THE TARGET: ENG
- Membrane protein of endothelial cells
- Internalization capability
- TGF-beta receptor pathway
- Overexpression in tumor microvasculature cells
- In healthy adult tissues, ENG expression is detectable only in kidney and placenta.
- Optimal accessibility from blood
- Associated to angiogenesis and neovascularization in different types of cancer
THE ANTIBODY: OMTX003
- OMTX003 anti-ENG human mAb A5 and mE12 IgG1s bind in a concentration-dependent manner to human and murine ENG, respectively, at subnanomolar and nanomolar E50 values
- OMTX003 anti-ENG human mAb A5 is rapidly internalized within cells. (75% after 60min)
- OMTX003 anti-ENG human mAb A5 binds primate ENG
- HUVEC apoptosis increases in response to human mAb OMTX005 A5
- Angiogenesis is reduced in response to human mAb OMTX005 A5
THE PAYLOAD: CYTOLYSINS
Natural cytoysins, Tubulysins:
- Isolated from Myxobacteria
- Very strong cytotoxic activity (nM to pM range)
- Tubulin polymerization inhibitors that block formation of mitotic spindles
- Stable in lysosome enriched cell fraction
Synthetic Cytolysins
- Synthetic Tetrapeptidic analogues of the natural class Tubulysins
- Low MW: 780 g/mol
- Not a substrate of Multiple Drug Resistance proteins
- Highly cytotoxic
- Anti-angiogenic
- Easy to conjugate
- Achievable by total synthesis in sufficient amount for preclinical and clinical development
- Functional group for linker technology can be modified
- Several linker technologies applicable
- Robust IP position
- Different combinations of cytolysins and linkers were evaluated in vitro as well as in vivo models and TAM558 was selected as the optimal structure for highest activity and stability
THE ADC: OMTX703
TAM558, a selected cytolysin-linker has been conjugated to OMTX003 human anti-ENG antibodies to generate OMTX703.
OMTX703 shows 100% tumor growth inhibition in preclinical models for Ewing sarcoma of MD Anderson Cancer Center.