This is a multi-center, open-label Ph 1b basket study to assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, biomarker response, and preliminary efficacy of multiple doses of S-4321 in adults with autoimmune or immune-mediated disease including rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (PsO), cutaneous lupus erythematosus (CLE) with or without systemic manifestations, or atopic dermatitis (AD).

All Participants Major Inclusion Criteria:

1. Adult males and females, 18 to 75 years of age (inclusive)
2. Body mass index (BMI) ≥18.0 and <40.0 kg/m2 with a minimum body weight of 45 kg
3. Use of adequate contraception for both males and females. Female volunteers must be of nonchildbearing potential or if of childbearing potential, must have a negative pregnancy test.

All Participants Major Exclusion Criteria:

1. Have received a PD-1 agonist, immune checkpoint agonist, immune checkpoint inhibitor, anti-CD19 or anti-CD20 agents, cell therapy, B cell modulating agents, alkylating agents, or any other immune cell depleting therapy.
2. Have received azathioprine, cyclosporine, mycophenolate mofetil, or tacrolimus within 4 weeks
3. Unable or unwilling to discontinue a prohibited medication
4. Presence of clinically relevant immunosuppression
5. Current infection or history of severe infection
6. Any history of malignant disease, with some exceptions

Major inclusion/exclusion for each autoimmune or immune-mediated disease:

For RA:

1. Confirmed diagnosis of moderate to severe active RA by the American College of Rheumatology (ACR) 2010/European League Against Rheumatism (EULAR) criteria for at least 3 months prior to the Screening 1 visit, and:

   1. ≥6 swollen joint count based on 66 joint count
   2. ≥6 tender joint count based on 68 joint count
   3. Seropositive for RF and/or ACPA
   4. Elevated hsCRP ≥1.2 times greater than the ULN
   5. Does not have Class IV RA according to ACR revised criteria

2. Inadequate response to, or loss of response, or intolerance to:

   1. >1 conventional synthetic DMARD after 3 months of therapy OR
   2. >1 biologic DMARD/targeted synthetic DMARD after 3 months of therapy
   3. Has not failed 3 or more bDMARDs and/or tsDMARDs

For PsA:

1. Confirmed diagnosis of adult-onset PsA classified by the Classification Criteria for Psoriatic Arthritis (CASPAR) for at least 3 months prior to the Screening 1 visit, with all of the following:

   1. Active PsO defined by at least 1 psoriasis lesion
   2. Active disease defined by >3 swollen joints and >3 tender joints using the 76/78 swollen and tender joint count

2. Received standard doses of NSAIDs for >4 weeks or csDMARDs for >3 months and has been on a stable dose for >8 weeks, or participant has intolerance to NSAIDs or DMARDs

3. Participants may be TNF inhibitor therapy naïve or may have received 1 prior TNF inhibitor

4. Has not had inadequate response or intolerance to 2 or more bDMARDs or csDMARDs

For PsO:

1. Confirmed diagnosis of moderate to severe plaque PsO for at least 6 months, with all of the following:

   1. Psoriasis Area and Severity Index (PASI) >12 points
   2. Static Physician's Global Assessment (sPGA) >3 points
   3. Body surface area (BSA) of PsO involvement >10%

2. Cannot have a clinically significant flare within 12 weeks

3. Does not have history of erythrodermic psoriasis, generalized or localized pustular psoriasis, predominantly guttate psoriasis, or medication-induced or medication-exacerbated psoriasis

4. Has not had inadequate response to more than 2 prior bDMARDs

For CLE (with or without systemic manifestations):

1. Histologically confirmed diagnosis of CLE with or without systemic manifestations for at least 6 months
2. Has active skin manifestations as measured by CLASI-A >10 or CLASI-A >8, if there is no alopecia or mucous membrane lesions
3. Participant must have an active CLE lesion despite an adequate trial of antimalarial treatment for at least 6 months.
4. Cannot have active lupus nephritis or moderate-to-severe or chronic kidney disease with eGFR <45 mL/min/1.73m2
5. Cannot have active neuropsychiatric SLE

For AD:

1. Confirmed diagnosis of AD as defined by the American Academy of Dermatology: Guidelines of Care for the Management of Atopic Dermatitis for at least 12 months

   1. Eczema Area and Severity Index (EASI) >16
   2. Validated Investigator Global Assessment (vIGA-AD) >3
   3. BSA of AD involvement >10%
   4. PP-NRS) >4 (average of daily scores) during the 7 days prior to dosing

2. Inadequate response to existing topical medications within 6 months or has a history of intolerance to topical therapy as defined by at least 1 of the following:

   1. Inability to achieve good disease control after use TCS for at least 4 weeks
   2. Documented history of clinically significant AEs with the use of TCS
   3. Failed systemic therapies intended to treat AD within 6 months

Additional inclusion/exclusion criteria will apply.

IPD sharing plan is not yet developed. Sponsor will consider data sharing at a later date.