The main purpose of this study is to evaluate the safety and tolerability of a study drug known as LY3471851 in participants with SLE. The study will last about 79 days for each participant.

LY3471851 is a potential first-in-class therapeutic that may address an underlying immune system imbalance in people with many autoimmune conditions. It targets the interleukin (IL-2) receptor complex in the body in order to stimulate proliferation of inhibitory immune cells known as regulatory T cells. By activating these cells, LY3471851 may act to bring the immune system back into balance.

This study will evaluate the safety, tolerability, pharmacokinetics (PK), and immunologic effects of multiple doses of LY3471851 in participants with minimal to moderate SLE. The effects on SLE disease activity will also be evaluated. SLE participants will be randomized to receive multiple subcutaneous (SC) doses of LY3471851 or receive placebo. After receiving the last dose of LY3471851 or placebo, participants will be followed for an additional 50 days to evaluate safety, PK, pharmacodynamics (PD), and preliminary efficacy.

Inclusion Criteria:

• Willing and able to give written informed consent and comply with study procedures and requirements.

• Body mass index (BMI) between 18.0 and 32.0 kilograms per square meter (kg/m²).

• Systolic blood pressure between 90 to 140 millimeters of mercury (mm Hg), diastolic blood pressure between 50 to 90 mm Hg, and resting heart rate between 40 to 100 beats per minute.

• Diagnosis of adult SLE according to the 1997 ACR classification criteria for at least 6 months prior to signing the informed consent form (ICF).

• Minimal to moderate SLE disease activity (active SLE clinical disease is not required for enrollment into the study and participants with severe SLE clinical disease activity, based on the evaluation of the investigator, should be excluded).

• If a participant is taking oral prednisone (or prednisone equivalent) for their SLE, the dose must be less than or equal to (≤) 10 milligrams per day (mg/day) for a minimum of 8 weeks prior to screening. In addition, the dose of oral prednisone or prednisone equivalent the participant is taking must be stable for a minimum of 2 weeks prior to screening.

• If a participant is taking any of the medications below for their SLE, the medication must have been administered for a minimum of 12 weeks prior to signing the ICF, and at a stable dose for a minimum of 8 weeks prior to signing the ICF:

  • Azathioprine ≤ 200 mg/day
  • Antimalarial (e.g., chloroquine, hydroxychloroquine, quinacrine)
  • Mycophenolate mofetil ≤ 2 grams per day (g/day) or mycophenolic acid ≤ 1.44 g/day
  • Oral, SC, or intramuscular methotrexate ≤ 15 milligrams per week (mg/week).

• Willing and able to participate in the study for a duration of up to 4 months.

• Willing and able to abstain from participating in another clinical study for a duration of up to 4 months.

• Female participants will be non-pregnant, non-lactating, and either postmenopausal for at least 2 years, or surgically sterile for at least 3 months, or will agree to use double barrier contraception from period prior to study enrollment until 5 months following the last dose received; women of child-bearing potential must have a negative serum beta-human chorionic gonadotropin (β-hCG) test at screening and randomization prior to administration of investigational product.

• Male participants with female partners of childbearing potential must agree to use double barrier contraception during the study (until 5 months following the last dose received). Sperm donation is also restricted during the time-frame that males must be using double barrier contraception. This criterion may be waived for male participants who have had a vasectomy greater than (>) 6 months prior to enrollment.

Exclusion Criteria:

Medical Conditions:

• Current active bacterial, viral, or fungal infection.

• Evidence of significant hematologic dysfunction.

• Evidence of significant liver or kidney dysfunction.

• History of, or current diagnosis of, a clinically significant non SLE-related vasculitis syndrome.

• Active severe or unstable neuropsychiatric SLE.

• Active severe SLE-driven renal disease or history of severe active lupus nephritis with persisting proteinuria levels greater than 0.5 grams/24 hours.

• Diagnosis (within 1 year of signing the ICF) of mixed connective tissue disease or any history of overlap syndromes of SLE.

• History of, or current, inflammatory joint or skin disease other than SLE.

• History of any non-SLE disease that has required treatment with oral or parenteral corticosteroids for more than 2 weeks within the last 24 weeks prior to signing the ICF.

• Active tuberculosis (TB) on the basis of positive medical history or chest radiograph (OR) evidence of latent TB or by positive (or persistently indeterminate) Quantiferon-TB Gold or T-Spot test.

• Known history of a primary immunodeficiency, splenectomy, or any underlying condition that predisposes the participant to infection.

• Confirmed positive serology for hepatitis B, hepatitis C (Viral Hepatitis C Antibody Screen [anti-HCV]), or a positive result for human immunodeficiency virus (HIV) antibody screen.

• Any severe herpes infection at any time prior to screening per judgement of the investigator.

• History of opportunistic infection requiring hospitalization or intravenous antimicrobial treatment within 3 years prior to randomization.

• History of major surgery within 12 weeks of screening or will require major surgery during the study.

• Clinically significant electrocardiographic abnormalities.

• History of any significant cardiovascular disease (e.g., myocardial infarction, congestive heart failure, uncontrolled hypertension, cerebrovascular accident), thrombotic episode, or any severe non-SLE medical illness within the previous 1 year.

• History of cancer, apart from:

  • Squamous or basal cell carcinoma of the skin that has been successfully treated.
  • Cervical cancer in situ that has been successfully treated.

Medications:

• Receipt of any investigational product (small molecule or biologic agent) within 4 weeks or 5 half-lives prior to signing of the ICF, whichever is greater.
• Receipt of belimumab in 6 months prior to screening.
• History of treatment with rituximab or ocrelizumab (or other B cell depleting agent) within 6 months prior to screening. For participants who received their last treatment with rituximab or ocrelizumab more than 6 months earlier, evidence of significant and persisting low B cell levels in blood.
• History of cytotoxic medications (e.g., cyclophosphamide) within preceding 12 months.
• Receipt of any intra-articular, intramuscular, or intravenous (IV) glucocorticoids within 6 weeks prior to screening.
• Receipt of blood products within 6 months prior to screening.

General:

• Receipt of blood products within 6 months prior to screening and donation of blood or plasma to a blood bank or for a clinical study (except for screening of this study) within 28 days prior to screening.
• Participants who have a history of organ or bone marrow transplant.