The primary objective of Parts 1 and 2 is to evaluate the safety and tolerability of either single-ascending intravenous (IV) doses or a single subcutaneous (SC) dose of BIIB059 (litifilimab) in healthy volunteers (HV), and a single IV dose in participants with Systemic Lupus Erythematosus (SLE). The primary objective of Part 3 is to evaluate the safety and tolerability of multiple SC doses of BIIB059 in healthy volunteers and in participants with SLE.

Secondary objectives of Parts 1 and 2 are as follows: To estimate the PK parameters of single-ascending IV doses of BIIB059 in healthy volunteers and a single IV dose of BIIB059 in participants with SLE; To estimate the PK parameters and bioavailability (F) of a single SC dose of BIIB059 in healthy volunteers; To evaluate the immunogenicity of BIIB059 administered to healthy volunteers and participants with SLE. Secondary objectives of Part 3 are as follows: To estimate the PK parameters of multiple SC doses of BIIB059 in healthy volunteers and in participants with SLE; To evaluate the immunogenicity of BIIB059 administered SC to healthy volunteers and participants with SLE.

Part 1 (single ascending dose in healthy volunteers) has closed to enrollment.

Part 1: Key Inclusion Criteria For Healthy Volunteers:

• Be in good health as determined by the Investigator, based on medical history, physical examination, and 12-lead ECG.
• Body mass index (BMI) between 18 and 30 kg/m2 and body weight ≥45 kg.

Part 1: Key Exclusion Criteria For Healthy Volunteers:

• History of or positive test results at screening for the following: for human immunodeficiency virus (HIV), hepatitis C virus antibody (HCV Ab), hepatitis B virus (defined as positive for hepatitis B surface antigen [HBsAg] or hepatitis B core antibody [HBcAb]).
• - History of chronic, recurrent, or recent serious infection (e.g., pneumonia, septicemia) as determined by the Investigator within 3 months prior to screening and randomization.
• History of severe allergic or anaphylactic reactions or history of allergic reactions likely to be exacerbated by any component of the study drug.
• History of any clinically significant cardiovascular, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, or other major disease, as determined by the Investigator.
• Any live or attenuated immunization/vaccination within 1 month prior to randomization or planned to occur during the study period.
• Blood donation (1 unit or more) within 1 month prior to randomization.
• Vigorous exercise (e.g., jogging, swimming laps, heavy gardening, hiking uphill, etc.) within 48 hours prior to Day -1

Part II: Key Inclusion Criteria for SLE Participants:

• Definite SLE for at least 6 months duration or anti-dsDNA antibody, prior to screening.
• Presence of active lupus skin disease including acute, sub acute, and/or chronic cutaneous lupus (e.g., discoid) at the time of screening and randomization.
• BMI between 18 and <40 kg/m2 and body weight ≥45 kg.

Part II: Key Exclusion Criteria for SLE Participants:

• Active neuropsychiatric SLE including but not limited to the following: seizure, new or worsening impaired level of consciousness, psychosis, delirium or confusional state, aseptic meningitis, ascending or transverse myelitis, chorea, cerebellar ataxia, mononeuritis multiplex, or demyelinating syndromes.
• History of chronic, recurrent, or recent serious infection (e.g., pneumonia, septicemia) as determined by the Investigator within 3 months prior to screening and randomization.
• Symptoms of bacterial or viral infection (including upper respiratory tract infection) within 28 days prior to randomization.
• History of severe allergic or anaphylactic reactions or history of allergic reactions likely to be exacerbated by any component of the study drug.
• Evidence of skin conditions other than lupus skin disease (e.g., eczema) at screening or at the time of randomization that would interfere with evaluations of the effect of study treatment on lupus skin disease.
• Treatment with oral prednisone >15 mg daily (or equivalent). Any prednisone regimen must be stable for at least 28 days before randomization and expected to remain stable for the duration of the study.
• Treatment with any antibiotics within 14 days prior to randomization.

Part IIIa: Key Inclusion Criteria for Healthy Volunteers :

• Must be in good health as determined by the Investigator, based on medical history, physical examination, and 12-lead ECG.
• Must have a body mass index (BMI) between 18 and 30 kg/m2 and body weight ≥45 kg.

Part IIIa: Key Exclusion Criteria for Healthy Volunteers:

• History of chronic, recurrent, or recent serious infection (e.g., pneumonia, septicemia) as determined by the Investigator within 3 months prior to screening and randomization
• History of severe allergic or anaphylactic reactions or history of allergic reactions likely to be exacerbated by any component of the study treatment.
• Treatment with any antibiotics within 14 days prior to randomization.

Part IIIb: Key Inclusion Criteria for SLE Participants:

• Definite SLE for at least 6 months duration prior to screening
• Presence of active lupus skin disease including acute, subacute, and/or chronic cutaneous lupus (e.g., discoid), and/or hypocomplementemia , and/or positive anti-dsDNA antibody at the time of screening.
• Must have a BMI between 18 and <40 kg/m2 and body weight ≥45 kg.

Part IIIb: Key Exclusion Criteria for SLE Participants:

• Active neuropsychiatric SLE including but not limited to the following: seizure, new or worsening impaired level of consciousness, psychosis, delirium or confusional state, aseptic meningitis, ascending or transverse myelitis, chorea, cerebellar ataxia, mononeuritis multiplex, or demyelinating syndromes.
• History of chronic, recurrent, or recent serious infection (e.g., pneumonia, septicemia) as determined by the Investigator within 3 months prior to screening and randomization.
• History of severe allergic or anaphylactic reactions or history of allergic reactions likely to be exacerbated by any component of the study drug.
• Treatment with any antibiotics within 14 days prior to randomization.

NOTE: Other protocol-defined inclusion/exclusion Criteria May Apply