This is a 2-part, multi-center, randomized, double-blind, placebo-controlled, multiple dose escalation study, enrolling approximately 40 subjects. Part A of the study will enroll subjects with Systemic Lupus Erythematosus (SLE) without Glomerulonephritis (GN) into 3 cohorts. Part B of the study will enroll SLE subjects with GN into 2 cohorts. The purpose of the study is to evaluate the multiple dose of AMG 811 on safety. Tolerability and pharmacokinetics.

• Lupus
• Nephritis

• Placebo Comparator: 2 subjects of each cohort (cohort 1 to 5) will receive placebo
• Other: Six subjects in each cohort (cohort 1 to 5) will receive AMG 811

Inclusion Criteria:

• Men and women, between the ages of 18 and 70 years of age, inclusive, at the time of randomization;
• Body mass index from 18 to 40 kg/m2 [Body Weight (kg)/Height2 (m2)] at screening;
• Diagnosis of SLE at least 6 months before randomization, as defined by the most recent American College of Rheumatology criteria, including a positive antinuclear antibodies (ANA) during screening; if screening ANA is negative, documented historical ANA with a titer of at least 1:80 will be acceptable;
• Any concurrent SLE pharmacologic regimen (including mycophenolate mofetil, azathioprine, leflunomide, methotrexate, and anti-malarials) must be stable for at least 30 days before randomization;
• Prednisone ≤ 20 mg/day (or equivalent) is permitted; one increase or one decrease of ≤ 5 mg/day prednisone equivalent will be allowed within 30 days before randomization;
• Immunizations up to date with locally established guidelines, with a minimum of tetanus, diphtheria, pertussis (Td/Tdap), pneumococcal (polysaccharide) and influenza (during flu season) vaccinations, as determined by the Principal Investigator. Subjects not able to receive required vaccines will be excluded from the study;
• Normal or clinically acceptable ECG (12-lead reporting RR, PR, QRS, QT, QTcF intervals) at screening based on the opinion of the investigator;
• Women with normal Pap smear within the past 24 months before randomization;
• Able and willing to complete entire study according to study schedule.

Additional inclusion criteria for Part B:

• Active SLE with GN with no other apparent cause, defined by the following:

Renal biopsy evidence (within 12 months) of nephritis using the WHO or International Society of Nephrology (ISN)/Renal Pathology Society (RPS) classification of SLE with GN (Class III or IV); Urine protein/creatinine ratio (UP/Cr) > 1 or 24 hour urine protein > 1g after at least 12 weeks of treatment with mycophenolate mofetil (at least 1.5 grams/day) or azathioprine (at least 100 mg orally per day); Superimposed membranous changes are allowed for those with Class III or Class IV SLE with GN; SLE subjects with GN who have had either a first episode of glomerulonephritis or reactivation of nephritis that has been previously controlled (with or without maintenance therapy) are eligible;

• Prednisone ≤ 20 mg/day (or equivalent) at the time of randomization.

Exclusion Criteria:

• Any disorder (including psychiatric), condition or clinically significant disease (other than a diagnosis of SLE) that would, by its progressive nature and/or severity, interfere with the study evaluation, completion and/or procedures per the investigator's discretion;
• History of malignancies (other than resected squamous and basal cell carcinomas of the skin);
• Subjects who, in the clinical judgment of the Investigator, have unstable or severe disease;
• Uncontrolled hypertension (> systolic 150 / diastolic 95) confirmed by repeat assessment during the screening period;
• Poorly controlled diabetes (defined as HbA1c ≥ 8.0%) during the screening period;
• Presence or history of vasculitis (compromising internal organs or extremities or leading to peripheral neuropathy, excludes subcutaneous vasculitis) within the last 3 years, presence or history of active CNS lupus (defined as seizure disorder, cerebral vascular accident, psychosis ascribed to SLE, encephalitis, meningitis, or myelitis) requiring therapy within the last 3 years;
• Creatinine clearance within the screening period of less than 50 mL/min as calculated by the Cockcroft-Gault method
• Evidence of liver disease (eg, serum ALT or AST > 2x upper limit of normal) during the screening period;
• Hemoglobin < 9 g/L during the screening period;
• Neutropenia (neutrophils < 1,500/μL) during the screening period;
• Thrombocytopenia (platelets < 75,000/μL) during the screening period;
• Total WBC < 2500 x 106/L during the screening period;
• Signs or symptoms of a viral, bacterial or fungal infection within 30 days of study randomization, or recent history of repeated infections;
• Underlying condition other than SLE or being on allowed immunosuppressants that predisposes one to infections (eg, history of splenectomy);
• Subjects with evidence of past or active tuberculosis on chest x-ray during screening; known tuberculosis antecedents; known exposure (within 6 months) to a person with active tuberculosis; or positive protein purified derivative (PPD) test in subjects that have not been vaccinated with bacille Calmette-Guérin (BCG) at screening where a positive result is defined as induration greater than 5 mm 48-72 hours after administration;
• Positive serology for HIV antibodies, hepatitis B surface antigen or hepatitis C antibodies (confirmed by PCR or RIBA) during the screening period;
• Known or suspected parasitic infestation per local incidence or prevalence of parasites;
• Positive screening test for strongyloides;
• History of valley fever or positive screening test for coccidioidomycosis;
• Known hypersensitivity to any component of the study drug;
• Receipt of a live vaccine within 3 months of study randomization;
• Prior use of the following agents:
• Administration of an investigational biologic agent that primarily targets the immune system
• Rituximab, Lymphostat-B, and TACl-Ig within 9 months prior to randomization; Rituximab treated patients must demonstrate a return of CD19+ B cells to > 5/μL;
• CTLA4-Ig within 3 months prior to randomization;
• Other agents within 5 half-lives prior to randomization;
• Administration of cyclosporine, tacrolimus, sirolimus, IV immunoglobulin, and/or plasmapheresis within 3 months of randomization;
• Administration of oral or IV cyclophosphamide (or any other alkylating agent) within 12 months (Part A) or 3 months (Part B) of randomization;
• Administration of another investigational drug that does not target the immune system within the previous 30 days or 5 half-lives prior to randomization, whichever time period is longest.
• Received AMG 811 previously and tested positive for the presence of anti-AMG 811 antibodies;
• Any disorder or condition that prevents the subject from providing informed consent;
• Have donated blood or experienced a loss of blood > 500 mL within 4 weeks of randomization;
• History of ethanol or drug abuse within the last one year prior to randomization;
• Unwilling to practice highly effective method of birth control during the study. Highly effective methods of birth control include abstinence, vasectomy, or a condom in combination with either hormonal birth control or barrier methods used by women;
• Positive pregnancy test at screening or baseline; or females who are currently lactating;

Additional exclusion criteria for Part B:

• Rapidly progressive GN (defined as a doubling of serum creatinine within the past 3 months);
• Evidence of significant chronicity, defined as:

> 50% glomeruli with sclerosis or > 50% interstitial fibrosis on renal biopsy; or International Society of Nephrology (ISN)/Renal Pathology Society (RPS) 2003 Class III (C), IV-S (C) or IV-G (C).