MTS109 in Patients With Refractory Autoimmune Diseases

This is an open-label, single-arm, basket-designed clinical trial.A maximum of 10 subjects with moderate to severe autoimmune diseases (including but not limited to SLE, IIM, SSc, AAV, and SS) will be enrolled. Following enrollment, subjects will receive MTS109 via subcutaneous injection; each subject will be followed up for up to 26 weeks after the first dose administration.This study consists of three periods: Screening Period (Day -28 to Day -1), Treatment Period (Day 1 to Day 32), and Follow-up Period (Month 2 to Month 6).Screening Period: After signing the Informed Consent Form (ICF), subjects will complete general screening procedures and disease-specific baseline assessments corresponding to their autoimmune conditions.Treatment Period: Subjects will receive MTS109 via subcutaneous injection in a stepwise titration to the target dose on Day 1 (D1), Day 4 (D4), and Day 7 (D7), followed by maintenance doses of MTS109 at the target dose on Day 14 (D14), Day 21 (D21), and Day 28 (D28). During the treatment period, subjects will undergo safety assessments, sample collection for pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity analyses after each dose administration, and the first efficacy assessment will be completed on Day 30 (D30).Follow-up Period: Subjects will attend safety follow-up visits, provide samples for PD and immunogenicity analyses at Month 2 (M2), Month 3 (M3), Month 4 (M4), Month 5 (M5), and Month 6 (M6); efficacy assessments will be performed at M2, M3, and M6. Among these follow-up visits, M4 and M5 will be conducted remotely.

An interim analysis will be conducted after a minimum of 5 enrolled subjects complete the Month 3 visit to ensure subject safety and evaluate the preliminary benefit-risk ratio of the drug. Details: 1. Timing: Initiated within 7 working days after all subjects complete M3 visit, with the statistician completing data cleaning, analysis and report for EC and sponsor review. 2. Population: Subjects who received at least one dose of MTS109, completed M3 visit with complete data; excluding those who failed screening, missed visit or had missing key data. 3. Content: Safety (incidence and correlation of AEs/SAEs), preliminary efficacy (therapeutic response and score changes), PK/PD (preliminary parameter analysis), immunogenicity (antibody positive rate at M3). 4. Decision: Reviewed by sponsor, collaborators, statistician and EC to determine trial continuation, suspension, termination or enrollment adjustment. 5. Statistics: Descriptive statistics, paired tests and Fisher's exact test (two-sided α=0.05); interim analysis for trial decision only, final efficacy based on M6 final analysis. 6. Data management: Clean data set verified by monitoring, data cleaning completed within 5 working days with retained statistical codes and logs.

Inclusion criteria

• The subject or his/her legal representative has voluntarily signed a written informed consent form and is willing and able to comply with study procedures. 2) Aged 18 to 65 years (inclusive) at the time of signing the informed consent form, with no gender restriction.

• Subjects with SLE must meet the following criteria: a) Meet the 2019 EULAR/ACR classification criteria for systemic lupus erythematosus (SLE); b) SLEDAI-2K score ≥6, with at least 1 BILAG-2004 organ domain score of Grade A (severe manifestation) or 2 Grade B (moderate manifestation), or both; or SLEDAI-2000 score ≥8; c) Meet the definition of refractory and relapsing disease: inadequate response to conventional therapy for more than 6 months, or disease flare after remission. Conventional therapy is defined as: glucocorticoids plus at least 2 of the following immunomodulatory agents: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics including rituximab, belimumab, and telitacicept.

• Subjects with idiopathic inflammatory myopathy (IIM) must meet the following criteria: a) Meet the 2017 EULAR/ACR classification criteria for idiopathic inflammatory myopathies (including dermatomyositis [DM], polymyositis [PM], anti-synthetase syndrome [ASS], and necrotizing myopathy [NM]); b) Positive for myositis-specific antibodies; c) Moderate-to-severe IIM during screening, defined as: MMT-8 ≥142 with active interstitial lung disease (ILD) (ground-glass opacity on HRCT); OR MMT-8 <142 and at least 2 of the following: Physician's Global Assessment (PGA, VAS) ≥2 cm (10-cm VAS scale); Patient's Global Assessment (PtGA, VAS) ≥2 cm (10-cm VAS scale); Health Assessment Questionnaire Disability Index (HAQ-DI) >0.25; One or more muscle enzymes (CK, LDH, AST, ALT) ≥1.5 × upper limit of normal (ULN); d) Meet the definition of refractory, relapsing, or progressive disease: Refractory: inadequate response to conventional therapy for more than 6 months, or disease flare after remission; conventional therapy as defined for SLE; Progressive: worsening myositis or rapidly progressive interstitial lung disease.

• Subjects with systemic sclerosis (SSc) must meet the following criteria: a) Meet the 2013 ACR classification criteria for systemic sclerosis; b) Positive for SSc-related specific antibodies; c) Meet the definition of refractory or progressive disease: Refractory: inadequate response to conventional therapy for more than 6 months, or disease flare after remission; conventional therapy as defined for SLE; Progressive: rapid skin progression (increase in mRSS >25%); or progressive lung disease (decrease in FVC ≥10%, or decrease in FVC >5% with decrease in DLCO ≥15%).

• Subjects with ANCA-associated vasculitis (AAV) must meet the following criteria: a) Meet the 2022 ACR/EULAR classification criteria for ANCA-associated vasculitis, including microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis; b) Positive for ANCA-associated antibodies (MPO-ANCA or PR3-ANCA); c) Birmingham Vasculitis Activity Score (BVAS) ≥15 (total score 63), indicating active vasculitis; d) Meet the definition of refractory: inadequate response to conventional therapy for more than 6 months, or disease flare after remission; conventional therapy as defined for SLE.

• Subjects with Sjögren's syndrome (SS) must meet the following criteria: a) Meet the 2002 AECG criteria for primary Sjögren's syndrome or the 2016 ACR/EULAR classification criteria; b) Disease activity ESSDAI ≥6; c) Positive for anti-SSA/Ro antibody; d) Meet the definition of refractory: inadequate response to conventional therapy for more than 6 months, or disease flare after remission; conventional therapy as defined for SLE.

• Screening laboratory results meet the following criteria (excluding abnormalities related to the study disease): a) Neutrophil count ≥1.5 ×10⁹/L; b) Hemoglobin ≥80 g/L; platelet count ≥50 ×10⁹/L; c) Alanine aminotransferase (ALT) ≤3 × ULN; aspartate aminotransferase (AST) ≤3 × ULN (unless elevation is judged by the investigator to be related to PM or DM); total bilirubin (TBIL) <2 × ULN (for subjects with Gilbert syndrome, direct bilirubin [DBIL] ≤1.5 × ULN); d) Creatinine clearance ≥30 mL/min; e) Activated partial thromboplastin time (APTT) ≤1.5 × ULN; prothrombin time (PT) ≤1.5 × ULN; f) Echocardiogram shows left ventricular ejection fraction (LVEF) ≥50%, with no clinically significant electrocardiogram (ECG) abnormalities; g) Baseline oxygen saturation >92% while breathing room air.

• Female subjects of childbearing potential: negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test at screening.

• Male subjects with female partners and female subjects of childbearing potential agree to use effective contraceptive methods (e.g., oral contraceptives, intrauterine device, condom) from screening until at least 1 year after the last dose of MTS109.

Exclusion criteria

• SLE subjects: a) Drug-induced SLE; b) Subjects with lupus crisis, or who require medications prohibited by the protocol due to comorbidities, or who are considered ineligible by the investigator.
• IIM subjects: a) Subjects with documented inclusion body myositis (IBM), drug-induced PM or DM, malignancy-associated PM or DM, or non-inflammatory myopathy (e.g., muscular dystrophy); b) Uncontrolled extramuscular involvement related to PM or DM: ILD: FVC <55% or requiring oxygen therapy (FVC ≥55% to be evaluated for eligibility by the lead investigator); Severe dysphagia that, in the investigator's judgment, would increase subject risk by participating in the clinical trial; Severe cardiac manifestations (e.g., congestive heart failure, arrhythmia, treatable conduction abnormality, or myocardial infarction) that, in the investigator's judgment, would increase subject risk by participating in the clinical trial.
• SSc subjects: a) Uncontrolled severe pulmonary arterial hypertension (PAH) related to SSc; b) Rapidly progressive lower gastrointestinal tract (small and large intestine) involvement related to SSc requiring parenteral nutrition; active gastric antral vascular ectasia; c) Uncontrolled or rapidly progressive ILD with oxygen saturation (SaO2) <92% on room air; or requiring mechanical ventilatory support within 1 year prior to signing informed consent.
• AAV subjects: a) Crescentic glomerulonephritis, acute polyneuritis, or central nervous system (CNS) involvement other than AAV at screening; b) Life-threatening severe vasculitis (including diffuse alveolar hemorrhage, respiratory failure, intestinal perforation or massive bleeding, cerebral vasculitis, cardiac vasculitis, etc.); c) Secondary vasculitis (e.g., SLE, Henoch-Schönlein purpura, drug-induced, malignancy-associated, infection-induced, primary immunodeficiency, etc.).
• SS subjects: a) Poorly controlled severe systemic primary Sjögren's syndrome (pSS) manifestations at baseline that, in the investigator's assessment, may place the subject at excessive risk; b) Secondary Sjögren's syndrome with other confirmed autoimmune diseases (e.g., rheumatoid arthritis, SLE, scleroderma, inflammatory bowel disease); c) Subjects requiring regular use of medications known to cause dry mouth/dry eye as common major side effects; d) Subjects with other diseases that may interfere with efficacy assessment of primary Sjögren's syndrome, such as inflammatory bowel disease, gout, sarcoidosis, amyloidosis, IgG4-related disease, etc. All subjects:
• Subjects with a history of severe hypersensitivity or anaphylaxis;
• Subjects with contraindications or hypersensitivity to any component of the investigational product;
• Subjects with any of the following cardiac diseases: a) New York Heart Association (NYHA) Class III or IV congestive heart failure; b) Myocardial infarction or coronary artery bypass grafting within 6 months prior to screening; c) Clinically significant ventricular arrhythmia at screening, history of unexplained syncope not due to vasovagal reaction or dehydration, corrected QT interval (QTc) >480 ms, or history of severe non-ischemic cardiomyopathy;
• Subjects with any active malignancy or history of malignancy within 5 years prior to screening, excluding: early-stage tumors treated with curative intent (carcinoma in situ or Stage I tumor, non-ulcerated primary melanoma <1 mm depth without lymph node involvement), basal cell carcinoma of the skin, squamous cell carcinoma of the skin, cervical carcinoma in situ, or breast carcinoma in situ treated with potentially curative therapy;
• Subjects with any other known autoimmune disease other than the study disease;
• Subjects requiring long-term use of anticoagulants affecting coagulation function;
• Subjects with clinically significant bleeding symptoms or obvious 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, coagulopathy, hypersplenism, etc.); subjects with arterial or venous 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;
• Subjects with any severe underlying disease at screening, e.g.: a) Evidence of uncontrolled infection or viral, bacterial, fungal, or other infection treated with systemic intravenous antibiotics; b) Evidence of clinically significant dementia or altered mental status; c) History of any other central nervous system disease or neurodegenerative disease, such as epilepsy, seizure, paralysis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, psychosis;
• Subjects with positive screening results for any of the following: a) Positive human immunodeficiency virus (HIV) antibody; b) Positive hepatitis B surface antigen (HBsAg); or positive hepatitis B core antibody (HBcAb) with HBV-DNA above the lower limit of detection of the assay; c) Positive hepatitis C virus (HCV) antibody with HCV RNA above the lower limit of detection of the assay; d) Active syphilis (excluding false-positive due to disease);
• Subjects with positive plasma cytomegalovirus (CMV) DNA or plasma Epstein-Barr virus (EBV) DNA (viral active);
• Subjects with active tuberculosis or untreated latent tuberculosis prior to screening;
• Subjects who received other investigational drugs within 4 weeks prior to signing informed consent form (ICF), or for whom the time from the last dose of a previous investigational drug to the date of signing ICF is less than 5 elimination half-lives of that drug (whichever is longer);
• Subjects who received plasmapheresis or immunoadsorption therapy within 4 weeks prior to dosing;
• Subjects who received B-cell targeted therapy within 6 months prior to dosing, including but not limited to belimumab, telitacicept, etc.;
• Subjects who received biologic therapy such as anti-TNF-α antibody within 12 weeks prior to dosing;
• Subjects who received tacrolimus, cyclosporine, azathioprine, mycophenolate mofetil, mycophenolic acid, methotrexate, etc., within 2 weeks prior to dosing;
• Subjects who received neonatal Fc receptor (FcRn) antagonist therapy (e.g., efgartigimod) within 3 weeks prior to dosing;
• Subjects who received complement inhibition therapy (e.g., eculizumab) within 3 weeks prior to dosing;
• Subjects who received live attenuated vaccine or mRNA vaccine within 8 weeks prior to enrollment, or inactivated vaccine within 2 weeks prior to enrollment;
• Subjects who underwent major surgery within 8 weeks prior to screening or plan to undergo surgery during the study;
• Subjects with a history of organ/bone marrow/peripheral blood/umbilical cord blood transplantation;
• Subjects who previously received CAR-T product therapy targeting any target;
• Subjects with any condition that, in the investigator's judgment, may prevent completion of the entire study, interfere with study results, or make participation in the study not in the subject's best interest.