Ex vivo mass spectrometry-based biodistribution analysis of an antibody-Resiquimod conjugate bearing a protease-cleavable and acid-labile linker

  • Front Pharmacol. 2023 Dec 6:14:1320524. doi: 10.3389/fphar.2023.1320524.
Lydia Bisbal Lopez  1 ,  Domenico Ravazza  2 ,  Matilde Bocci  2 ,  Aureliano Zana  2 ,  Lucrezia Principi  2 ,  Sheila Dakhel Plaza  2 ,  Andrea Galbiati  2 ,  Ettore Gilardoni  2 ,  Jörg Scheuermann  3 ,  Dario Neri  2  3  4 ,  Luca Pignataro  1 ,  Cesare Gennari  1 ,  Samuele Cazzamalli  2 ,  Alberto Dal Corso  1
Affiliations
  • 1. Chemistry Department, Università degli Studi di Milano, Milano, Italy.
  • 2. R&D Department, Philochem AG, Otelfingen, Switzerland.
  • 3. Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland.
  • 4. Philogen S.p.A, Siena, Italy.
PMID: 38125888 DOI: 10.3389/fphar.2023.1320524
Abstract

Immune-stimulating antibody conjugates (ISACs) equipped with imidazoquinoline (IMD) payloads can stimulate endogenous immune cells to kill Cancer cells, ultimately inducing long-lasting Anticancer effects. A novel ISAC was designed, featuring the IMD Resiquimod (R848), a tumor-targeting antibody specific for Carbonic Anhydrase IX (CAIX) and the protease-cleavable Val-Cit-PABC linker. In vitro stability analysis showed not only R848 release in the presence of the protease Cathepsin B but also under acidic conditions. The ex vivo mass spectrometry-based biodistribution data confirmed the low stability of the linker-drug connection while highlighting the selective accumulation of the IgG in Tumors and its long circulatory half-life.

Keywords
Resiquimod; immune stimulating antibody conjugates; prodrugs; quantitative biodistribution; toll-like receptors.
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