Abstract A hallmark of aggressive tumors is the dense infiltration of tumor-associated macrophages (TAMs), which often constitute 30-50% or more of the total cells within a tumor. TAMs foster an immunosuppressive microenvironment and promote resistance to chemotherapy, immunotherapy, and radiation. They also facilitate macrophage vascular mimicry, a non-endothelial microcirculation in hypoxic tumor regions as described by Barnett et al., 2016. Resolute Science, Inc. has developed macrophage-targeted conjugates (MAC-TACs), a novel class of synthetic drug conjugates that exploit TAM biology and the TAM microcirculation for targeted delivery of payloads to tumor cells. By targeting TAMs rather than tumor cells, this platform bypasses resistance from tumor heterogeneity and receptor evolution. Our lead candidate, RS-5, an MMAE-conjugated MAC-TAC, has shown near-complete to complete regressions in 22 studies across 10 solid tumor models, including CDX, syngeneic and PDX models. MAC-TACs comprise four components: a receptor targeting ligand, backbone, linker, and payload. This modular design enables the development of therapeutic and imaging molecules, including radiopharmaceuticals. MAC-TACs target an overexpressed receptor found on TAMs. Immunohistochemical analysis reveals a high and relatively uniform expression of the TAM-targeted receptor across a range of metastatic tumor types, including sarcoma, melanoma, bladder, prostate, pancreatic and gastric cancers. In vitro and in vivo studies demonstrate selective uptake by TAMs, which internalize and release the payload to adjacent cancer cells. Receptor expression correlates with therapeutic response. A complete response was observed in a doxorubicin-resistant soft tissue sarcoma (STS) PDX model. In a second PDX STS model, a near-complete response was observed over two months of treatment. In an A375 melanoma CDX model, a near-complete response was also observed. In an intracranial U87MG glioma model, RS-5 demonstrated a 79% increase in median survival, and in an HT1080 luciferase brain metastasis model, a 100% increase in median survival was observed. Across studies, body weight and hematologic/chemical parameters remained within normal ranges. RS-5 exhibits a favorable PK/PD profile; MTD and DRF are complete, and 4-week toxicology studies are underway.These preclinical results support broad clinical utility, particularly for TAM-rich tumors. A first-in-human dose-escalation study is planned for the summer of 2026. Citation Format: Faith H. Barnett, Joyce James, Sean Premeau, Richard R. Crum, Andre Basbaum, Robert Schmidt. A novel TAM-targeted therapeutic for rare and aggressive solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4043.
Barnett et al. (Fri,) studied this question.