Monoclonal Antibody Treatment for Systemic Lupus Erythematosus

• IINCLUSION CRITERIA: Age at entry at least 18 years Must give written informed consent prior to entry in the protocol Must fulfill at least 4 of the following criteria for SLE as defined by the AmericanCollege of Rheumatology:

• Malar rash. Fixed Erythema, flat or raised, over the malar eminences.

• Discoid rash. Erythematous raised patches with adherent keratotic scaling andfollicular plugging; atrophic scarring may occur.

• Photosensitivity. Exposure to UV light causes rash.

• Oral Ulcers. Includes oral and nasopharyngeal, observed by physician.

• Arthritis. Nonerosive arthritis involving two or more peripheral joints, characterizedby tenderness, swelling or effusion.

• Serositis. Pleuritis or pericarditis documented by ECG or rub or evidence ofpericardial effusion.

• Renal disorder. Proteinuria greater than 0.5 g/d or greater than 3+, or cellularcasts.

• Neurologic disorder. Seizures without other cause or psychosis without other cause.

• Hematologic disorder. Hemolytic anemia or leukopenia (less than 4000/microL) orlymphopenia (less than 1500/microL) or thrombocytopenia (less than 100,000/microL) inthe absence of offending drugs.

• Immunologic disorder. Anti-dsDNA, anti-Sm, and/or anti-phospholipid.

• Antinuclear antibodies. An abnormal titer of ANAs by immunofluorescence or anequivalent assay at any point in time in the absence of drugs known to induce ANAs. Moderately active lupus not requiring immediate immunosuppressive therapy other than oralprednisone less than or equal to 0.3 mg/kg/day (or its equivalent). Moderately active lupusis defined by either of these two (a and b) sets of criteria: a. Chronic glomerulonephritis with inadequate response to at least 6 months of adequateimmunosuppressive therapy (with pulse methylprednisolone, cyclophosphamide, azathioprine,cyclosporine, mycophenolate mofetil or high dose daily corticosteroids, MTX or IV Ig), and i. less than 30% increase in creatinine compared to lowest level during treatment, ii. proteinuria less than or equal to 1.5 times the baseline before treatment, iii. less than or equal to 2+ cellular casts in the urinary sediment (on a scale of 0-4),and iv. Extra-renal disease activity does not exceed 10 on the non-renal components of theSELENA-SLEDAI score. b. Patients with moderately active extra-renal lupus defined as an extra-renalSELENA-SLEDAI score in the range of 3 to 10, inclusive. The SELENA-SLEDAI score should havebeen stable for at least two weeks prior to screening. One or more of the following: i) Serum dsDNA level greater than or equal to 30 IU ii) IgG anticardiolipin antibody levels greater than or equal to 20 GPL iii) CRP greater than 0.8 mg/dL iv) ESR greater than 25 mm/hr for men; ESR greater than 42 mm/hr for women. Stable doses of prednisone less than or equal to 0.3 mg/kg/day (or its equivalent) for atleast 2 weeks before the first treatment.

EXCLUSION CRITERIA: Pregnant or lactating women. Women of childbearing potential are required to have anegative pregnancy test at screening. Women of childbearing potential and fertile men who are not practicing or who are unwillingto practice birth control during and for a period of three months after the completion ofthe study Any therapy with human or murine antibodies or any experimental therapy within 3 months Therapy with cyclophosphamide; pulse methylprednisolone or IV Ig within 4 weeks; orazathioprine, mycophenolate mofetil, cyclosporine or methotrexate within 2 weeks of firststudy treatment Initiation or a change in the dose of an ACE-inhibitor within 2 weeks of first studytreatment Allergy to murine or human antibodies History of anaphylaxis Serum creatinine greater than 3.0 mg/dL Active severe CNS lupus (encephalopathy, cerebrovascular accident, transverse myelitis,severe depression, psychosis) Previous history of ischemic heart disease or evidence of ischemic heart disease on ECG Congestive heart failure or cardiomyopathy History of thrombosis or recurrent 2nd trimester abortions (3 or more) and elevated levelsof anti-cardiolipin antibodies or lupus anticoagulant unless the patient is onanticoagulation History of malignancy with the exception of basal cell or squamous cell carcinoma of theskin or in situ carcinoma of the cervix within the last 3 years Active infection that requires the use of intravenous antibiotics and does not resolvewithin 1 week of Day 1 Any active viral infection that does not resolve within 10 days prior to Day 1 History of reactivation on EB viral infection or greater than 1,000 EBV genomeequivalent/10(6) cells in PBMC preparations Active hepatitis B, hepatitis C or HIV infection WBC less than 3500/microL or ANC less than 3000/microL or Hgb less than 8.0 g/dL orplatelets less than 50,000/microL or absolute lymphocyte count less than or equal to 500/microL. ALT and/or AST greater than 2 times the upper limit of normal (ULN) or alkaline phosphatasegreater than 1.5 times the ULN Significant concurrent medical condition that, in the opinion of the principalinvestigator, could affect the patient's ability to tolerate or complete the study Live vaccines within 4 weeks of first infusion