Phase I/II Study of AD-PluReceptor Plus Tafasitamab-cxix and Lymphodepleting Chemotherapy in Patients With Autoimmune Disorders

Eligibility Criteria

• 1. Progressive ILD as defined by Raghu et al47 (≥ 2 of the following):
• 1. worsening respiratory symptoms
• 2. physiological evidence of disease progression (≥ 1 of the following):
• 2. FVC \< 80% predicted and moderate to severe ILD, as assessed by a radiologist. C. Inadequate response to at least 2 of the following treatments used for at least 3 months: mycophenolate, cyclophosphamide, rituximab, and/or tocilizumab.
• 1. A clinical diagnosis of SLE, based on the 2019 EULAR/ ACR classification criteria for adult SLE.
• 2. Positive ANA titer ≥1:80 or positive anti-dsDNA antibody at screening.
• 3. For LN subjects only: Active, biopsy-proven lupus nephritis (kidney biopsy should have been done within 6 months of study enrollment) class III or IV, with or without the presence of Class V, using the 2018 Revised International Society of Nephrology/Renal Pathology Society criteria48.
• 4. Diagnosed with active SLE. Subjects with either LN or without LN will be eligible if they meet the following criteria:
• 1. For LN subjects: urine protein-to-creatinine ratio (UPCR) ≥1 mg/mg on 2 first morning void urine samples during screening despite prior or current treatment with standard of care therapy for at least 12 weeks, including corticosteroids, MMF/mycophenolic acid (MPA), CY, calcineurin inhibitors, belimumab, and/or rituximab. Patients should have failed at least 2 standard of care immunosuppressive therapies tried for 3 months,
• 2. For non-renal SLE subjects: SLEDAI-2K ≥8 and clinical SLEDAI-2K ≥6 (excluding headache, alopecia, mucosal ulcers, fever, and organic brain syndrome) during screening despite prior or current treatment with standard of care therapy, including corticosteroids, rituximab or other B cell depleting agents, CY, MMF/MPA, azathioprine, methotrexate, 6-mercaptopurine, sirolimus, tacrolimus, thalidomide, leflunomide, mizorbine, anifrolumab, and/or belimumab. Patients should have failed at least 2 standard of care immunosuppressive therapies tired for 3 months.
• 5. If a subject is currently receiving:
• 1. Standard immunosuppressive therapy (including MMF/MPA, CY, azathioprine, antimalarial therapy, methotrexate, 6-mercaptopurine, sirolimus, tacrolimus, thalidomide, leflunomide, or mizorbine), the therapy must have been initiated at least 12 weeks prior to screening and on a stable dose for at least 8 weeks prior to screening, except for dose reduction due to safety or tolerability.
• 2. A renin-angiotensin-aldosterone inhibitor, (including direct renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and mineralocorticoid receptor blockers), the subject must be on a stable dose for at least 8 weeks prior to screening.A sodium-glucose cotransporter-2 (SGLT2) inhibitor, the subject must be on a stable dose for at least 8 weeks prior to screening.
• 3. Regarding oral corticosteroid, doses \<0.5 mg/kg prednisone equivalent at the time of infusion are required.
• 6. Adequate renal function, defined as:
• 1. For LN subjects: Estimated glomerular filtration rate of ≥45 mL/min/1.73m2 using the chronic kidney disease-epidemiology equation.
• 2. For non-renal SLE subjects: Estimated glomerular filtration rate of ≥60 mL/min/1.73m2 using the chronic kidney disease-epidemiology equation
• 1. SSc related pulmonary arterial hypertension (PAH) requiring active treatment.
• 2. Rapidly progressive SSc related lower GI (small and large intestines) involvement (requiring parenteral nutrition); active gastric antral vascular ectasia.
• 3. Prior scleroderma renal crisis.
• 4. Uncontrolled or rapidly progressive ILD (FVC \< 50; DLCO \< 50%); oxygen saturation (SaO2) \< 92% (room air at rest); or who have required mechanical breathing assistance (ventilator) within 1 year of signing informed consent.
• 1. Treatment with rituximab or other B cell-depleting agent within 26 weeks prior to screening, or within 12 weeks if there are laboratory results indicating presence of CD19+ B cells.
• 2. Treatment with voclosporin or other calcineurin inhibitor within 8 weeks prior to screening.
• 3. Treatment with anifrolumab, belimumab, or other biologic agent within 12 weeks prior to screening.
• 4. For LN subjects only: Evidence of severe chronicity on kidney biopsy, defined as a modified National Institute of Health chronicity index score of 3+ for any of the following individual biopsy features: total glomerulosclerosis score, fibrous crescents, tubular atrophy, or interstitial fibrosis.
• 5. A diagnosis of antiphospholipid antibody syndrome by the 2006 Revised Sapporo International Consensus Criteria at the time of screening49
• 6. The presence of biopsy-proven kidney disease other than active lupus nephritis
• 7. Moderate-to-severe chronic pulmonary disease, including asthma requiring or refractory to medium or high-dose inhaled corticosteroids combined with other longer-acting medications, In subjects who have had pulmonary function tests: Spirometry results of forced expiratory volume (FEV1)/forced vital capacity \<0.7 and FEV1 \<80% predicted after bronchodilators, or diffusing capacity of the lungs for carbon monoxide results \<60% predicted.
• 8. Active, severe cardiac manifestations of SLE, including constrictive pericarditis, hemodynamically significant pericardial effusions, and myocarditis at the time of screening.