks prior to signing the informed consent form (ICF), or the interval between the ICF signing date and the last dose of the previous investigational drug trial is still within 5 half-lives of the drug, whichever is longer.

• 21. Receipt of plasma exchange therapy or immunoadsorption therapy within 4 weeks prior to lymphodepletion conditioning.

• 22. Receipt of B-cell-targeted drug therapy within 1 week prior to lymphodepletion conditioning, including but not limited to rituximab, obinutuzumab, belimumab, telitacicept, etc.

• 23. Receipt of tacrolimus, cyclosporine, azathioprine, mycophenolate mofetil, mycophenolic acid, methotrexate, etc., within 2 weeks prior to lymphodepletion conditioning.

• 24. Receipt of neonatal Fc receptor (FcRn) antagonist therapy (e.g., efgartigimod, etc.) within 3 weeks prior to lymphodepletion conditioning.

• 25. Receipt of complement inhibition therapy (e.g., eculizumab, etc.) within 3 weeks prior to lymphodepletion conditioning.

• 26. Receipt of live attenuated vaccine within 4 weeks prior to lymphodepletion conditioning.

• 27. Performance of major surgery within 8 weeks prior to screening, or planned surgery during the study period.

• 28. History of organ transplantation.

• 29. Previous receipt of CAR-T product therapy targeting any antigen (except for GT719 treatment).

• 30. Presence of any condition that, in the investigator's judgment, would prevent the participant from completing the entire trial, confound trial results, or make trial participation not in the participant's best interest.

• 31. Presence of donor-specific anti-HLA antibodies against GT719 cells.