Endo180 (MRC2) antibody-drug conjugate for the treatment of sarcoma.
Rachel J EvansDouglas W PerkinsJoanna L SelfeAnna KelseyGavin P BirchJanet M ShipleyKoen SchipperClare M IsackePublished in: Molecular cancer therapeutics (2022)
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.
Keyphrases
- soft tissue
- end stage renal disease
- gene expression
- cell death
- newly diagnosed
- chronic kidney disease
- ejection fraction
- squamous cell carcinoma
- lymph node
- monoclonal antibody
- small cell lung cancer
- endothelial cells
- poor prognosis
- type diabetes
- magnetic resonance imaging
- peritoneal dialysis
- single cell
- multiple sclerosis
- dna methylation
- high grade
- magnetic resonance
- binding protein
- cancer therapy
- machine learning
- systemic lupus erythematosus
- adipose tissue
- induced apoptosis
- cell therapy
- stem cells
- diffusion weighted imaging
- photodynamic therapy
- artificial intelligence
- drug delivery
- cell cycle arrest
- metabolic syndrome
- electronic health record
- rectal cancer
- insulin resistance
- bone mineral density
- free survival
- cell cycle
- flow cytometry
- locally advanced
- body composition
- sentinel lymph node
- disease activity
- long non coding rna
- contrast enhanced
- high fat diet induced