Antibody Treatment for Advanced Celiac Disease

Background:

- Celiac disease is a complex inflammatory disorder with an autoimmune component
characterized by a dramatic expansion of intraepithelial cytotoxic T lymphocytes that
usually regress on a gluten-free diet.

- It is estimated that approximately 10% of patients become refractory on a gluten-free
diet.

- A subgroup of refractory celiac disease is characterized by expansion of a highly
oligoclonal intraepithelial T-lymphocyte population that exhibits a high risk of
developing enteropathy associated T-cell lymphoma (EATL).

- There is presently no effective therapy for refractory celiac disease.

- A number of studies indicate that intestinal epithelial derived IL-15 plays a critical
role in the disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis that
characterizes refractory celiac disease.

- A pivotal role for IL-15 in refractory celiac disease and EATL is further supported by
the finding that in two murine models of celiac disease the pathognomonic features were
reversed completely by administration of an antibody to CD122 (IL-2/IL-15R beta) that
blocks IL-15 transpresentation and action.

- A Phase I clinical trial in patients with T-cell LGL and hematocytopenia using the
monoclonal antibody, Hu-Mik-Beta-1 that blocks IL-15 action produced under cGMP
conditions by the BDP NCI has been completed in the Metabolism Branch, NCI at the
Clinical Center NIH.

Objectives:

Primary Objectives:

- Phase I trial to define the safety of Hu-Mik-Beta-1 infusions to 2 groups of patients
each with refractory celiac disease at escalating 0.5 (7 patients) and 1.0 (2 patients)
mg/kg doses.

- To define the clinical efficacy of Hu-Mik-Beta-1 infusions in 9 patients with refractory
celiac disease and to correlate these findings with celiac disease specific tests.

Secondary Objectives:

- Definition of the receptor saturation capacity on CD122 (IL-2/IL-15R beta) of
intravenously administered Hu-Mik-Beta-1 administered at 0.5 and 1.0 mg/kg body weight
to 2 groups of patients on three occasions separated by 3 weeks in patients with
refractory celiac disease.

- Determine the immunogenicity of intravenously administered Hu-Mik-Beta-1.

- Determine the effects of Hu-Mik-Beta-1 on the phenotype and the state of activation of
the elements of the cellular immune system in the circulation and in intestinal biopsies
with special focus on the cells implicated in the pathogenesis of celiac disease.

Eligibility:

- Patients with refractory celiac disease (RCD) defined by the following internationally
accepted criteria: persistent or recurrent symptoms (diarrhea, weight loss, and
abdominal pain) associated with intestinal damage characterized by partial to total
villous atrophy with intraepithelial lymphocytes (defined by >25 intraepithelial
lymphocytes per 100 epithelial cells) despite strict adherence to a gluten-free diet for
6-12 months.

- Lack of antibodies to Hu-Mik-Beta-1.

- Patients are not to have circulating antibodies to tissue transglutaminase that are
greater than 10 assay units using recombinant human transglutaminase antibodies.

Design:

- Patients will be enrolled and treated at the Mayo Clinic with the University of Chicago
and the Clinical Center at the NIH involved as laboratory sites. This is a nonrandomized
openlabel phase I trial.

- In this phase I trial initial patients are enrolled to receive 0.5 mg/kg of
Hu-Mik-Beta-1 (3 patients). Patients receive Hu-Mik-Beta-1 every 3 weeks for a total of
3 doses (given on day 1, week 3 and week 6). At specific points in time the patients are
monitored (see below). If 1 or more of the 3 patients receiving 0.5 mg/kg of
Hu-Mik-Beta-1 experience a NCI CTCAE version 4.0 grade 3 or greater toxicity with the
exception of fatigue of >4days duration possibly, probably or definitely related to the
infusion of Hu-Mik-Beta-1, subject enrollment and dosing is stopped.

- At the completion of Week 9, the safety data are reviewed by the Principal Investigator
and DSMB. If the safety data in the 0.5 mg/kg cohort are acceptable, the Sponsor may
then enroll additional patients in doses greater than 0.5 mg/kg, evaluated in a similar
manner as the 0.5 mg/kg (e.g., 3 more patients to receive 1 mg/kg Hu-Mik-Beta-1 every 3
weeks for a total of 3 doses.

- Modification: Three subjects completed study dosing with 0.5mg/kg without serious
adverse events. Two subjects were then randomized to 1.0mg/kg dose and both experienced
serious adverse events with a possible connection to the agent. Subject 5 experienced an
event during the study, acute diverticulitis associated with free intraperitoneal air
treated with antibiotics with resolution. Subject 4 who also received 1.0 mg / kg
experienced a colon perforation many months after completing dosing associated with
severe constipation. These events were reviewed by the DSMP. It was determined that even
though direct cause and effect cannot be established because these occurred in subjects
treated with the 1.0mg/kg that dose escalation be abandoned and the study completed with
the lowest dose used 0.5mg/Kg. This modification proposed that any further subjects be
recruited only at the 0.5mg/kg dose in the remaining 4 subjects.

Monitoring:

- At specific points in time the following cardiac tests/studies are obtained, the results
reviewed prior to subsequent doses (at week 3 and week 6):

i. EKG at screening (Week -4 to 0), Day 1, Week 3, Week 6 and Week 7.

ii. CK-MB and troponin I at screening (Week -4 to 0), Day 1, Day 7, Week 3, Week 6, and Week
7.

In addition, an echocardiogram at screening (Week -4 to 0) and Week 7.

- FACS of peripheral blood mononuclear cells and peroral intestinal biopsies for
expression of NKG2D, CD94, NKG2C, NKG2A, NKb44, NKb30, CD158 and granzyme.

- Immune profiling on intestinal biopsies performed on the first infusion and one week +
or -3 days following the third infusion to analyze for CD8 T-cells, TCR gamma
rearrangements by multiplex PCR and fluorescence analysis of CD8 and CD3 expression,
high-resolution PCR expression for immunoglobulin gene rearrangement and for IEL, ERK
and JNK phosphorylation reflecting abnormal IEL activation.

- Furthermore, IL-15, IL-15R alpha and interferon alpha expression will be assayed in the
cells of the intestinal biopsy and in the serum.

- FACS of PBMCs with Hu-Mik-Beta-1 and Hu-Mik-Beta-3 to define saturation of CD122
(IL2/IL-15R beta).

Endpoints:

- Complete clinical response and by clinical biochemical results at the 20-week time
point.

- Secondary partial response, duration of response, toxicities, immunogenicity of
Hu-Mik-Beta- 1.

- INCLUSION CRITERIA

2.1.1.1 Patients must be greater than or equal to 18-years-old.

2.1.1.2 All patients must have a pathologically confirmed diagnosis of refractory celiac
disease(RCD) defined by internationally accepted criteria of persistent and recurrent
symptoms(diarrhea, weight loss, and abdominal pain) associated with intestinal damage,
characterized by partial to total villous atrophy with intraepithelial lymphocytes defined
by > 25 intraepithelial lymphocytes per 100 epithelial cells.

2.1.1.3 Persistence of the above signs and symptoms despite strict adherence to a
gluten-free diet for 6-12 months

2.1.1.4 Patients are to have had circulating antibodies to transglutaminase-1 or similar
celiac specific serology

2.1.1.5 Patients must have a life expectancy of > 3 months

2.1.1.6 Patients must have a creatinine of less than 2.0 mg/dL or if the patient has an
elevated creatinine measured creatinine clearance (Ccr) must be > 60 mL/min/1.73m(2)

2.1.1.7 Patients must have a serum alkaline phosphatase, ALT (SGPT) and AST (SGOT) less
than 3x the upper limits of normal (ULN)

2.1.1.8 Patients must have a total bilirubin of less than 2.5 x ULN

2.1.1.9 Women of childbearing potential must have a negative beta HCG pregnancy test at
initial screening and within 3 days prior to registration

2.1.1.10 Patients receiving a stable dose (> 4 weeks) of corticosteroid therapy equal to 20
mg of prednisone per day or less are eligible

2.1.1.11 Patients with a history of curatively treated basal cell carcinoma or
intraepithelial neoplasia of the uterine surface will be allowed on the study

2.1.1.12 Patients must be able to understand and sign an informed consent

EXCLUSION CRITERIA

2.1.2.1 Patients enrolled in another therapeutic study

2.1.2.2 Patients with a history of venous thrombosis

2.1.2.3 Patients with antibodies to Hu-Mik-Beta-1

2.1.2.4 A contraindication to monoclonal antibody therapy including adverse events related
to prior monoclonal antibody therapy. Patients who have received prior antibody therapy
will have permanent medical records reviewed by the study investigator.

2.1.2.5 Any uncontrolled or chronic bacterial, mycobacterial or other viral (e.g., herpes
virus), fungal, parasitic or protozoal infection

2.1.2.6 History of malignancy (active or within the previous 5 years)

2.1.2.7 Patients with HIV infection (antibody positive) with positive confirmatory
molecular tests

2.1.2.8 Patients who have chronic hepatitis B or chronic hepatitis C

2.1.2.9 Pregnant or breastfeeding women. Women who not using an acceptable method of
contraception. Acceptability of various methods of contraception will be determined by the
investigator. Postmenopausal or surgically sterile women who have documentation of
postmenopausal status or surgical sterility availability prior to enrollment.

2.1.2.10 Patients with significant co-morbidities including uncontrolled hypertension
(diastolic B/P > 115 mm/Hg), unstable angina, congestive heart failure (> N.Y.H.A. Class
II), poorly controlled diabetes, severe chronic pulmonary disease, coronary angioplasty or
myocardial infarction within the last 6 months or uncontrolled atrial or ventricular
cardiac arrhythmias.

2.1.2.11 Abnormal screening/baseline tests exceeding the limits outlined below:

- Total white blood cell count (WBC) <300/mm(3)

- Platelet count <85,000/mm(3)

- INR greater than or equal to 1.5

- Serum creatinine level > 1.5 mg/dL

- Serum alanine transaminase, aspartate transaminase or creatinine kinase > 2 x the
upper limits of normal

2.1.2.12 Patients with a history of a psychiatric disorder that may interfere with the
understanding and compliance with this protocol, and the required follow-up

2.1.2.13 Exclusion at the discretion of the PI or delegate if participation in the study is
deemed too risky (e.g., clinically significant pleural or pericardial effusion or ascites)

2.1.2.14 Inability to give informed consent

2.1.2.15 History of diverticulitis