Wolf, Babette, Jeliazkova-Mecheva, Valentina, Del Rio Espinola, Alberto, Cochin de Billy, Benjamin, Boisclair, Julie, Walker, Dana, Flaherty, Meghan and Flandre, Thierry (2021) An afucosylated anti-CD32b monoclonal antibody induced platelet-mediated adverse events in human Fcg receptor transgenic mouse model and its potential human translatability. Toxicological sciences. ISSN 1096-0929; 1096-6080

Abstract

A monoclonal, afucosylated, anti-CD32b (FCGR2B) antibody, NVS32b, was developed internally as a therapeutic candidate for treatment of B-cell malignancies. To assess its safety and tolerability, a humanized transgenic (Tg) mouse model that reportedly expresses all human Fc gamma receptors (FCGRs) while lacking all mouse FCGRs was used. Prior to its use, the model was extensively characterized and found to express all human FCGRs in a pattern similar to humans, with some deviations, such as low CD32 expression on T cells, substantial individual variation in the transgene copy number, integration of additional human genes, and overall higher expression of all FCGRs on myeloid cells compared to human. Unexpectedly, NVS32b induced severe thrombosis in huFCGR mice. The mechanism and relevance for human was further investigated. Species differences, in the NVS32b-driven in vitro platelet binding, activation and aggregation were observed (CD32a-binding by Fc and CDR of NVS32b causing platelet activation in huFCGR mice opposing to CD32a-binding by Fc and off-target-binding by CDR of NVS32b only after platelet activation in human). Therefore huFCGR mice may not be fully predictive of the risk of NVS32b-induced thromboembolic events in the clinic. Nevertheless the program was terminated as a result of this potential safety liability. This model could be considered beneficial in the pre-clinical research of immunotherapies targeting or involving FCGRs. While potential biological implications resulting from the differences in theFCGR expression pattern in humans cannot be predicted, these deviations should be considered and further evaluated when using this huFCGR mouse model.

Item Type:	Article
Keywords:	human FcgR transgenic mouse model, CD32b, Fc enhancement, platelets, thrombosis
Date Deposited:	25 Nov 2021 00:45
Last Modified:	25 Nov 2021 00:45
URI:	https://oak.novartis.com/id/eprint/44109