This study is a first-in-human, open-label, nonrandomized, single center Phase 1 dose-escalation study to assess the safety, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of AB821 monotherapy given every 2 weeks (Q2W) or every 3 weeks (Q3W) in participants with recurrent locally advanced or metastatic melanoma and other immune-responsive solid tumors. Immune-responsive solid tumors are defined as those for which immune checkpoint inhibitors form part of the standard-of-care therapy.

Phase 1 Dose-Escalation Participants with recurrent locally advanced or metastatic melanoma and immune-responsive solid tumors will be enrolled into dose-escalation cohorts. Patients with melanoma are required to have previously been treated with an inhibitor of PD1/L1, while patients with other solid tumors are required to have had previous systemic treatment regimen that may or may not include an inhibitor of PD1/L1. For DL3 and above, n ≥3; for DL1 and DL2, n=1, unless a Grade ≥2 AE or a DLT is observed, in which case the cohort will be expanded to at least 3 participants before further dose escalation. This will help determine the MTD or MAD and select the recommended Phase 1b or Phase 2 dose (RP1bD or RP2D).

Under protocol versions up to and including V 4.0, participants in dose-escalation cohorts were enrolled at least 48 hours apart, treated on a Q2W schedule, and followed for dose-limiting toxicities for 28 days (completion of two 14-day cycles of treatment).

Dose-Escalation Backfill Cohorts ased on emerging safety, PK, and pharmacodynamic data, additional participants may be enrolled in backfill cohorts, backfill slots may be used for other tumor types, not only melanoma, upon discussion with the sponsor-investigator at or below dose levels that cleared the dose-limiting toxicity (DLT) assessment and were determined to be safe and tolerable by the Data and Safety Monitoring Board (DSMB). Up to a maximum of 20 total participants may be enrolled in backfill cohorts, at the RP2D or at lower levels deemed efficacious to better assess safety and efficacy based on emerging data. Dose levels and justification are described in Section 4.3.

This study consists of a Screening phase, a Treatment phase, an end of treatment (EOT) Visit, a 30-, 60-, 90- day Safety Follow-up (SFU) phase, and a long-term follow-up (LTFU) phase. Upon completion of the SFU phase post EOT, ongoing safety, disease progression, survival status, and subsequent anticancer therapies will be assessed in the LTFU period.

During the treatment phase, participants who demonstrate disease progression per RECIST criteria may be allowed to continue AB821 if, in the opinion of the treating investigator, the participant is tolerating study treatment and deriving clinical benefit from continuing study treatment. If further progression is noted on subsequent imaging, participants may be allowed to continue on study based on discussion with the sponsor-investigator.

Inclusion Criteria:

1. ≥18 years at the time consent is signed.

2. Ability to provide written informed consent for the study.

3. ECOG PS of 0 or 1.

4. Participants of childbearing potential must not be pregnant at enrollment and agree to comply with contraception requirements. Participants with partners of childbearing potential must also comply with contraception requirements.

5. Adequate organ function as defined below. Specimens must be collected within seven days prior to the start of the study treatment (i.e., Cycle 1 Day 1 [C1D1]) including:

   ANC> 1500/ul Platelet count>100,000 Hb>9 g/dl Calculated creatinine clearance> 50 mL/min Total bilirubin greater than or equal to 1.5 x ULN or direct bilirubin greater than or equal to ULN for participants with total bilirubin > 1.5 x ULN PT INR > 1.5 x ULN unless on anticoagulation Albumin > 3g/dl

6. Life expectancy of ≥12 weeks, per treating investigator's judgment.

7. For Melanoma participants: Participants with unresectable or metastatic melanoma that have progressed on or after PD-1/PD-L1 checkpoint blockade (alone or with either CTLA-4 or LAG-3 checkpoint blockade).

8. For other tumor types: Must have a recurrent histologically or cytologically proven metastatic or locally advanced solid tumor (non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), Merkel-cell carcinoma, bladder cancer, or squamous cell carcinoma of the head and neck (SCCHN)), meeting each of the following:

   1. Tumor that is not amenable to curative treatment with surgery or radiation.
   2. Tumor for which immune checkpoint inhibitors form part of standard-of-care therapy.
   3. Participant has received at least one prior line of systemic anticancer therapy in the recurrent or metastatic setting.

9. Has measurable disease per RECIST v1.1 as assessed by the local site investigator/radiology.

Exclusion Criteria:

1. Has a diagnosis of immunodeficiency.
2. Prior stem cell, bone marrow, or organ transplant.
3. Known history of HIV infection. No HIV testing is required unless mandated by local health authority.
4. History of HBV (defined as HBV surface antigen reactive) or active HCV.
5. Active autoimmune disease (non-immunotherapy induced conditions) that has required systemic treatment in the past two years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic immune-suppressive treatment and is allowed.
6. Active Grade ≥2 diarrhea or enterocolitis.
7. Known active CNS metastases and/or carcinomatous meningitis. Individuals with previously treated brain metastases may participate provided they are radiologically stable (i.e., without evidence of progression for at least two weeks by repeat imaging, clinically stable, and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment).
8. Any other current or previous malignancy within the previous three years except neoplasms that, in the opinion of the treating investigator and with the agreement of the sponsor-investigator, will not interfere with study-specific endpoints, e.g. basal cell carcinoma, localized tumors that have been fully excised with curative intent and no evidence of recurrence or metastasis, prostate cancer that is asymptomatic and does not require therapy other than anti-androgen therapy.
9. Participant is a regular user, as determined by treating investigator judgment (including recreational use), of any illicit drugs or has a recent history (within the last year) of substance abuse (including alcohol), at the time of signing the Informed Consent Form (ICF).
10. Has clinically significant heart disease that affects normal activities, including, unstable angina, or history of congestive heart failure (New York Heart Association Class II IV).
11. History of acute myocardial infarction within the last six months.
12. Has a history of new or worsening thrombosis (DVT/PE, other thrombo-embolic disease) within the last six months.
13. Has a mean QTcF value of >470 ms.
14. Has a history or current evidence of any condition, therapy, or laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the individuals' participation for the full duration of the study, such that it is not in the best interest of the individual to participate, in the opinion of the treating investigator.
15. Has an active infection, requiring systemic therapy.
16. Has had a severe hypersensitivity reaction to any components of the study treatment or any of their excipients.
17. Is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within seven days prior the first dose of study treatment.
18. Has received more than five prior lines of systemic treatment in the recurrent/metastatic setting.
19. Has received prior radiotherapy within two weeks of start of study treatment or has had a history of radiation pneumonitis.
20. Has a history of grade 3-4 autoimmune myocarditis or a history of Guillain Barre Syndrome.
21. History of congestive heart failure with an ejection fraction < 40%.
22. Participant with NSCLC only: Has received radiation therapy to the lung that is >30 Gy within six months of the first dose of study treatment.
23. Has received previous IL-21 based therapy or prior therapy with AB248
24. Prior systemic anticancer therapy including investigational agents within four weeks or, if shorter, within five half-lives prior to first dose of study treatment.
25. Major surgery from which the participant has not fully recovered
26. Has received a live or live attenuated vaccine within 30 days
27. Current use of any prohibited concomitant medications.
28. A participant of childbearing potential who has a positive serum pregnancy test within 14 days prior to treatment.