OMTX705, a Novel FAP-Targeting ADC Demonstrates Activity in Chemotherapy and Pembrolizumab-Resistant Solid Tumor Models

  • Clin Cancer Res. 2020 Jul 1;26(13):3420-3430. doi: 10.1158/1078-0432.CCR-19-2238.
Myriam Fabre  1 ,  Cristina Ferrer  2 ,  Saioa Domínguez-Hormaetxe  2 ,  Bruno Bockorny  3 ,  Laura Murias  2 ,  Oliver Seifert  4 ,  Stephan A Eisler  4 ,  Roland E Kontermann  4 ,  Klaus Pfizenmaier  4 ,  So Young Lee  5 ,  María dM Vivanco  5 ,  Pedro P López-Casas  6 ,  Sofia Perea  3  6 ,  Muhammad Abbas  7 ,  Wolfgang Richter  7 ,  Laureano Simon  2 ,  Manuel Hidalgo  8  9
Affiliations
  • 1. Oncomatryx Biopharma S.L., Derio, Spain. [email protected] [email protected].
  • 2. Oncomatryx Biopharma S.L., Derio, Spain.
  • 3. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
  • 4. Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
  • 5. CIC BioGUNE, Derio, Spain.
  • 6. Gastrointestinal Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 7. TUBE Pharmaceuticals, Wien, Austria.
  • 8. Gastrointestinal Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. [email protected] [email protected].
  • 9. Weill Cornell Medical College, New York, New York.
PMID: 32161121 DOI: 10.1158/1078-0432.CCR-19-2238
Abstract

Purpose: The tumor microenvironment plays a key role in Cancer development and progression and is involved in resistance to chemo- and immunotherapy. Cancer-associated fibroblast expressing fibroblast-activating protein α (FAPα) is one of the predominant stroma cell types and is involved in resistance to immunotherapy.

Experimental design: We generated OMTX705, a novel antibody-drug conjugate from a humanized anti-FAP antibody linked to a new cytolysin. Here, we studied its antineoplastic activity in vitro and in preclinical mouse models alone and in combination with chemotherapy as well as immunotherapy in PD-1-resistant tumors.

Results: In Avatar models, OMTX705 showed a 100% tumor growth inhibition and prolonged tumor regressions as single agent and in combination with chemotherapy. Treatment rechallenge following treatment discontinuation induced additional tumor regression, suggesting lack of treatment resistance. In a mouse model with a humanized immune system resistant to PD-1 inhibition, OMTX705 increased tumor infiltration by CD8+ T cells, induced complete regressions, and delayed tumor recurrence.

Conclusions: These data suggest that FAP targeting with OMTX705 represents a novel and potent strategy for Cancer treatment, including tumors resistant to immunotherapy, and support its clinical development.

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