Endo180 (MRC2) Antibody–Drug Conjugate for the Treatment of Sarcoma

Abstract

Although the 5-year survival rates for sarcoma patients have improved, the proportion of patients relapsing after first line treatment remains high and survival of patients with metastatic disease is dismal. Moreover, the extensive molecular heterogeneity of the multiple different sarcoma subtypes poses a substantial challenge to developing more personalized treatment strategies. From immunohistochemical staining of a large set of 625 human soft tissue sarcomas we demonstrate strong tumor cell staining of the Endo180 (MRC2) receptor in a high proportion of samples, findings echoed in gene expression datasets showing a significantly increased expression in both soft tissue and bone sarcomas compared to normal tissue. Endo180 is a constitutively recycling transmembrane receptor and therefore an ideal target for an antibody-drug conjugate (ADC). An anti-Endo180 monoclonal antibody conjugated to the anti-mitotic agent, MMAE via a cleavable linker, is rapidly internalized into target cells and trafficked to the lysosome for degradation, causing cell death specifically in Endo180 expressing sarcoma cell lines. In a sarcoma tumor xenograft model, the Endo180-vc-MMAE ADC, but not an Isotype-vc-MMAE control or the unconjugated Endo180 antibody, drives on target cytotoxicity resulting in tumor regression and a significant impairment of metastatic colonization of the lungs, liver and lymph nodes. These data, together with the lack of a phenotype in mice with an Mrc2 genetic deletion, provide pre-clinical proof-of-principle evidence for the future development of an Endo180-ADC as a therapeutic strategy in a broad range of sarcoma subtypes and, importantly, with potential impact both on the primary tumor and in metastatic disease.

Current Role of Topoisomerase I Inhibitors for the Treatment of Mesenchymal Malignancies and Their Potential Future Use as Payload of Sarcoma-Specific Antibody-Drug Conjugates

“…uPARAP (product of MRC2 gene, also known as Endo180 or CD280) is a highly interesting target. It is an endocytic receptor that collagen binds to, and uP-ARAP plays an important role in tissue collagen turnover [110,119,120]. On healthy cells, uPARAP expression is limited, but there is a high level of expression on tumor cells including glioblastoma, mesothelioma, osteosarcoma, STS, bone sarcoma, and acute myeloid leukemia [110,119,120].…”

“…It is an endocytic receptor that collagen binds to, and uP-ARAP plays an important role in tissue collagen turnover [110,119,120]. On healthy cells, uPARAP expression is limited, but there is a high level of expression on tumor cells including glioblastoma, mesothelioma, osteosarcoma, STS, bone sarcoma, and acute myeloid leukemia [110,119,120]. In vitro studies with the tubulin inhibitor MMAE-ADC directed against uPARAP showed strong cytotoxicity in uPARAP-positive sarcoma cancer cell lines [110,119].…”

“…On healthy cells, uPARAP expression is limited, but there is a high level of expression on tumor cells including glioblastoma, mesothelioma, osteosarcoma, STS, bone sarcoma, and acute myeloid leukemia [110,119,120]. In vitro studies with the tubulin inhibitor MMAE-ADC directed against uPARAP showed strong cytotoxicity in uPARAP-positive sarcoma cancer cell lines [110,119]. uPARAP-targeted ADCs containing microtubulin and alkylating agent payloads showed antitumor activity in patient-derived xenograft models of osteosarcoma [121].…”

“…There has been a rapid development of ADCs to target topoisomerase I inhibitors to cancer cells [ 5 , 7 , 109 ], and the schematic mechanism of action of topoisomerase I-ADCs is shown in Figure 1 b. In clinical development, topoisomerase I-ADCs are competing with monomethyl auristatin E (MMAE)-based ADCs for the treatment of patients with sarcoma, where preclinical studies targeting the Endo180 (also known as urokinase plasminogen activator receptor-associated protein [uPARAP]) receptor with the MMAE-ADC showed to be effective in Endo180-expressing sarcoma cell lines and in sarcoma xenografts [ 110 ].…”

Recent Advances in Targeted Cancer Therapy: Are PDCs the Next Generation of ADCs?

“…26 Evans et al reported that the Endo180 receptor is highly expressed in human soft-tissue sarcomas; at the same time, Endo180 is also a circular transmembrane receptor, which makes it an ideal target for treating ADCs. 27 By using antibodies targeting nontumor tissues, ADCs have also been designed to treat other diseases. Yu et al reviewed antibody-antimicrobial conjugates made from antibodies targeting bacteria-related targets that can be used as antibacterial drugs.…”