The collagen receptor uPARAP/Endo180 as a novel target for antibody-drug conjugate mediated treatment of mesenchymal and leukemic cancers

Abstract

A key task in developing the field of personalized cancer therapy is the identification of novel molecular targets that enable treatment of cancers not susceptible to other means of specific therapy. The collagen receptor uPARAP/Endo180 is overexpressed by malignant cells in several non-epithelial cancers, notably including sarcomas, glioblastomas and subsets of acute myeloid leukemia. In contrast, in healthy adult individuals, expression is restricted to minor subsets of mesenchymal cells. Functionally, uPARAP/Endo180 is a rapidly recycling endocytic receptor that delivers its cargo directly into the endosomal-lysosomal system, thus opening a potential route of entry into receptor-positive cells. This combination of specific expression and endocytic function appears well suited for targeting of uPARAP/Endo180-positive cancers by antibody-drug conjugate (ADC) mediated drug delivery. Therefore, we utilized a specific monoclonal antibody against uPARAP/Endo180, raised through immunization of a uPARAP/Endo180 knock-out mouse, which reacts with both the human and the murine receptor, to construct a uPARAP-directed ADC. This antibody was coupled to the highly toxic dolastatin derivative, monomethyl auristatin E, via a cathepsin-labile valine-citrulline linker. With this ADC, we show strong and receptor-dependent cytotoxicity in vitro in uPARAP/Endo180-positive cancer cell lines of sarcoma, glioblastoma and leukemic origin. Furthermore, we demonstrate the potency of the ADC in vivo in a xenograft mouse model with human uPARAP/Endo180-positive leukemic cells, obtaining a complete cure of all tested mice following intravenous ADC treatment with no sign of adverse effects. Our study identifies uPARAP/Endo180 as a promising target for novel therapy against several highly malignant cancer types.

Impairment of a distinct cancer-associated fibroblast population limits tumour growth and metastasis

“…One question arising from these findings is whether Endo180-expressing cells in the tumour stroma represent a suitable therapeutic target. An Endo180 targeting antibody drug conjugate (ADC) has been investigated in mice inoculated with human Endo180-positive U937 cells and shown antitumour activity with no discernible toxicity of normal tissue 63 , however it is unclear whether this ADC effectively recognises mouse Endo180, hence its utility as stromal targeting agent remains to be established. Consequently, additional reagents, including a fibroblast-specific Endo180 knockout mouse, will be required to fully assess the efficacy of such an approach and potential on-target toxicities in normal tissues.…”

Targeted Drug Delivery via the Use of ECM-Mimetic Materials

“…Under particular pathological conditions, these collagen receptors are highly expressed. Endo180/uPARAP receptor is overexpressed by malignant cells in sarcomas, glioblastomas, subsets of acute myeloid leukemia (Nielsen et al, 2017). For integrins, expression of α 1 β 1 and α 2 β 1 was localized to scleral fibroblast focal adhesions and expression of integrin α 11 β 1 is restricted to tumor stroma or other fibrotic disease (McBrien et al, 2006;Schnittert et al, 2018).…”

Immunoconjugates for Osteosarcoma Therapy: Preclinical Experiences and Future Perspectives

“…The resulting immunoconjugate was tested in vitro on several sarcoma cell lines, but not OS, showing encouraging results. Thus, this conjugate could also find useful applications in OS that highly express this antigen [ 49 ].…”