PII-048 - APPARENT FCRN DYSFUNCTION IN CANCER CACHEXIA DECREASES EXTRAVASCULAR IMMUNOGLOBULIN G ABSORPTION.

A. Adeluola¹, J. Thomas², L. Granchie², B. Remaily², M. Hai², G. Young², K. Kim², I. Dickess², Z. Xie², S. Kulp², D. Owen², X. mo², C. Coss², M. Phelps²; ¹The Ohio State University, Columbus, OH, , ²The Ohio State University.

Background: The neonatal Fc receptor (FcRn) prolongs the half-life of IgG-based mAbs by recycling and facilitating their transport across biological membranes. In cancer-associated cachexia, elevated ICI clearance suggests FcRn’s function may be altered leading to faster clearance of IgG-based therapies. Moreover, hematopoietic cells have been reported to play critical roles in the presystemic catabolism of mAbs after extravascular administration. We hypothesized extravascular absorption of therapeutic mAbs may also be reduced due to alteration in FcRn function in cancer-associated cachexia.

Methods: We conducted pharmacokinetic studies comparing absorption and bioavailability of subcutaneous pembrolizumab and I253D (FcRn null-binding IgG1) in cachectic LLC (Lewis Lung Carcinoma) tumor-bearing and non-cachectic tumor-free mice. mAb concentrations were measured in plasma, and data were fit to a compartmental model incorporating multiple routes of administration to simultaneously estimate clearance, bioavailability, and rate of absorption through extravascular routes. Tumor-dependent changes in FcRn in hematopoietic cell populations was assessed in splenocytes and axillary lymph nodes draining the subcutaneous tissue using mass and flow cytometry, respectively.

Results: Systemic pembrolizumab clearance was elevated, and bioavailability was reduced in LLC mice vs. tumor-free controls after subcutaneous administration, though this effect was not observed with FcRn null-binding I253D. FcRn expression was unchanged in splenocytes, though in lymph nodes, macrophage and dendritic cell populations increased in LLC compared to tumor-free mice.

Conclusion: These results suggest increased pre-systemic catabolism of pembrolizumab in LLC tumor-bearing mice may be mediated by altered FcRn function, but not expression, in specific immune cell populations within the context of cancer-associated cachexia.