Background: SGN-CD228A is an investigational antibody-drug conjugate (ADC) that targets CD228, a cell-surface oncofetal protein with prevalent expression in several types of cancer and limited expression on normal tissues. SGN-CD228A consists of a humanized IgG1 anti-CD228 monoclonal antibody conjugated to an average of 8 molecules of monomethyl auristatin E (MMAE) via a PEGylated β-glucuronidase cleavable linker. MMAE is a well-studied and highly active chemotype with an established safety profile. The proposed mechanism of action involves binding CD228 on cell surfaces, ADC internalization, and trafficking to lysosomes. MMAE is then released through β-glucuronidase cleavage of the glucuronide MMAE linker. MMAE then binds tubulin, which disrupts microtubule networks and causes cell cycle arrest and apoptosis. Methods: SGN228-001 (NCT04042480) is a phase 1, open label, multicenter, dose escalation, and expansion study enrolling up to 240 subjects to evaluate the safety, tolerability, PK, and antitumor activity of SGN-CD228A in select advanced solid tumors. Eligible subjects are ≥18 years of age and have metastatic cutaneous melanoma, malignant pleural mesothelioma, human epidermal growth factor receptor 2-negative metastatic breast cancer, advanced non-small cell lung cancer, metastatic colorectal cancer, or advanced pancreatic ductal adenocarcinoma. Subjects must have relapsed, refractory, or progressive disease, and should have no appropriate standard therapy available. Measurable disease per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), Eastern Cooperative Oncology Group (ECOG) performance status score of ≤1, and adequate renal, hepatic, and hematologic function are required. The study includes dose escalation and dose expansion, with multiple disease-specific dose expansion cohorts and a biology cohort. Dose escalation will be conducted using the modified toxicity probability interval method (Ji 2010) to evaluate the safety and identify the maximum tolerated dose of SGN-CD228A. Following dose escalation, disease-specific expansion cohorts and a biology cohort (to evaluate exploratory biomarkers) are planned. Response assessments will be conducted every 6 weeks per RECIST v1.1 and all subjects will be followed for safety. Pharmacokinetics and markers of pharmacodynamics will be assessed regularly. Key efficacy endpoints include objective response rate, progression-free survival, and duration of objective response. Enrollment is ongoing in the US and planned in Europe. Clinical trial information: NCT04042480.