Belimumab Treatment of Emphysema Patients With Anti-GRP78 Autoantibodies

Specific Aim 1: To conduct a double-blind, Phase IIa trial, in which 18 former smokers with
pulmonary emphysema (per chest CT scans), and circulating anti-GRP78 autoantibody levels
>mean normal values (by ELISA), will be randomized 2:1 to belimumab vs. placebo. Subjects
will receive 8 infusions of either belimumab or placebo over a 6 month interval. Plasma
anti-GRP78 will be measured pre-treatment, and at 1, 3, 5, and 7 months. The investigators
hypothesize belimumab therapy will more effectively reduce anti-GRP78 IgG autoantibodies, the
primary endpoint of this trial, compared to placebo.

Specific Aim 2: To determine effects of the belimumab therapy on secondary endpoints (at the
times detailed for Aim 1) that include levels of pneumococcal-binding antibodies (by ELISA),
circulating B-cell numbers and phenotypes (by flow cytometry), and the rate and severity of
adverse events (AE) at any time during treatment. The investigators hypothesize belimumab
will have dose-related effects on B-cell numbers and their differentiation, while minimally
reducing host defense antibodies, and will also have an acceptable AE profile.

Inclusion Criteria:

1. A history of past tobacco smoking (>10 pack years), but quit for >6 months at the time
of enrollment. Smoking cessation will be confirmed by serum cotinine assays.

2. Pulmonary emphysema per chest CT scans (F950>5%). About 60% of COPD patients followed
in the LHC registry meet these criteria.6 Chest CTs are routine, standard of practice
evaluations for patients with COPD, so no new radiographic studies will be necessary
for this project.

3. Ability and willingness to give informed consent.

4. Plasma anti-GRP78 binding IgG >mean values in former smokers with no lung disease
(standardized OD >0.390) (hence this is a "personalized medicine" approach). Of the
330 emphysema subjects assayed for anti-GRP78 to date, 111 (67%) met this criterion.

5. Age 40-75 y.o. COPD is a disease of older individuals.

Exclusion Criteria:

1. History of prior acute COPD exacerbations or no more than one moderate exacerbation in
the last year and no exacerbations four months prior to enrollment. A past history of
an acute exacerbation is the single biggest risk for recurrence.36 Exclusion of these
higher-risk subjects will minimize drop-outs.

2. Oral steroids or cellular immunosuppressant use (e.g., cyclophosphamide) within 6
months.

3. History or clinical or laboratory evidence of other autoimmune syndromes.

4. Inability or unwillingness to complete the treatment and surveillance protocols.

5. Eligible for lung transplant at time of enrollment. This exclusion will mitigate any
potential, however slight, that a patient could be rejected for transplantation due to
surgeon concerns about this novel therapy (and will also obviate early drop-outs due
to transplantation).

6. History of malignant neoplasm within the last 5 years.

7. Evidence of serious suicide risk including any history of suicidal behavior in the
last 6 months and/or any suicidal ideation in the last 2 months or those, in the
investigator's judgment, pose a significant suicide risk.

8. History of a primary immunodeficiency.

9. Significant IgG deficiency (IgG level < 400 mg/dL).

10. Have an IgA deficiency (IgA level < 10 mg/dL).

11. Currently on any suppressive therapy for a chronic infection (such as tuberculosis,
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster or atypical
mycobacteria).

12. Hospitalization for treatment of infection within 60 days of Day 0.

13. Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or
anti parasitic agents) within 60 days of Day 0.

14. Current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or
dependence within 365 days prior to Day 0.

15. History of a positive HIV test or positive screening test for HIV.

16. Serologic evidence of current or past Hepatitis B (HB) or Hepatitis C (HC) infection
based on positive tests for HBsAg or HBcAb, or HCAb.

17. History of an anaphylactic reaction to parenteral administration of contrast agents,
human or murine proteins or monoclonal antibodies.

18. Any other clinically significant abnormal laboratory value in the opinion of the
investigator.

19. Any intercurrent significant medical or psychiatric illness that the investigator
considers would make the candidate unsuitable for the study.

20. Women of Child Bearing Potential (WCBP) must have a negative serum pregnancy test
(either blood or urine) at screening, and agree to 1 of the following:

Complete abstinence from intercourse from 2 weeks prior to administration of the 1st
dose of study agent until 16 weeks after the last dose of study agent (Sexual
inactivity by abstinence must be consistent with the preferred and usual lifestyle of
the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of contraception)

OR

Consistent and correct use of 1 of the following acceptable methods of birth control
for 1 month prior to the start of the study agent, during the study, and 16 weeks
after the last dose of study agent:

- Oral contraceptive, either combined or progestogen alone

- Injectable progestogen

- Implants of levonorgestrel or etonogestrel

- Estrogenic vaginal ring

- Percutaneous contraceptive patches

- Intrauterine device (IUD) or intrauterine system (IUS) with <1% failure rate as
stated in the product label

- Male partner sterilization (vasectomy with documentation of azoospermia) prior to
the female subject's entry into the study, and this male is the sole partner for
that subject. For this definition, "documented" refers to the outcome of the
investigator's/designee's medical examination of the subject or review of the
subject's medical history for study eligibility, as obtained via a verbal
interview with the subject or from the subject's medical records

- Double barrier method: condom and occlusive cap (diaphragm or cervical/vault
caps) plus spermicidal agent (foam/gel/film/cream/suppository)

21. Use of Excluded Medications:

- Anti-B-cell therapy:

- Wash out of 5 therapeutic half lives after prior B-cell therapy, or until
pharmacodynamic effect would be minimal (e.g., 1 year following rituximab)

- 365 days Prior to Belimumab:

- Any biologic investigational agent (e.g., abetimus sodium, anti CD40L
antibody, BG9588/ IDEC 131)

- Investigational agent applies to any drug not approved for sale in the country in
which it is being used

- 30 Days Prior to Belimumab (or 5 half lives, whichever is greater)

- Any non-biologic investigational agent

- Investigational agent applies to any drug not approved for sale in the country in
which it is being use

- Live vaccines within 30 days prior to baseline or concurrently with belimumab