1. Academic Validation
  2. In vivo activation of FAP-cleavable small molecule-drug conjugates for the targeted delivery of camptothecins and tubulin poisons to the tumor microenvironment

In vivo activation of FAP-cleavable small molecule-drug conjugates for the targeted delivery of camptothecins and tubulin poisons to the tumor microenvironment

  • J Control Release. 2024 Feb 13:367:779-790. doi: 10.1016/j.jconrel.2024.02.014.
Matilde Bocci 1 Aureliano Zana 2 Lucrezia Principi 2 Laura Lucaroni 2 Luca Prati 2 Ettore Gilardoni 2 Dario Neri 3 Samuele Cazzamalli 4 Andrea Galbiati 5
Affiliations

Affiliations

  • 1 Philochem AG, R&D Department, CH-8112 Otelfingen, Switzerland. Electronic address: matilde.bocci@philochem.ch.
  • 2 Philochem AG, R&D Department, CH-8112 Otelfingen, Switzerland.
  • 3 Swiss Federal Institute of Technology, Department of Chemistry and Applied Biosciences, Zurich CH-8093, Switzerland; Philogen S.p.A., Siena 53100, Italy.
  • 4 Philochem AG, R&D Department, CH-8112 Otelfingen, Switzerland. Electronic address: samuele.cazzamalli@philochem.ch.
  • 5 Philochem AG, R&D Department, CH-8112 Otelfingen, Switzerland. Electronic address: andrea.galbiati@philochem.ch.
Abstract

Small molecule-drug conjugates (SMDCs) are increasingly considered as a therapeutic alternative to antibody-drug conjugates (ADCs) for Cancer therapy. OncoFAP is an ultra-high affinity ligand of Fibroblast Activation Protein (FAP), a stromal tumor-associated antigen overexpressed in a wide variety of solid human malignancies. We have recently reported the development of non-internalizing OncoFAP-based SMDCs, which are activated by FAP thanks to selective proteolytic cleavage of the -GlyPro- linker with consequent release of monomethyl Auristatin E (MMAE) in the tumor microenvironment. In this article, we describe the generation and the in vivo characterization of FAP-cleavable OncoFAP-drug conjugates based on potent Topoisomerase I inhibitors (DXd, SN-38, and exatecan) and an anti-tubulin payload (MMAE), which are already exploited in clinical-stage and approved ADCs. The Glycine-Proline FAP-cleavable technology was directly benchmarked against linkers found in Adcetris™, Enhertu™, and Trodelvy™ structures by means of in vivo therapeutic experiments in mice bearing tumors with cellular or stromal FAP expression. OncoFAP-GlyPro-Exatecan and OncoFAP-GlyPro-MMAE emerged as the most efficacious anti-cancer therapeutics against FAP-positive cellular models. OncoFAP-GlyPro-MMAE exhibited a potent antitumor activity also against stromal models, and was therefore selected for clinical development.

Keywords

Cytotoxic payloads; FAP; In vivo activation; Small molecule-drug conjugates; Targeted therapy.

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