Heterogeneity of Platelet Fc-receptor-dependent Response to Activating Monoclonal Antibodies

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Abstract
Platelet activation induced by monoclonal antibodies (mAB) was studied using three stimulatory mAB (all IgG1) against different platelet surface glycoproteins: VM58 against GPIV, LeoAl against PTA1, and FMC 56 against CD9. F(ab')2 fragments of these antibodies failed to activate platelets themselves but blocked platelet aggregation induced by the relevant intact antibody. Platelet aggregation was also completely blocked by the anti-FcγRII (Fc-receptor) monoclonal antibody, IV.3. A heterogeneity of platelet response to stimulatory mAB was observed amongst normal donors. All three antibodies added to platelet-rich plasma (PRP) from responders induced full platelet aggregation and dense body release. However, in PRP from nonresponders, VM58 and LeoAl did not induce platelet activation whilst FMC 56 activated platelets but to a lesser extent than in responders (longer lag phase and reduced release). The ratio of responders to nonresponders was ∼ 1:1 (n = 110). The heterogeneity was not due to differences in the copy number of either the antigen (VM58) or FcγRII. The ability of donor platelets to be aggregated by stimulatory mAB in PRP correlated with the ability of these platelets to respond to aggregated murine IgG1 (mAB irrelevant to platelets). The combined results suggest that both the Fab and Fc region of stimulatory mAB are necessary in order to induce a platelet response and that this response is mediated through FcγRII. The difference between responders and nonresponders can be explained by the known polymorphism of FcγRII (Looney et al, 1988) and the capacity of the polymorphic forms of FcγRII to bind and to respond to murine IgG1.