Low‐affinity FcγR interactions can decide the fate of novel human IgG‐sensitised red blood cells and platelets |
| |
| Authors: | Kathryn L. Armour Cheryl S. Smith Craig P. Turner Christopher M. Kirton Anthony M. Wilkes Andrew G. Hadley Cedric Ghevaert Lorna M. Williamson Michael R. Clark |
| |
| Affiliation: | 1. Department of Pathology, University of Cambridge, Cambridge, UK;2. Bristol Institute for Transfusion Sciences, Bristol, UK;3. NHS Blood and Transplant, Cambridge, UK;4. Department of Haematology, University of Cambridge, Cambridge, UK |
| |
| Abstract: | G1Δnab is a mutant human IgG1 constant region with a lower ability to interact with FcγR than the natural IgG constant regions. Radiolabelled RBCs and platelets sensitised with specific G1Δnab Abs were cleared more slowly from human circulation than IgG1‐sensitised counterparts. However, non‐destructive splenic retention of G1Δnab‐coated RBCs required investigation and plasma radioactivities now suggest this also occurred for platelets sensitised with an IgG1/G1Δnab mixture. In vitro assays with human cells showed that G1Δnab‐sensitised RBCs did not cause FcγRI‐mediated monocyte activation, FcγRIIIa‐mediated antibody‐dependent cell‐mediated cytotoxicity (ADCC) or macrophage phagocytosis although they did adhere to macrophages. Thus, FcγRII was implicated in the adhesion despite the Δnab mutation reducing the already low‐affinity binding to this receptor class. Additional contacts via P‐selectin enhance the interaction of sensitised platelets with monocytes and this system provided evidence of FcγRII‐dependent activation by G1Δnab. These results emphasise the physiological relevance of low‐affinity interactions: It appears that FcγRII interactions of G1Δnab allowed splenic retention of G1Δnab‐coated RBCs with inhibitory FcγRIIb binding preventing RBC destruction and that FcγRIIb engagement by G1Δnab on IgG1/G1Δnab‐sensitised platelets overcame activation by IgG1. Considering therapeutic blocking Abs, G1Δnab offers lower FcγR binding and a greater bias towards inhibition than IgG2 and IgG4 constant regions. |
| |
| Keywords: | Blocking antibody Fc engineering IgG effector function Low‐affinity Fc receptors |
|
|
