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)

1. Any previous solid organ or islet allotransplant.

2. Body mass index (BMI) \>30 kg/m2.

3. Weight ≤50 kg.

4. Insulin requirement \>1.0 unit/kg/day or \<15 units/day.

5. Uncontrolled proliferative diabetic retinopathy.

6. Blood pressure: systolic blood pressure (SBP) \>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 \<60 mL/min/1.73 m2.

8. Diagnosis of macroalbuminuria (\>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 \<30%.

23. History of significant gastrointestinal disease such as symptomatic cholecystolithiasis; acute or chronic pancreatitis; symptomatic peptic ulcer disease; severe unremitting diarrhea, vomiting or other disorders potentially interfering with the ability to absorb oral medications.

24. Significant hyperlipidemia despite medical therapy defined as fasting low-density lipoprotein (LDL) cholesterol \>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 (\<1,000/µL), neutropenia (\<1,500/µL), or thrombocytopenia (platelets \<100,000/µL). Participants with lymphopenia are allowed if the Principal Investigator determines there is no additional risk and obtains clearance from a hematologist.

28. Any coagulopathy or medical condition requiring long-term anticoagulant therapy (e.g., warfarin) after islet cell transplantation (low-dose aspirin treatment is allowed) or participants with an international normalized ratio (INR) \>1.5. The use of Plavix is allowed only when portal vein access is obtained using a mini-laparotomy procedure at the time of islet cell transplant.

29. History of factor V deficiency.

30. Administration of live attenuated vaccine(s) within 2 months of Screening.

31. Any previous treatment with Tegoprubart (AT-1501) or any other anti-CD40L therapy

32. Baseline Panel-reactive Antibody (PRA) over 20%

33. Patients with COVID-19 positive PCR tests at the time of Thymoglulin infusion.

What this study is about