Low-affinity FcγR interactions can decide the fate of novel human IgG-sensitised red blood cells and platelets.
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.
['Armour|Kathryn L|KL|', 'Smith|Cheryl S|CS|', 'Turner|Craig P|CP|', 'Kirton|Christopher M|CM|', 'Wilkes|Anthony M|AM|', 'Hadley|Andrew G|AG|', 'Ghevaert|Cedric|C|', 'Williamson|Lorna M|LM|', 'Clark|Michael R|MR|']
D016824:Antigens, Human Platelet D001792:Blood Platelets D002470:Cell Survival D004912:Erythrocytes D006801:Humans D007074:Immunoglobulin G D039661:Integrin beta3 D009000:Monocytes D009687:Nuclear Proteins D011485:Protein Binding D017452:Receptors, IgG D012204:Rh-Hr Blood-Group System D014157:Transcription Factors
Blocking antibody Fc engineering IgG effector function Low-affinity Fc receptors