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. Epub 2020 Mar 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / drug effects*
  • Endopeptidases
  • Humans
  • Immunoconjugates / pharmacology*
  • Immunomodulation / drug effects
  • Membrane Proteins / antagonists & inhibitors*
  • Mice
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Immunoconjugates
  • Membrane Proteins
  • pembrolizumab
  • Endopeptidases
  • fibroblast activation protein alpha