Targeting Endo180 with an antibody-drug conjugate for cancer treatment

Abstract

Antibody-drug conjugates (ADCs) are formed of an antibody attached to a cytotoxic drug via a linker which is cleaved upon internalisation of the ADC into the cell. This allows very toxic drugs to be directed to specific cells in the body. Endo180 is a constitutively recycling transmembrane receptor and therefore an ideal target for an antibody-drug conjugate. Endo180 is highly expressed on many tumours of mesenchymal origin, including a large proportion of sarcomas. Endo180 is also upregulated on cancer-associated fibroblasts (CAFs) in the stroma of breast and other epithelial cancers. Previous work by our laboratory has demonstrated a tumour promoting and immune restrictive role of Endo180 CAFs.

The aim of this PhD was to assess the utility of targeting Endo180 with an ADC and the efficacy of an Endo180-ADC in both tumour cell-targeting and CAF-targeting contexts. In vitro characterisation established that an anti-Endo180 monoclonal antibody conjugated to the anti-mitotic agent, MMAE, via a cleavable linker, is rapidly internalised into target cells, causing cell death specifically in Endo180-expressing sarcoma cell lines. In a sarcoma tumour xenograft model, the Endo180-vc-MMAE ADC drove on target cytotoxicity resulting in tumour regression and a significant impairment of metastatic colonisation of the lungs, liver and lymph nodes. Investigation of this Endo180-vc-MMAE ADC in fibroblasts determined that whilst the fibroblasts were not as sensitive to the ADC, they were able to process the ADC and release free drug, killing surrounding tumours cells in a bystander effect.

This thesis proposes that an Endo180-ADC is a potential candidate for targeted therapy of solid mesenchymal tumours. Further studies are required to develop an antibody recognising mouse Endo180, which was unsuccessful during this PhD, in order to assess of off-tumour toxicities of an Endo180-ADC and to gain a better understanding of the efficacy of an Endo180-ADC targeting CAFs in animal models.