Cell Adhesion Molecule 1-Targeting Antibodies Enhance Nose-to-Brain Delivery of Monomethyl Auristatin E

Cell adhesion molecule 1 (CADM1) is an intercellular adhesion molecule belonging to the immunoglobulin superfamily that is abundantly expressed in the olfactory epithelium. Previously, we demonstrated efficient intracellular drug delivery to CADM1-expressing tumor cells using anti-CADM1 antibodies. In this study, we explored the potential of anti-CADM1 antibodies as a cargo for nose-to-brain (N2B) delivery of antitumor agents in mice. CADM1 expression and distribution in the mouse olfactory epithelium were confirmed by immunoblotting and immunohistochemistry. In the mouse nasal cavity, CADM1 is distributed in the olfactory epithelium and is prominent in the sustentacular cell layer of the olfactory epithelia. When CADM1 antibodies that recognize extracellular domain of CADM1 (3E1 and 9D2) were administered intranasally to mice, 3E1 exhibited both prolonged retention and greater accumulation specifically in the olfactory epithelium compared to a non-targeting control antibody. To quantitatively evaluate N2B drug delivery, we developed a simple and highly sensitive liquid chromatography–tandem mass spectrometry method capable of detecting monomethyl auristatin E (MMAE) in brain tissue at concentrations as low as 0.5 fmol/mg tissue. Using this method, the MMAE concentrations in the olfactory bulbs were quantified following intranasal administration of 3E1-MMAE. 3E1-mediated delivery resulted in significantly higher MMAE concentrations than those achieved with the control antibody on both days 4 (22.8 vs. 13.4 fmol/mg tissue) and 8 (19.0 vs. 14.7 fmol/mg tissue). These findings provide the first evidence that targeting a specific cell-surface protein in the olfactory epithelium can improve N2B drug delivery, offering a promising strategy for developing intranasal therapeutics. CADM1 targeting enhances nose-to-brain delivery of MMAE. Anti-CADM1 antibody (3E1) enhances nose-to-brain delivery of monomethyl auristatin E (MMAE) by targeting the olfactory epithelium. LC–MS/MS quantified increased MMAE accumulation in the olfactory bulb. Created with BioRender