Safety, Tolerability, and Efficacy of Immunomodulation With A Monoclonal Antibody Against CD40L in Combination With Transplanted Islet Cells in Adults With Brittle Type 1 Diabetes Mellitus (T1D)

Tegoprubart (AT-1501) is a monoclonal antibody. Antibodies are Y-shaped proteins that are produced naturally by the subject's immune system to attack and fight foreign substances that cause illness. Monoclonal antibodies are man-made proteins manufactured to serve as substitute antibodies to fight diseases. Monoclonal antibodies can restore, enhance, or mimic (copy) the immune system's attack process; they can also tone down the immune system. Tegoprubart (AT-1501) is thought to work by dampening down the immune system so that it will be less likely to attack the transplanted cells. For other types of transplants, like kidney, a drug called a calcineurin inhibitor is usually used to prevent rejection. That class of drugs can be toxic to islet cells. Tegoprubart (AT-1501) is an experimental agent that is anticipated to prevent rejection without harming the islet cells.

Inclusion Criteria: 1. Men and women 18-65 years of age. 2. A diagnosis of T1D ≥5 years with onset of disease at \1.0 unit/kg/day or \140 mmHg or diastolic blood pressure (DBP) \>90 mmHg. 7. Estimated glomerular filtration rate (eGFR) calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation \300 mg/g creatinine). 9. For female participants: Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of the study and 90 days after discontinuation. For male participants: intent to procreate during the duration of the study or within 90 days after discontinuation or unwillingness to use effective measures of contraception. 10. History of malignancy except for completely resected squamous or basal cell carcinoma of the skin. 11. History of a thromboembolic event (TE), known hypercoagulable state, or condition requiring long-term anticoagulation. a. Participants with a history of clotted venous access not requiring long- term anticoagulation may be included at the Principal Investigator's discretion if they have no other history of TEs or known hypercoagulable state. 12. Known heparin allergy. 13. Receiving treatment for a medical condition requiring chronic use of systemic steroids, except for physiologic replacement for example in Addison disease. 14. Presence of ongoing active infection including tuberculosis (TB), human immunodeficiency virus (HIV), hepatitis B, hepatitis C. Laboratory evidence of active infection even in the absence of clinical symptoms of infection is exclusionary. 15. Invasive aspergillus, histoplasmosis or coccidioidomycosis infection within one year prior to Screening. 16. Negative screen for Epstein-Barr Virus (EBV) by immunoglobulin G (IgG) determination. 17. Current treatment with any immunosuppressive regimen, and treatment with biologic immune modulating agents, Janus kinase (JAK) inhibitors, sphingosine-1-phosphate (S1P) receptor agonists, azathioprine, Mercaptopurine (6- MP), or systemic corticosteroids in the previous 5 years. 18. Persistent elevation of serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value greater than 3 times the upper limit of normal (ULN); elevation of total bilirubin \>1.5 ULN. 19. Any history of receiving experimental cell or gene therapy. Exposure to any other experimental or investigational agent within 30 days or 5 half-lives; whichever is longer. 20. History of substance abuse within the past 6 months. 21. Allergy to the Boost drink necessary for MMTT 22. Severe cardiovascular disease characterized by any one of these conditions: a) stroke; b) recent myocardial infarction (within past 6 months); c) evidence of ischemia on functional cardiac exam within the last year; d) left ventricular ejection fraction \130 mg/dL and/ or triglycerides \>200 mg/dL. 25. History of any conditions that can interfere in the assessment of HbA1c due to increased red blood cell turnover or requirement for regular blood transfusions such as sickle cell disease (HbSS, hematopoietic blood stem cell (HbSC), HbS/beta thalassemia); Beta thalassemia major; Alpha Thalassemia (HbH) disease, Hemoglobin H-Constant Spring. 26. History of any other acute or chronic medical condition or pre-planned medical/surgical procedure that, in the opinion of the Principal Investigator, would compromise the safety of participants or the integrity of study results; non- compliance with recommended diabetes care in the preceding 12 months. 27. Baseline Hb below the lower limits of normal at the local laboratory; lymphopenia (\