Preventative and therapeutic effects of a novel humanized anti-glycoprotein Ibα fragment of antigen-binding region in a murine model of thrombotic thrombocytopenic purpura.

BACKGROUND

Thrombotic thrombocytopenic purpura (TTP) is a potentially fatal blood disorder resulting from severe deficiency of plasma ADAMTS-13 activity. Current treatment for immune-mediated TTP includes daily therapeutic plasma exchange plus caplacizumab and immunosuppressives. For hereditary TTP resulting from mutations of ADAMTS-13, plasma infusion or recombinant ADAMTS-13 is the treatment of choice. However, there are still unmet needs for an effective alternative therapy for TTP.

OBJECTIVES

The present study aimed to evaluate the therapeutic efficacy of a novel humanized antibody fragment of antigen binding against platelet glycoprotein Ibα (CA1001) in a murine model of TTP.

METHODS

Platelet agglutination profiles, microfluidic shear-based assay, intravital microscopy thrombosis model, and lysine histone-induced murine "TTP-like" model were employed.

RESULTS

CA1001 exhibited potent inhibition of botrocetin-induced murine platelet agglutination in a dose- and time-dependent manner. CA1001 also significantly inhibited shear-dependent adhesion and aggregation of murine platelets to endothelial von Willebrand factor (VWF) released from calcium ionophore-activated cremaster venules in Adamts-13 null mice and blocked the formation of platelet-VWF rich thrombosis. More importantly, CA1001 appeared to be efficacious in preventing and treating a histone-induced "TTP-like" syndrome in Adamts-13 null mice, demonstrated by the alleviation of thrombocytopenia, prerenal injury, and formation of microvascular thrombosis in major organ tissues.

CONCLUSION

CA1001 can effectively inhibit VWF-platelet interaction and thrombus formation under various (patho)physiological conditions. Thus, CA1001 may be a potential candidate for further development as a novel therapeutic for immune-mediated and hereditary TTP and perhaps for other inflammatory thrombotic disorders such as ischemic stroke.