Early Clinical Study on the Safety, Tolerability, Pharmacokinetics, and Efficacy of STR-P005

Early Clinical Study on the Safety, Tolerability, Pharmacokinetics, and Efficacy of STR-P005 in the Treatment of Relapsed/Refractory Autoimmune Diseases

This study is a single-center, single-arm, open-label, investigator-initiated early exploratory clinical trial designed to evaluate the safety and efficacy of STR-P005 in subjects with relapsed/refractory autoimmune diseases.

The study will employ the traditional "3+3" dose escalation model, setting up 3 dose groups: Amg/kg, Bmg/kg, C mg/kg. Dose Group 1 will serve as the starting dose, with two cohorts A and B within this group aimed at optimizing the dosing frequency of STR-P005. Cohort A will receive dosing every 3 days (Q3D), on D1, D4, D7 (3 doses) constituting one cycle, which can be repeated for 2 cycles. Cohort B will receive dosing every 4 days (Q4D), on D1, D4 (2 doses) constituting one cycle, which can be repeated for 2 cycles. Based on the preliminary safety data, efficacy information, and PK/PD parameters obtained from Cohorts 1A and 1B, the investigators will select the superior regimen and escalate sequentially to Dose Groups 2 and 3. If no MTD is found after dose escalation through the 3 groups, based on all available preliminary safety data, efficacy information, and PK/PD parameters, higher doses may be added for further exploration of safety and efficacy after discussion by the SRC.

Inclusion Criteria:

1. Voluntarily participate in this study and sign the informed consent form.

2. Aged 18 to 75 years (inclusive).

3. Confirmation of positive CD19 expression on peripheral blood B cells by flow cytometry.

4. Adequate organ function:

   1. Hematology: Absolute Neutrophil Count (ANC) ≥1.0×10^9^/L, Absolute Lymphocyte Count (ALC) ≥0.1×10^9^/L, Hemoglobin ≥80 g/L, Platelet count (PLT) ≥50×10^9^/L. Blood transfusion and growth factors cannot be used within 7 days prior to eligibility screening to meet these requirements.

   2. Coagulation: International Normalized Ratio (INR) ≤1.5 × Upper Limit of Normal (ULN), and Activated Partial Thromboplastin Time (APTT) ≤1.5 × ULN.

   3. Liver function: Serum AST, ALT ≤3.0 × ULN, Total Bilirubin ≤1.5 × ULN (for subjects with Gilbert's syndrome, Total Bilirubin <3.0 × ULN).

   4. Renal function: Serum creatinine ≤1.5 × ULN or Creatinine Clearance (CrCl) ≥60 mL/min (calculated by Cockcroft-Gault formula); if with renal involvement, CrCl ≥45 mL/min.

   5. Cardiac function: New York Heart Association (NYHA) Class I or II, and Left Ventricular Ejection Fraction (LVEF) ≥50% by Echocardiography (ECHO), and no clinically significant arrhythmia, pericardial effusion, valvular disease, or Ischemic Heart Disease (IHD) within 8 weeks prior to screening.

   6. Oxygen saturation: ≥92% while breathing room air at rest (by pulse oximetry); no clinically significant pleural effusion.

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Exclusion Criteria:

1. Patients who have received any cell immunotherapy in the past, except where there is evidence that the engineered immune cells have disappeared and peripheral blood B cells are still present.

2. Unable to meet the following washout periods for therapeutic drugs:

   1. Use of therapeutic doses of corticosteroids (Prednisone ≥20mg/day or equivalent dose of other corticosteroids) within 72 hours prior to first dose, but topical or inhaled steroids are allowed.
   2. Use of mycophenolate mofetil or its derivatives, azathioprine, calcineurin inhibitors (e.g., tacrolimus, cyclosporine), mTOR inhibitors (e.g., sirolimus, everolimus), JAK inhibitors (e.g., tofacitinib, ruxolitinib, upadacitinib) within at least 2 weeks prior to screening.
   3. Use of cytotoxic drugs such as cyclophosphamide, methotrexate within at least 3 weeks prior to screening.
   4. Use of belimumab, B-cell targeting antibodies (e.g., anti-CD20) within at least 1 month prior to screening; anti-cytokine antibodies within at least 2 months; natalizumab, anti-CD52 mAb, anti-CD38 mAb, ATG within at least 3 months.
   5. Other monoclonal antibodies, bispecific antibodies, trispecific antibodies, antibody-drug conjugates (ADC), or any B-cell depleting drugs require a washout of 3 months or 5 half-lives (whichever is shorter) prior to screening.
   6. Undergone plasmapheresis, plasma separation, hemodialysis, intravenous immunoglobulin (IVIG) within 2 weeks prior to screening.

3. History of ≥ Grade 2 bleeding within 30 days prior to screening; or requiring long-term continuous use of anticoagulants (e.g., warfarin, low molecular weight heparin, or Factor Xa inhibitors), except if INR ≤ 1.5 × ULN.

4. Severe renal disease: Severe lupus nephritis within 8 weeks prior to screening [defined as urine protein > 6g/24 hours or serum creatinine > 2.5 mg/dL or 221 μmol/L or creatinine clearance (Cockcroft-Gault formula) < 30 mL/min], or active nephritis requiring treatment with prohibited medications, or requiring prednisone >100mg/day or equivalent corticosteroid for ≥14 days.

5. Severe pulmonary disease within 3 months prior to screening, such as moderate-to-severe pulmonary hypertension (mean pulmonary artery pressure > 60 mmHg by echocardiography), requiring oxygen therapy via reservoir mask or non-invasive/invasive mechanical ventilation at screening.

6. Occurrence of lupus crisis within 3 months prior to screening, such as active central nervous system lupus, severe hemolytic anemia, severe thrombocytopenic purpura, severe granulocytopenia, severe myocardial injury, severe lupus pneumonitis or pulmonary hemorrhage, severe lupus hepatitis, severe vasculitis, etc.

7. History or related symptoms of active non-lupus-induced central nervous system disease (excluding isolated trigeminal nerve disease) within 6 months prior to screening, including but not limited to: cerebrovascular disease, encephalitis, brain injury, aneurysm, cerebellar disease, organic brain syndrome, Parkinson's disease, and symptoms such as epilepsy, convulsions, aphasia, dementia, etc.

8. Occurrence of any of the following cardiovascular diseases within 6 months prior to screening (including but not limited to):

   1. Congestive heart failure, myocardial infarction, unstable angina pectoris, coronary angioplasty, stent implantation, coronary/peripheral artery bypass surgery.
   2. Severe arrhythmias requiring treatment (e.g., sustained ventricular tachycardia, ventricular fibrillation, Torsade de Pointes); congenital long QT syndrome, left anterior hemiblock (bifascicular block), complete left bundle branch block or high-grade AV block; history of severe non-ischemic cardiomyopathy; asymptomatic right bundle branch block is allowed for study entry.
   3. Uncontrolled hypertension (systolic blood pressure >160 mmHg and/or diastolic blood pressure >100 mmHg), history of hypertensive crisis or hypertensive encephalopathy.
   4. Current active cardiac involvement, such as pericarditis, pericardial effusion, and myocarditis.

9. Active tuberculosis or latent tuberculosis at screening (defined as positive tuberculin skin test or interferon-gamma release assay without clinical symptoms or radiographic evidence).

10. Screening results showing HBV-DNA, HCV-RNA, CMV-DNA above the laboratory's detection limit, or HIV antibody positive.

11. Presence of uncontrolled fungal, bacterial, viral or other infections deemed unsuitable for study participation by the investigator.

12. Presence of uncontrolled diabetes mellitus (HbA1c ≥ 7.0%); and uncontrolled thyroid disease (TSH > 10 mIU/L or < 0.1 mIU/L, and FT4 outside normal range).

13. History of major organ transplant (e.g., heart, lung, kidney, liver) or history of allogeneic hematopoietic stem cell transplant within 12 weeks or autologous hematopoietic stem cell transplant within 6 weeks prior to screening.

14. Congenital immunoglobulin deficiency.

15. Thrombotic Thrombocytopenic Purpura (TTP)/Thrombotic Microangiopathy (TMA).

16. Concomitant history of other autoimmune diseases (including but not limited to eosinophilic granulomatosis with polyangiitis, cryoglobulinemic vasculitis, inclusion body myositis, anti-glomerular basement membrane disease, Behçet's disease, or Takayasu's arteritis) requiring systemic treatment, besides the target indications.

17. Family history of non-IIM conditions such as drug-induced myopathy, HIV-associated myopathy.

18. History or concurrent presence of other active malignancies, including patients with malignancy-associated polymyositis/dermatomyositis. Exceptions: carcinoma in situ of the cervix, non-invasive basal cell or squamous cell skin cancer, locally treated prostate cancer, ductal carcinoma in situ of the breast post-resection, and papillary thyroid cancer that have been cured and without recurrence for at least 2 years.

19. History of hypersensitivity or life-threatening reaction to the study drug or any of its components or formulation ingredients.

20. Pregnant or breastfeeding women.

21. Received any live attenuated vaccine within 6 weeks prior to first dose, or planned to receive one within 3 months after treatment.

22. Participation in another interventional clinical study and received an active investigational drug within 3 months prior to signing ICF, or intention to participate in another clinical trial or receive treatment for autoimmune diseases outside the protocol during the entire study period.

23. Patients with mental illness such as depression or suicidal tendencies.

24. Other factors considered by the investigator to make the subject unsuitable for enrollment or affect the subject's participation or completion of the study.

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