Abstract 4784: ADCE-D01: a first in class antibody drug conjugate against urokinase plasminogen activator receptor-associated protein (uPARAP) demonstrates excellent preclinical efficacy and tolerability
Authors: Jonathan H. Wardman, Anne Bie, Christophe Come, Pernille Barkholt, Sander van Putten, Cecillie Løkke, Ida Gregersen, Jette Lange, Mette Gillberg, Mikkel Krogh-Madsen, Karen Bannister, Thomas Tuxen Poulsen, Christoffer Nielsen, Lars Engelholm, Niels Behrendt, Carmel Lynch, Pernille Hemmingsen, Dominik Mumberg
Journal: Cancer Research (2025)

Abstract The urokinase plasminogen activator receptor-associated protein (uPARAP, endo180, CD280) is a type-1 membrane protein which acts as an endocytic receptor for collagen. uPARAP binds and internalizes both intact and partially degraded collagens. uPARAP-bound collagen is internalized via clathrin-mediated endocytosis and routed to the lysosome for further degradation, while uPARAP is rapidly recycled to the cell surface. In healthy tissues, uPARAP is expressed in a restricted number of cell types, mostly mesenchymal cell types in tissues characterized by an active matrix turnover such as skin during wound healing and in bone. In contrast, high expression levels of uPARAP are found on malignant cells of various non-epithelial cancers, including soft tissue sarcoma (STS) and osteosarcoma, glioblastoma multiforme and mesothelioma. Recent publications on immunohistochemistry (IHC)-based expression analysis with tumor samples from more than 900 patients1, 2 demonstrate that uPARAP is widely expressed at high levels across most sarcoma subtypes. The efficient internalization of uPARAP combined with the highly prevalent expression in non-epithelial tumors makes it a very attractive antibody-drug conjugate (ADC) target for the treatment of sarcomas. ADCE-D01 is a first-in-class uPARAP-ADC composed of a humanized anti-uPARAP IgG1 monoclonal antibody conjugated via a GFGG tetra-peptide linker moiety to the Topoisomerase I inhibitor P-1021 payload3 at a drug-to-antibody ratio (DAR) of 8. ADCE-D01 binds with high affinity to human recombinant uPARAP protein and multiple uPARAP positive cell lines. Binding of ADCE-D01 to uPARAP on the cell surface triggers internalization, resulting in intracellular payload release, induction of DNA damage and cell death. In addition, ADCE-D01 induces potent bystander cytotoxicity in uPARAP negative cells. In vivo, ADCE-D01 shows strong anti-tumor efficacy in a range of mesenchymal solid tumor models including soft-tissue sarcoma and is well tolerated in non-human primate toxicology studies with no evidence of target-specific toxicity. In summary, ADCE-D01 constitutes a novel First-in-Class ADC targeting uPARAP with an excellent therapeutic as well as safety profile. A phase I/II clinical study of ADCE-D01 in patients with advanced STS is imminent. 1Barkholt et al., Cancer Res (2024), (6_Supplement): 6355; 2Evans et al., Mol Cancer Ther (2023); 3Lin et al., J Transl Med (2024) Citation Format: Jonathan H. Wardman, Anne Bie, Christophe Come, Pernille Barkholt, Sander van Putten, Cecillie Løkke, Ida Gregersen, Jette Lange, Mette Gillberg, Mikkel Krogh-Madsen, Karen Bannister, Thomas Tuxen Poulsen, Christoffer Nielsen, Lars Engelholm, Niels Behrendt, Carmel Lynch, Pernille Hemmingsen, Dominik Mumberg. ADCE-D01: a first in class antibody drug conjugate against urokinase plasminogen activator receptor-associated protein (uPARAP) demonstrates excellent preclinical efficacy and tolerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4784.