Background: DSP107 is a bi-functional, trimeric, fusion protein composed of sequences from the extracellular domain of SIRPα and 4-1BBL. The SIRPα arm targets CD47 overexpressed on tumor cells, blocking the “don’t eat me” checkpoint and triggering tumor cell phagocytosis. The trimeric 4-1BBL arm, once cross-presented and immobilized by SIRPα binding to CD47, interacts with 4-1BB expressed on activated immune cells, mainly T- and NK cells in the tumor microenvironment, and stimulates their proliferation and activation. Thereby, DSP107 triggers both an innate and an adaptive immune response. Here we describe data from the completed DSP107 monotherapy dose escalation portion of study NCT04440735. Methods: Adult patients with advanced solid tumors were treated with weekly intravenous DSP107 infusions (0.01 - 10 mg/kg) during 3-week treatment cycles. An accelerated dose escalation in single patient cohorts (dose levels 1-3) was followed by a standard 3 + 3 design. The primary objective was to determine safety, tolerability and pharmacokinetic (PK) parameters. Paired biopsies were obtained from 8 patients (screening, after cycle 2). Restaging imaging was performed every two months and evaluated by RECIST criteria. Results: In 23 patients, DSP107 demonstrated no treatment related hematologic or hepatic adverse events (AEs) and no dose limiting toxicities. Grade 1-2 treatment related AEs were observed in 70% of patients (16/23). The most frequent AEs included infusion related reaction (IRR; 26%), diarrhea (17%), fatigue (17%), nausea (13%) and constipation (9%). IRRs were managed during subsequent infusions by reducing the infusion rate and administering IV fluids. No significant systemic cytokine release was measured at any dose level using a 10-plex, pro-inflammatory panel. PK analysis revealed 100% CD47 receptor engagement on peripheral T and NK cells at doses of 3 mg/kg and above. DSP107 did not bind CD47 on red blood cells at any dose. Preliminary histologic assessment of paired biopsies by an independent, blinded pathologist demonstrated increased tumor necrosis compared to screening in 3 out of 4 patients associated with immune cell infiltration. Immuno-profiling of tumor by immunofluorescence is on-going. Stable disease as best response was observed in 11/22 patients with treatment duration up to 26 weeks. Conclusions: DSP107 is a novel, CD47 and 4-1BB targeting fusion protein with a differentiated safety, binding and pharmacodynamic profile compared to other CD47 and 4-1BB targeting agents. Clinical trial information: NCT04440735.