Therapeutic targeting of FcgRIIb on B cells in SLE
B cells play a central role in SLE pathogenesis, and therapeutic targeting of B cells has emerged as an attractive approach. Experience accrued to date strongly suggests that the clinical efficacy of a B cell-targeted approach requires the global disarming of autoreactive B cells, whereas clinical safety requires survival of the protective non-autoreactive B cells. Accordingly, a preferred B cell-targeted approach in SLE should be one which inhibits, rather than depletes, B cells.
Inhibition, rather than depletion, is naturally employed by the immune system. Immune complexes (IC) down-regulate ongoing immune responses by co-engaging cognate BCR with FcgRIIb. By extension, a candidate therapeutic that co-engages FcgRIIb and the BCR complex on all B cells should potently inhibit B cells (including pathogenic autoreactive B cells) and, in the context of SLE, dramatically ameliorate disease.
XmAb5871 is a mAb which bears a humanized Fv against human CD19 (part of the BCR complex) and whose Fc domain is genetically engineered to display ~430-fold greater affinity for human FcgRIIb relative to that of native human IgG1. XmAb5781, but not anti-CD19 mAb bearing native Fc, strongly inhibits BCR-induced calcium mobilization of primary human B cells from both normal and SLE donors without physically depleting the B cells from the cultures. In addition, initial experiments indicate that XmAb5781 not only inhibits ex vivo activation of B cells but also inhibits in vivo antibody responses generated in immunodeficient SCID mice engrafted with SLE peripheral blood mononuclear cells (SLE-huSCID mice). Thus, a single agent that effects high-affinity co-engagement of the BCR complex and FcgRIIb can potently inhibit the activation/function of SLE B cells.
We propose to extend our initial observations to a model in which clinical disease reliably develops. To that end, we have spent the past three years generating SLE-prone NZM 2328 mice that have the human FcgRIIb gene knocked in (NZM.hRIIb mice), and we propose to test the murine surrogate of XmAb5781 (XENP8206, which bears the same fully human FcgRIIb-enhanced Fc domain as does XmAb5871 but recognizes murine CD19 rather than human CD19) in this bona fide model of SLE which is unique to our laboratory. We will assess the effects of in vivo high-affinity BCR/FcgRIIb co-engagement on B cell activation in NZM.hRIIb mice as well as the effects of such high-affinity BCR/FcgRIIb co-engagement on the clinical, immunological, and pathological features of SLE in these mice.
We anticipate that our studies will lay the foundation for rapid translation of our approach into human SLE clinical trials.