TPS9597 Background: SGN-BB228 is an investigational costimulatory Antibody Anticalin bispecific (Mabcalin) molecule directed to CD228 and 4-1BB. CD228 is a tumor-associated antigen selectively expressed by multiple tumor types including melanoma, mesothelioma, pancreatic, colorectal, and lung cancers with minimal expression in normal tissue. 4-1BB is an inducible costimulatory receptor expressed on activated T cells and other immune cell populations. The clinical development of 4-1BB agonist antibodies has been hampered by limited efficacy and/or poor tolerability at active doses (Segal et al 2017, Segal et al 2018). SGN-BB228 is designed to deliver a potent costimulatory bridge between tumor-specific T cells and tumor cells, potentially localizing antitumor activity to the tumor microenvironment and expanding the therapeutic window for 4-1BB agonism. In vitro, SGN-BB228 shows potent CD228-conditional 4-1BB stimulation and cytotoxic T cell activation (Updegraff et al 2022) providing rationale for evaluating SGN-BB228 in patients (pts) with melanoma or other solid tumors. Methods: SGNBB228-001 (NCT05571839) is a phase 1, open label, multicenter study designed to evaluate the safety, tolerability, PK, and antitumor activity of SGN-BB228 in adults ≥18 years of age with advanced melanoma or other solid tumors. The study includes dose escalation (Part A), dose and schedule optimization (Part B; optional), and dose expansion in disease-specific cohorts (Part C). Parts A and B will enroll pts with histologically or cytologically confirmed metastatic or unresectable cutaneous melanoma, and Part C will enroll pts with cutaneous melanoma, mesothelioma, pancreatic, colorectal, or non-small cell lung cancer. Pts must have disease that is relapsed, refractory, or intolerant to standard of care therapies, ECOG PS 0-1, and adequate organ function. Pts with known active CNS metastases or prior use of agents targeting CD228 or 4-1BB are excluded. Pts with cutaneous melanoma must have received anti PD(L)-1 agent as monotherapy or in combination. Pts with a targetable BRAF mutation must have received, been intolerant to, or declined treatment with BRAF/MEK targeted therapy prior to study entry. Primary endpoints include rate of adverse events, laboratory abnormalities, dose-limiting toxicities, and cumulative dose-level safety. Secondary endpoints are PK, ORR, DOR, PFS, OS, and incidence of antidrug antibodies. Safety and antitumor activity endpoints will be assessed by dose, schedule, and tumor type using descriptive statistics. The ORR and its 95% CI will be estimated. DOR, PFS, and OS will be estimated using Kaplan-Meier method. Enrollment is ongoing in the US and planned in Europe. Clinical trial information: NCT05571839 .