PII-011 - FC GAMMA RECEPTORS CONTRIBUTE TO CACHEXIA MEDIATED INCREASES IN MONOCLONAL ANTIBODY CLEARANCE

B. Remaily, J. Thomas, K. Kim, Z. Xie, C. Stanton, M. Manna, D. Owen, S. Kulp, T. Mace, L. Ganesan, C. Coss, M. Phelps; The Ohio State University.

Background: Cancer cachexia is a multifactorial syndrome characterized by increased energy expenditure, catabolism, and inflammation that displays phenotypically as irreversible losses of skeletal muscle and adipose tissue. Patients with cancer cachexia display elevated immune checkpoint inhibitor (ICI) catabolic clearance (CL), and this increased ICI CL serves as a prognostic indicator of overall survival, independent of dose and drug exposure. This phenomenon of increased ICI CL is replicated in the murine Lewis Lung Carcinoma (LLC) model of cancer cachexia but is absent in the non-cachectic MC38 colon adenocarcinoma model. The elevated CL of these therapeutic monoclonal antibodies (mAbs) is independent of its variable region and target binding, suggesting an important role for the Fc constant region interaction with Fc receptors (FcRs). FcRs are FcRs that have been highly implicated in the efficacy of mAbs. The aim of this study was to understand the contribution of FcRs to cachexia-mediated increases in ICI CL.

Methods: A PK study was conducted utilizing a mutant IgG1 antibody that does not bind FcRs, D265A, and its wild-type IgG1 (WT) control in tumor-free and LLC mice. Mice were inoculated with LLC cells (n=20) or PBS (n=20). On day 14 post-inoculation, mice received a single 200 µg intravenous dose of either D265A or WT IgG1 and blood samples were collected for PK analysis at 1, 48, 96, 144, and 192 hours post dose. At day 22, mice were euthanized, and tissues were harvested.

Results: Mice in the LLC group displayed phenotypic effects of cancer-associated cachexia such as significant decreases in terminal tumor adjusted body weight, change in body weight over the course of the study, skeletal muscle mass, and adipose tissue mass compared to tumor-free mice. The CL of both WT IgG1 and D265A was increased in tumor-bearing mice compared to tumor-free mice. A covariate analysis revealed that presence of tumor, but not drug (p = 0.058), had a statistically significant effect upon CL. However, a multivariate analysis investigating both tumor and drug against the univariate models showed a significant effect on CL for both nested models, suggesting that the magnitude of tumor dependent increases in ICI CL is significantly impacted by FcR binding.

Conclusion: This supports a role for FcRs as a pathway of antibody catabolism in cachexia mediated increases in ICI CL.