Towards Safer Transfusion Therapies: The Role of Non-Inflammatory Fcy Receptor 1 Blockade

Abstract

Introduction

The ongoing need to reduce reliance on intravenous immunoglobulin (IVIg) in treating autoimmune and inflammatory diseases calls for novel, targeted therapeutic strategies. Given the adverse events linked with Fcγ receptor (FcγR) III blockade, this study investigates the therapeutic potential of targeting FcγRI, demonstrated herein to be non-inflammatory, offering a more specific and safer alternative to the generalized action of IVIg.

Objective

This work aims to develop an in vivo anti-FcγRI therapy as a more focused and safer alternative to both IVIg therapy and FcγRIII blockade, with potential implications for improving patient outcomes and quality of life.

Design and Methods

From a phage display library, novel anti-human FcγRI antibodies were selected based on their high affinity and specificity for FcγRI. These antibodies were characterized for their ability to block Fc-FcγRI interactions using a human macrophage cell line and to prevent macrophage-mediated phagocytosis of sensitized red blood cells. The inflammatory nature of anti-FcγRI antibodies, compared to those engaging FcγRIII, was assessed through temperature changes and cytokine responses in FcγR-humanized mice, as well as in C57BL/6 and BALB/c mice, providing a comprehensive safety profile.

Results

We developed five novel anti-human FcγRI antibodies, each demonstrating a significant ability to inhibit FcγRI-mediated phagocytosis in vitro, without eliciting adverse inflammatory responses in vivo. Notably, anti-FcγRI administration did not result in the temperature changes or inflammatory responses observed with anti-FcγRIII, highlighting the non-inflammatory benefits of FcγRI targeting.

Conclusions

Our findings support the development of anti-FcγRI antibodies as a promising, non-inflammatory therapeutic approach for transfusion medicine. This strategy not only has the potential to reduce the dependency on IVIg but also offers a safer and more specific method for modulating the immune response in patients.