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)

Inclusion Criteria:

1. Men and women 18-65 years of age.

2. A diagnosis of T1D ≥5 years with onset of disease at <40 years of age.

3. Ability to provide informed consent.

4. Able to comply with study procedures, including the requirement to utilizecontinuous glucose monitoring (CGM).

5. Involvement in appropriate diabetes management in accordance with the standard ofcare, as directed by an endocrinologist or diabetologist with at least 4 (quarterly)clinical evaluations within the 12 months prior to Screening; using CGM*: using aninsulin pump or multiple daily injection (MDI) of insulin therapy; and, unable toachieve acceptable metabolic control because of the occurrence of unexplained SHEs-at least 3 unexplained SHEs not secondary to a missed meal or dosing error, in the 12 months prior to Screening.

*CGM will be provide to subjects who otherwise qualify for study participation buthave not used CGM previously.

6. At least 3 unexplained SHEs not secondary to a missed meal or dosing error, in the 12 months prior to Screening.

7. HbA1c level 6.5% (48 mmol/mol) to 9.5% (80 mmol/mol), inclusive.

8. Absence of stimulated C-peptide (<0.3 ng/mL) in response to a 240-minute mixed- mealtolerance test (MMTT).

9. Impaired awareness of hypoglycemia (IAH) as defined by a Clarke Score [Clarke 1995]of 4 or more at the time of Screening, during the Screening period, and within thelast 6 months prior to the transplant.

10. If female, must be surgically sterile or 2 years postmenopausal. Women ofchildbearing potential may be enrolled if a serum pregnancy test is negative atscreening/baseline. Women of childbearing potential and men with partners that areof childbearing potential must agree to use 2 forms of highly effective methods ofcontraception from Screening, throughout the study, and while receivingimmunosuppressive therapy for the functioning graft after the conclusion of thestudy. Contraception use must continue for 90 days after the last administration ofthe study drug (see Appendix 5). Male participants must refrain from donating spermfor the duration of the study and agree to not donate sperm for 90 days after lastadministration of the study drug.

11. Patients with Coronavirus Disease 2019 (COVID-19) Polymerase chain reaction (PCR)negative test result at the time of Thymoglobulin infusion.

Exclusion Criteria:

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 DiseaseEpidemiology 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, orunwillingness to use effective contraceptive measures for the duration of the studyand 90 days after discontinuation. For male participants: intent to procreate duringthe duration of the study or within 90 days after discontinuation or unwillingnessto use effective measures of contraception.

10. History of malignancy except for completely resected squamous or basal cellcarcinoma of the skin.

11. History of a thromboembolic event (TE), known hypercoagulable state, or conditionrequiring long-term anticoagulation. a. Participants with a history of clotted venous access not requiring long- termanticoagulation may be included at the Principal Investigator's discretion if theyhave no other history of TEs or known hypercoagulable state.

12. Known heparin allergy.

13. Receiving treatment for a medical condition requiring chronic use of systemicsteroids, except for physiologic replacement for example in Addison disease.

14. Presence of ongoing active infection including tuberculosis (TB), humanimmunodeficiency virus (HIV), hepatitis B, hepatitis C. Laboratory evidence ofactive infection even in the absence of clinical symptoms of infection isexclusionary.

15. Invasive aspergillus, histoplasmosis or coccidioidomycosis infection within one yearprior 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 biologicimmune modulating agents, Janus kinase (JAK) inhibitors, sphingosine-1-phosphate (S1P) receptor agonists, azathioprine, Mercaptopurine (6- MP), or systemiccorticosteroids in the previous 5 years.

18. Persistent elevation of serum aspartate aminotransferase (AST) or alanineaminotransferase (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 otherexperimental or investigational agent within 30 days or 5 half-lives; whichever islonger.

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 onfunctional cardiac exam within the last year; d) left ventricular ejection fraction <30%.

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

24. Significant hyperlipidemia despite medical therapy defined as fasting low-densitylipoprotein (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 toincreased red blood cell turnover or requirement for regular blood transfusions suchas sickle cell disease (HbSS, hematopoietic blood stem cell (HbSC), HbS/betathalassemia); Beta thalassemia major; Alpha Thalassemia (HbH) disease, HemoglobinH-Constant Spring.

26. History of any other acute or chronic medical condition or pre-plannedmedical/surgical procedure that, in the opinion of the Principal Investigator, wouldcompromise 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 determinesthere 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 isallowed) or participants with an international normalized ratio (INR) >1.5. The useof Plavix is allowed only when portal vein access is obtained using amini-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.