Study summary
Graves' disease is an autoimmune thyroid disorder characterized by the production of autoantibodies against the thyroid-stimulating hormone receptor (TRAb), leading to excessive thyroid hormone secretion and systemic manifestations. A subset of patients develop refractory disease, failing to achieve durable remission despite prolonged antithyroid therapy.
This study aims to evaluate the safety and efficacy of HN2301, an in vivo CAR-T therapy in which host T lymphocytes are engineered and transformed to functional CAR-T cells via CD8 antibody-coated LNP delivery of CD19 CAR-mRNA. Participants with refractory Graves' disease will receive three to five administrations of HN2301 and will be regularly monitored for changes in thyroid function, TRAb levels, clinical response, and treatment-related adverse events. The study will provide preliminary evidence on whether HN2301 can induce sustained remission of refractory Graves' disease.
Eligibility criteria
Inclusion Criteria (Participants must meet all of the following criteria to be eligible for this study):
* Age 18-75 years (inclusive), male or female.
* Refractory Graves' disease, defined as meeting at least one of the following: a) Continuous antithyroid drug (ATD) therapy for ≥3 years without achieving criteria for ATD discontinuation; b) Meeting criteria for ATD discontinuation but experiencing ≥2 relapses after ATD withdrawal.
* Positive serum TRAb.
* Willing to use effective contraception for 12 months after study drug administration.
* Voluntarily agrees to participate in the study, has signed the informed consent form, and is able to comply with study procedures and follow-up requirements.
Exclusion Criteria (Participants meeting any of the following criteria will be excluded from the study):
* History of severe drug allergy or known allergic predisposition.
* Presence or suspected presence of uncontrolled active infection.
* History of major organ transplantation (e.g., heart, lung, liver, kidney) or bone marrow/hematopoietic stem cell transplantation.
* Presence of significant heart disease, such as angina, myocardial infarction, heart failure, or clinically significant arrhythmias.
* Receipt of any mRNA-LNP product or other lipid nanoparticle (LNP)-based therapy within the past 2 years.
* Receipt of a live vaccine within 30 days prior to screening.
* History of malignant tumors.
* Positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with peripheral blood HBV DNA above the detection limit; positive hepatitis C virus (HCV) antibody with detectable HCV RNA; positive human immunodeficiency virus (HIV) antibody; or positive syphilis test.
* Presence of psychiatric disorders or severe cognitive impairment.
* Hematologic dysfuction at screening, defined as any of the following: a. Neutrophil count \< 1.8 × 10⁹/L, b. Hemoglobin \< 110 g/L, c. Platelet count \< 50 × 10⁹/L
* Impaired liver function, defined as any of the following: Alanine aminotransferase (ALT) \> 3 × ULN, Aspartate aminotransferase (AST) \> 3 × ULN, Total bilirubin \> 2.5 × ULN.
* Impaired renal function: creatinine clearance rate (CrCl) \< 60 mL/min (Cockcroft-Gault formula).
* Left ventricular ejection fraction (LVEF) \< 55%.
* Coagulation abnormalities, defined as either: International normalized ratio (INR) \> 1.5 × ULN, Prothrombin time (PT) \> 1.5 × ULN
* Pregnant or breastfeeding women.
* Any other condition that, in the opinion of the investigator, would make the participant unsuitable for the study.