Successful prenatal therapy for anti-CD36-mediated severe FNAIT by deglycosylated antibodies in a novel murine model

Abstract

Recent studies have demonstrated that maternal anti-CD36 antibodies represent a frequent cause of fetal/neonatal alloimmune thrombocytopenia (FNAIT) in Asian and African populations. However, little is known about the pathomechanism and antenatal treatment of anti-CD36-mediated FNAIT. Here, we established a novel animal model to examine the clinical features of pups from immunized Cd36-/- female mice after breeding with wild-type male mice. Mild thrombocytopenia was observed, but high pup mortality was also documented (40.26%). IVIG (1 g/kg) administration on days 7, 12, and 17 to immunized Cd36-/- mothers after breeding reduced fetal death (12.70%). However, delaying the IVIG administration series on days 10, 15, and 20 did not reduce fetal death (40.00%). In contrast, injection of deglycosylated anti-CD36 (deg-anti-CD36) polyclonal antibodies (5 mg/kg) on days 10, 15, and 20 significantly reduced fetal death (5.26%). Subsequently, monoclonal antibodies (mAbs) against mouse CD36 were developed, and one clone producing high-affinity anti-CD36 (termed 32-106) effectively inhibited maternal antibody binding and was therefore selected. Using the same approach of deg-anti-CD36, the administration of deg-32-106 significantly reduced fetal death (2.17%). Furthermore, immunized Cd36-/- mothers showed placenta deficiency. Accordingly, maternal anti-CD36 antibodies inhibited angiogenesis of placenta endothelial cells, which could be restored by deg-32-106. In summary, maternal anti-CD36 antibodies caused a high frequency of fetal death in our animal model, associated with placental dysfunction. This deleterious effect could be diminished by the antenatal administration of IVIG and deg-mAb 32-106. Interestingly, treatment with deg-32-106 appears more beneficial considering the lower dose, later start of treatment, and therapy success.

Mechanism and intervention of murine transfusion-related acute lung injury caused by anti-CD36 antibodies

“…Administration of the competitive inhibitor GZ1 F(ab')2 was only effective to prevent TRALI, but not as a post-TRALI remedy. This condition seemed different from FNAIT, in which deglycosylated GZ1 has been shown to prevent fetal death caused by anti-CD36 antibodies (20). Significant inhibition, however, was observed before TRALI onset, as well as post-TRALI, when NAC was administered intravenously together with inhalation of atomized NAC.…”

“…This reaction is not only dependent on the sex of the mice, but also on the Fc part of the antibodies, the presence of monocytes, ROS generation by monocytes, TNF-α production and C5 complement activation. The fact that anti-CD36 from human sera could also induce TRALI in our murine model is likely due to the high degree of homology (around 85%) between the human and mouse CD36 protein (32) and by the fact that most CD36 antibodies have been shown to react with immunodominant epitopes (20,33).…”

“…Type I CD36 deficiency is extremely rare in Caucasians but is found at relatively high frequency among Asians (> 0.5%) (17,18). In Asians, anti-CD36 plays a critical role in the pathological mechanism of platelet transfusion refractoriness (PTR) and fetal/neonatal alloimmune thrombocytopenia (FNAIT) (19)(20)(21)(22).…”

New Horizons in Fetal and Neonatal Alloimmune Thrombocytopenia

“…Furthermore, superior therapeutic effects have been recorded with lower doses and delayed intervention regimens compared with IVIG. 47 It remains to be evaluated if prophylactic treatment with these deglycosylated mAb is effective in ameliorating all the clinical complications associated with anti-CD-36 antibodies.…”

A case of platelet transfusion refractoriness in a CD36‐negative patient with acute myeloid leukemia: Diagnostic and therapeutic management

“…In conclusion, this case illustrates the difficulty in France of managing platelet inefficiencies in patients with anti‐CD36 iso‐immunization. The inefficiency of the desensitization procedure leads to a priority search for blood donors deficient in CD36, potentially in a registry of CD36 phenotyped blood donors in Europe or to use other therapeutic strategy such effector silencing monoclonal antibody against CD36 4 ; The screening for CD36 deficiency in blood donor can be facilitated by using flow cytometry instead to MAIPA. 5 …”