THE TARGET: FAPα
– Membrane glycoprotein of cancer-associated fibroblasts
– Internalization capability
– Peritumoral stroma overexpression in >90% carcinomas
– No FAPα gene expression has been reported in healthy tissues, with the exception of low-level expression in adipocytes, smooth muscle, bone marrow and uterus
– Extracellular matrix remodeling, tumor growth and metastasis
– Tumor immune system suppression. Depletion of FAPα-expressing cells in pancreatic cancer allowed TNF-α and IFN-ƴ immunological control of tumor growth. Depletion of FAPα-expressing CAFs overcame the lack of anti-tumor response of PD-L1 antibodies, and thus synergizing with anti-PD-L1 immunotherapy in pancreatic cancer.
– Previous approaches blocking FAPα activity, have failed in Phase II due to lack of efficacy. Oncomatryx approach is not aimed at blocking FAPα, but at using it as a CAF-specific internalization vehicle for cytotoxic molecules.
THE ANTIBODY: OMTX005
– OMTX005 anti-FAPα humanized IgG1 monoclonal antibody (mAb) binds specifically, in a concentration-dependent manner, to both human and murine FAPα, at subnanomolar EC50 values (0.33 and 0.25 nM) in vitro, in FAPα-transfected HT1080 cells and in primary Cancer Associated Fibroblasts from patients, as well as in vivo in tumor stroma of pancreas cancer patient-derived xenograft mice after i.p administration.
– OMTX005 anti-FAPα humanized mAb affinity and specificity are not affected by conjugation to Oncomatryx TAM558 payload.
– OMTX005 anti-FAPα humanized mAb is rapidly internalized within cells (85% after 60min)
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 Tetrapeptidic analogues of the natural class Tubulysins
- Low MW: 780 g/mol
- Not a substrate of Multiple Drug Resistance proteins
- Highly cytotoxic
- 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: OMTX705
The in vivo antitumoral efficacy of Oncomatryx Anti-FAPα:Cytolysin ADC, OMTX705, was tested at at two different laboratories, in several different pancreatic cancer patient-derived subcutaneous xenograft murine models for pancreas cancer, triple-negative breast cancer and lung cancer..
OMTX705 led to 100% tumor growth inhibition as single agent and even tumor regression when combined with Gemcitabine and/or Abraxane.