Modulation Of Antibody-Dependent Cytokine Release Using Fc Engineering

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Antibodies can elicit multiple functions through its Fc region, including cell-killing through antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxity (CDC) and antibody-dependent cellular phagocytosis (ADCP). In addition to the cell-killing functions, antibodies also mediate antibody-dependent cytokine release (ADCR). In this study, we demonstrate that ADCR is regulated differentially in PBMC and macrophages. ADCR is FcγRIII-dependent in PBMC and mediated by NK cells. In contrast, ADCR in macrophages is FcγRI-dependent. In PBMC, ADCR is characterized by expression of primarily pro-inflammatory cytokines including IFN-γ, IL-1α, IL-1s, TNF-α. Meanwhile in macrophages, ADCR results in a mixture of the anti-inflammatory cytokine IL-10 and pro-inflammatory cytokines including IFN-γ, IL-1α, IL-1s, TNF-α, and RANTES. Using an Fc engineering approach, we generated antibody variants lacking FcγRI binding while maintaining binding to FcγRIIa and FcγRIII. These variants retain ADCC and ADCR in PBMC, but modulate ADCP without eliciting cytokine release in macrophages, separating the two processes. Ultimately, a better understanding of how cytokine release is regulated by antibodies and of strategies to modulate cytokine release through Fc engineering could be used to influence immune cell fate decisions in vivo. Citation Format: Michelle Kinder, Allison Greenplate, William Strohl, Robert Jordan, Randall Brezski. Modulation of antibody-dependent cytokine release using Fc engineering. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 638. doi:10.1158/1538-7445.AM2015-638