An Early Exploratory Clinical Study of GC012F Injection in the Treatment of Refractory Generalized Myasthenia Gravis

Inclusion Criteria:

* Subjects who meet all the following criteria can be included in this study:

  1. Subjects or their legal representative voluntary signing the ICF, and willing and able to follow the procedure in this study.
  2. Aged between 18 and 75 years old (including 75), no gender limitation;
  3. Patients with confirmed refractory GMG, and the clinical classification according to MGFA is IIa-IVb (including IIa, IIb, IIIa, IIIb, IVa and IVb) at screening;
  4. At screening, the MG-ADL score must be ≥6, with ocular symptoms accounting for less than 50% of the total score, and QMG must be ≥11;
  5. Ineffectiveness of conventional treatment and/or lack of effective therapeutic options, referring to relapse or exacerbation after standard treatments with hormones, immunosuppressants (e.g., azathioprine, mycophenolate mofetil, tacrolimus, cyclosporine A, cyclophosphamide, methotrexate, etc.), or biological agents (e.g., rituximab);
  6. If the subject is currently using corticosteroids, the dose of prednisone must not exceed 30 mg/day (or the equivalent dose of other corticosteroids) and must remain stable for at least 4 weeks prior to infusion;
  7. Only subjects with positive MG-specific autoantibodies: the titer/level of anti-acetylcholine receptor (anti-AChR) antibodies or muscle-specific kinase (anti-MuSK) antibodies must be above the reference laboratory's upper normal limit (UNL);
  8. The results of laboratory test during screening period shall meet all following criteria:

     1. Neu ≥1.0 × 109/L; Hb ≥8.0 g/dL; PLT ≥50 × 109/L;
     2. ALT ≤3 × ULN; AST ≤3 × ULN; TBIL \<2 × ULN (DBIL ≤1.5 × ULN for subjects with Gilbert's syndrome)
     3. Creatinine clearance (19.3 Appendix 3) ≥30 mL/min;
     4. APTT ≤1.5 × ULN, PT ≤1.5 × ULN;
     5. LVEF ≥50% based on echocardiography, no findings of pericardial effusion.
  9. Women of childbearing potential (WCBP) should:

     1. Have a negative serum β human chorionic gonadotropin (β-hCG) pregnancy test confirmed by investigators during the screening period;
     2. Agree to avoid breastfeeding during the study period until at least 1 year after the infusion of GC012F Injection or until two consecutive flow cytometry tests show the absence of CAR-T cells (whichever occurs later).
  10. Any male subjects who have sexual partners and female subjects with childbearing potential shall agree to take effective contraceptive methods (e.g. oral contraceptive pills, intrauterine device or condoms) from the screening starting until at least 1 year post GC012F Injection infusion or until two consecutive flow cytometry tests show the absence of CAR-T cells (whichever occurs later). Male subjects must agree to use condoms during sexual contact with pregnant females or females with fertility for at least 1 year after the infusion of GC012F Injection, even if a successful vasectomy has been performed;
  11. Venous access available for blood collection, and no contraindications for leukapheresis.

Exclusion Criteria:

* Subjects who meet any of the following criteria will be excluded from the study:

  1. Subjects have a history of severe hypersensitivity or allergy;
  2. Any contraindication for fludarabine, cyclophosphamide and any component of the investigational product;
  3. Administration of intravenous immunoglobulin or plasmapheresis or immunoadsorption treatment within 4 weeks prior to infusion;
  4. Use of B-cell targeting drugs, including but not limited to rituximab, Belimumab, and Telitacicept, within 6 months prior to apheresis;
  5. Used tacrolimus, cyclosporine, azathioprine, mycophenolate, mycophenolate, methotrexate, etc., within 3 weeks prior to apheresis;
  6. Treatment with neonatal Fc receptor (FcRn) antagonists (such as Efgartigimod, etc.) within 3 weeks prior to apheresis
  7. Use of complement inhibition therapy (such as eculizumab, etc.) within 3 weeks prior to apheresis;
  8. Subjects with any of the following heart diseases:

     1. Congestive heart failure (New York Heart Association (NYHA) Class III or IV);
     2. Experienced unstable angina, myocardial infarction or underwent coronary artery bypass grafting (CABG) within 6 months prior to screening period;
     3. Clinically significant ventricular arrhythmias or a history of unexplained syncope not due to vasovagal reaction or dehydration; or a QTc interval \>480 ms during screening;
     4. History of severe non-ischemic cardiomyopathy.
     5. Serious cardiovascular abnormalities (such as abnormal brain natriuretic peptide BNP/ troponin and other indicators) and the investigators estimate that the patients should not be enrolled;
  9. Accompanied by other uncontrolled malignant tumors. Subjects with the following conditions will be eligible: early-stage tumors that have received curative treatment (carcinoma in situ or stage I tumors, or non-ulcerated primary melanoma with a depth \<1 mm and no involvement of lymph nodes), basal cell skin cancer, skin squamous cell carcinoma, cervical carcinoma in situ, or breast cancer in situ that has received potential curative treatment;
  10. Severe underlying medical conditions, such as:

      1. Fungal, bacterial, viral or other infections or suspected fungal, bacterial, viral or other infections that cannot be controlled or require general intravenous administration (including tuberculosis infection where with clear evidence of disease activity);
      2. Significant clinical evidence of dementia or mental status changes;
      3. History of any central nervous system (CNS) or neurodegenerative diseases, (e.g., epilepsy, seizures, paralysis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, psychiatric disorders).
  11. Positive results in any of the following tests:

      1. HIV antibody positive;
      2. HBsAg positive; or HBcAb positive and HBV-DNA above the lower limit of detection of the analytical method;
      3. HCV antibody positive with HCV RNA above the lower limit of detection of the analysis method; or known history of hepatitis C without completion of antiviral therapy for ≥24 weeks;
      4. Syphilis antibody positive.
  12. Received prior therapy of CAR-T for any target;
  13. Previous organ transplant or allogeneic bone marrow transplants;
  14. Surgery within 2 weeks prior to lymphodepletion or planning to have surgery during the study period (except for planned local anesthesia procedures, provided they are not performed within 2 weeks after infusion);
  15. Receipt of a live-attenuated vaccine within 4 weeks prior to lymphodepletion;
  16. Participation in any other clinical trial within 4 weeks prior to signing ICF, or the date of signing the ICF still within 5 half-lives of the drug from the last dose in the last clinical trial (whichever is longer);
  17. Pregnant women or lactating women who do not agree to abstain from breastfeeding, men and women who have a fertility plan during participation in this study or within 1 year after receiving study treatment;
  18. Based on the Columbia-Suicide Severity Rating Scale (C-SSRS), subjects had a current intention to commit suicide, i.e., C-SSRS item 4 on "suicide" (intention to act, But active suicidal ideation without a specific plan) or question 5 (active suicidal ideation with a specific plan and intent) answered "yes" or had a current history of suicidal behavior
  19. Any situation that, in the investigator's judgment, may interfere with the subject's participation in the entire trial, confound trial results, or be contrary to the subject's best interests