MGA031, Sirolimus and Tacrolimus in Islet Transplantation

Type 1 diabetes mellitus continues to be a therapeutic challenge. Previous studies have
shown that failure to prevent hypoglycemia and hyperglycemia results in acute and chronic
complications, leading to poor quality of life, premature death, and considerable health
care costs in 30% to 50% of diabetic patients. Therefore, establishing safe and effective
ways to achieve and maintain normoglycemia would have substantial implications for the
well-being of individuals with diabetes. Intensive insulin therapy has been shown to reduce
the risk of chronic complications in patients who achieve near-normalization of glycemia.
However, such therapy is labor-intensive, difficult to implement for many patients, and
limited by the accompanying increased frequency of severe hypoglycemia. Currently, the only
way to restore and sustain normoglycemia without the associated risk of hypoglycemia is by
replacing the patient's islets of Langerhans, either by transplanting a vascularized
pancreas or, much less invasively, by infusing isolated islets.

Strategies that selectively inactivate autoreactive T cells and prevent allorejection of
transplanted islets in the absence of diabetogenic side effects need to be developed for
islet transplants to survive in autoimmune diabetic recipients. The current clinical study
will extend the observations made in our first pilot clinical trial (IND 8971, Study #1)
that provided preliminary information on the safety and efficacy of immunotherapy with the
anti-CD3 monoclonal antibody hOKT3γ1 (Ala-Ala), (currently called MGA031) combined with
sirolimus and tacrolimus in preventing rejection and autoimmune destruction of deceased
donor pancreatic islet transplants in type 1 diabetic recipients.

In the pilot study 4 of 6 single islet transplant recipients remained insulin independent
with normal HbA1c and no episodes of hypoglycemia throughout the 1 year post-transplant
period. Three of those four participants have maintained insulin independence for > 3.5,
>4.5 and >5 years post islet transplant. These preliminary findings warrant an extension
study involving more recipients and more comprehensive immunologic monitoring to examine in
greater detail the impact of MGA031 induction immunotherapy on T cell responses operative in
rejection and autoimmune destruction of transplanted islets as well as on formation of
regulatory T cell function for the protection of transplanted islets.

A total of 5 patients with type 1 diabetes will be transplanted under this protocol. Islet
transplant recipients will be admitted for 5 days and followed for one year after
transplantation.

Inclusion Criteria:

1. Age 18 to 65 years of age.

2. Ability to provide written informed consent.

3. Mentally stable and able to comply with the procedures of the study.

4. Clinical history compatible with type 1 diabetes with onset of disease at <40 years
of age and insulin-dependence for > 5 years at the time of enrollment.

5. Absent stimulated C-peptide (<0.3ng/ml) in response to a mixed meal tolerance test.

6. Involvement in intensive diabetes management defined as self monitoring of glucose
values no less than a mean of three times each day averaged over each week and by the
administration of three or more insulin injections each day or insulin pump therapy.
Such management must be under the direction of an endocrinologist, diabetologist, or
diabetes specialist with at least 3 clinical evaluations during the previous 12
months.

7. At least one episode of severe hypoglycemia in the past 3 years defined as an event
with symptoms compatible with hypoglycemia in which the subject required the
assistance of another person and which was associated with either a blood glucose
level < 50 mg/dl or prompt recovery after oral carbohydrate, intravenous glucose, or
glucagon administration).

8. Reduced awareness of hypoglycemia.

Exclusion Criteria:

1. Any previous transplant.

2. BMI >27 kg/m2 or patient weight ≤ 50kg.

3. Insulin requirement of > 0.8 IU/kg/day or 50 IU/day.

4. HbA1c >10%.

5. Untreated proliferative diabetic retinopathy.

6. Uncontrolled Hypertension.

7. Estimated glomerular filtration rate <70 ml/min/1.73 m2 for females and <80
ml/min/1.73 m2 for males

8. Presence or history of macroalbuminuria (>300mg/d).

9. Presence or history of panel-reactive anti-HLA antibodies >20% by flow cytometry.

10. Females: Positive pregnancy test, presently breast-feeding, or unwillingness to use
effective contraceptive measures for the duration of the study and 3 months after
discontinuation. Males: intent to procreate during the duration of the study or
within 3 months after discontinuation or unwillingness to use effective measures of
contraception.

11. Active infection.

12. Negative screen for Epstein-Barr Virus (EBV).

13. Invasive aspergillus infection within one year prior to study entry.

14. Any history of malignancy except for completely resected squamous or basal cell
carcinoma of the skin.

15. Active alcohol, tobacco or substance abuse.

16. Baseline Hgb below the lower limits of normal at the local laboratory; lymphopenia,
neutropenia, or thrombocytopenia.

17. A history of Factor V deficiency.

18. Any coagulopathy or medical condition requiring long-term anticoagulant therapy.

19. Severe co-existing cardiac disease.

20. Persistent elevation of liver function tests.

21. Symptomatic cholecystolithiasis.

22. Acute or chronic pancreatitis.

23. Symptomatic peptic ulcer disease.

24. Unremitting diarrhea, vomiting or other gastrointestinal disorders potentially
interfering with absorption.

25. Hyperlipidemia despite medical therapy (fasting LDL cholesterol > 130 mg/dl, treated
or untreated; and/or fasting triglycerides > 200 mg/dl).

26. Chronic use of systemic steroids.

27. Use of any other investigational agents within 4 weeks of participation.

28. Administration of live attenuated vaccine(s) within 2 months of enrollment.

29. Any medical condition that, in the opinion of the investigator, will interfere with
the safe completion of the trial.