Inclusion Criteria: Key Inclusion Criteria Summary

• Written informed consent
• Age 18 to 65
• Diagnosis of lupus for SLE onset ≥ 6 months prior to Screening
• Positive ANA and/or elevated anti-dsDNA and/or elevated anti-Smith antibody test at Screening test
• Active lupus at Screening and Baseline, as defined per-protocol and confirmed by the study's medical monitor, including a SLEDAI score at Screening of ≥ 6 and a clinical score at Baseline of ≥ 4
• Standard lupus medications must be stable prior to Screening
• Women must have a PAP smear and known HPV status within 12 months of Day 1
• All participants must use highly effective birth control if they/their partner are capable of becoming pregnant

Exclusion Criteria: Key Exclusion Criteria Summary:

• Life-threatening or organ system-threatening lupus activity that is anticipated to require increased treatment during the study
• Proteinuria consistent with nephrotic syndrome
• Active lupus-related neuropsychiatric disease
• Drug-induced lupus
• Any serious health condition that would place the subject at undue risk from the study or would confound interpretation of safety or efficacy outcomes
• Recent or serious ongoing infection; risk or history of serious infection
• Receipt of live vaccination within 8 weeks of Day 1, or expected to require live vaccination during the study
• Acceptable Screening laboratory results
• History of new, ongoing, or recurrent malignancy ≤ 5 years prior to Day 1, with some exceptions per-protocol
• Pregnant or breastfeeding at the time of screening, or plans to become pregnant ≤ 3 months following the last dose of study drug
• Prior diagnosis of, or fulfills diagnostic criteria for, another rheumatic disease that overlaps with lupus or another autoimmune or inflammatory disease that may confound clinical assessments or increase subject risk in the study
• Diagnosis of, or fulfills diagnostic criteria for, for fibromyalgia
• Functional class IV lupus IV
• Does not meet protocol washout periods for concomitant medications
• Serious lupus disease activity, which warrants immediate immunosuppressive therapy not appropriate for the study or which makes the possibility of receiving placebo or investigational agent an inappropriate risk
• Ongoing participation in another therapeutic clinical trial
• Known hypersensitivity to ALPN-101, components thereof, or excipients contained in the drug formulation