👤 Authors: Adeoluwa Adeluola, Justin Thomas, Bryan Remaily, Zhiliang Xie, Kyeongmin Kim, Alexandra D Partey, Gregory Young, Min Hai, Emma Hoelzen, Seolbin Lee, Henry Morris, Faith Jeffrey, Melisa Bilgin, Camille Stanton, Isaac Dickess, Lauren Granchie, Samuel K Kulp, Dwight H Owen, Mo Xiaokui, Latha P Ganesan, Thomas A Mace, Mitch A Phelps, Christopher C Coss
FcRn function alone cannot account for elevated IgG clearance in the Lewis lung carcinoma model of cancer cachexia.
PURPOSE
The neonatal Fc receptor (FcRn) protects IgG-based monoclonal antibodies (mAbs) from catabolism by direct binding within endosomes and facilitates their recycling to extracellular spaces. Elevated clearance of immune checkpoint inhibitors (ICIs) and other IgG-based mAbs is often observed in patients with cachexia phenotypes and is associated with worse outcomes.
We sought to understand if FcRn’s function is altered in cancer cachexia.
EXPERIMENTAL DESIGN
Clearance of IgGs with different FcRn-binding properties were evaluated in cachectic LLC tumor-bearing (TB) and non-cachectic tumor-free mice in both wild-type and FcRn knockout backgrounds. As macrophage depletion with liposomal clodronate affects IgG pharmacokinetics only in the absence of FcRn function, we compared IgG clearance in LLC-TB and TF mice with and without macrophage ablation to assess changes in FcRn’s functional status in cachectic tumor-bearing mice.
RESULTS
We noted that the induction of IgG clearance in the presence of a cachectic tumor was dampened by the lack of FcRn engagement in whole body FcRn knockout mice.
As expected, clodronate administration did not significantly affect systemic clearance of FcRn-binding IgG, though it significantly reduced clearance of FcRn-null IgG. More importantly, these effects were consistent in both TF and TB cachectic contexts.
CONCLUSIONS
These results suggest that while FcRn accounts for a portion of the observed changes in IgG pharmacokinetics in cancer cachexia, the functional status of FcRn is not significantly different in healthy mice without tumors compared to those with LLC tumors and associated cachexia, which indicates the potential involvement of FcRn-independent mechanisms.
