CD180-targeting ADCs with a topoisomerase I inhibitor payload achieve strong efficacy in AML tumors

CD180 (RP105) is a type I single-pass transmembrane protein that heterodimerizes with MD-1 or MD-2 to enable stable surface expression. Characterized as an orphan Toll-like receptor predominantly expressed on mature B cells, dendritic cells, and macrophages, CD180 is also upregulated in multiple hematologic malignancies, including diffuse large B-cell lymphoma, mantle cell lymphoma, and acute myeloid leukemia (AML). Here, we identify CD180 as a novel and promising therapeutic target for AML and describe the development of a CD180-directed antibody-drug conjugate (ADC) along with its biochemical properties, antitumor activity across AML models, and pharmacokinetic and safety characteristics in non-human primates.Consistent with emerging datasets, we observed high, homogeneous CD180 expression on AML blasts, including leukemic stem and progenitor compartments, across a large cohort of primary AML specimens, with minimal to no expression on healthy hematopoietic stem cells, common myeloid progenitors, or normal tissues. We generated a fully human monoclonal antibody with high-affinity, selective binding to the human and cynomolgus CD180/MD-1 complex and no reactivity to rodent CD180.This antibody was conjugated to a topoisomerase I inhibitor with a drug-to-antibody ratio (DAR) of 8, selected for its potency and favorable stability profile in hematologic malignancies. The ADC demonstrated rapid internalization, high specificity for CD180-expressing cells, and potent cytotoxicity in AML cell lines, primary ex vivo samples, and patient-derived xenograft models, with therapeutic response strongly correlating with CD180 expression levels.In an exploratory toxicity study in cynomolgus monkeys (10, 30, and 60 mg/kg), the ADC was well tolerated, with no target-related toxicities or cytopenias observed at any dose. All clinical and histopathological findings were mild and reversible, establishing a maximum tolerated dose of 60 mg/kg. The ADC also demonstrated excellent physicochemical stability and developability properties.Together, these findings support advancement of CD180-targeted ADC therapy into clinical development for patients with CD180-positive AML.