The purpose of this study is to investigate the safety and tolerability of LY4298445 in healthy participants and in participants with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). Participation in the study will last up to approximately 52 weeks.

Inclusion Criteria: Healthy Participants

Healthy participants between the ages of 18 and 55 years.

• Have body weight of at least 50 kilograms (kg) and body mass index (BMI) between 18 and 32 kilogram per square meter (kg/m²), inclusive.

Participants with Systemic Lupus Erythematosus (SLE)

• Are 18 to 75 years of age, inclusive.
• Have body weight between 45 and 145 kg, inclusive, and BMI between 18 and 35 kg/m², inclusive.
• Have a clinical diagnosis of SLE according to the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria at least 6 months prior to screening.

Participants with Rheumatoid Arthritis (RA)

• Are 18 to 75 years of age, inclusive.
• Have body weight between 45 and 145 kg, inclusive, and BMI between 18 and 35 kg/m², inclusive.
• Have a diagnosis of adult-onset RA for at least 6 months prior to screening, as defined by the 2010 ACR/EULAR classification criteria
• Have Disease Activity Score in 28 joints (DAS28)-high-sensitivity C-reactive protein (hsCRP) greater than or equal to 4.4.
• Have positive test results for rheumatoid factor or anti-citrullinated peptide antibodies
• Have had a history of failure (an inadequate response, intolerance, or loss of response) to at least 2 advanced therapies (biological disease-modifying antirheumatic drug [bDMARD] or targeted synthetic DMARD [tsDMARD]) after failing a conventional synthetic DMARD (csDMARD).

Exclusion Criteria:

• Have known allergies to LY4298445, related compounds, or any components of the formulation

• Are individuals assigned female at birth (AFAB) who are lactating or have a positive pregnancy test at screening or Day -1.

• Have severe active lupus-associated renal disease (lupus nephritis) defined clinically and/or by

  • urine protein/creatinine ratio greater than 200 milligrams per millimole (mg/mmol) (as an estimate of approximate proteinuria greater than 2 reams (g) per day) or
  • an estimated glomerular filtration rate (eGFR) less than 40 milliliters per minute (mL/min)/1.73 m² at screening, as calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) 2021.
  • requiring hemodialysis within 6 months prior to screening

• Have active central nervous system lupus as defined by ACR nomenclature for neuropsychiatric lupus syndromes and as captured by Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K); seizure, psychosis, organic brain syndrome, visual disturbance, cranial nerve disorder, lupus headache, and cerebrovascular accident, within 2 months prior to screening

• Have a Class 4 RA according to the ACR revised criteria