Characterization of the in vitro and in vivo properties of CFZ533, a blocking and non-depleting anti-CD40 monoclonal antibody

Abstract

The CD40-CD154 costimulatory pathway is essential for T cell-dependent immune responses, development of humoral memory, and antigen presenting cell function. These immune functions have been implicated in the pathology of multiple autoimmune diseases as well as allograft rejection. We have generated CFZ533, a fully human, pathway blocking anti-CD40 monoclonal antibody that has been modified with a N297A mutation to render it unable to mediate Fcγ-dependent effector functions. CFZ533 inhibited CD154-induced activation of human leukocytes in vitro, but failed to induce human leukocyte activation. Additionally, CFZ533 was unable to mediate depletion of human CD40 expressing B cells. In vivo, CFZ533 blocked primary and recall T cell-dependent antibody responses in nonhuman primates and abrogated germinal formation without depleting peripheral blood B cells. We also established a relationship between plasma concentrations of CFZ533 and CD40 pathway-relevant pharmacodynamic effects in tissue. Collectively these data support the scientific rationale and posology for clinical utility of this antibody in select autoimmune diseases and solid organ transplantation.

First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody

“…[12][13][14] Several lines of preclinical evidence indicate that the CD40-CD154 pathway plays a key role in affected tissues in various autoimmune diseases and inflamed kidney allografts. [12][13][14] Several lines of preclinical evidence indicate that the CD40-CD154 pathway plays a key role in affected tissues in various autoimmune diseases and inflamed kidney allografts.…”

“…[12][13][14] Several lines of preclinical evidence indicate that the CD40-CD154 pathway plays a key role in affected tissues in various autoimmune diseases and inflamed kidney allografts. 11,12 These results suggest that iscalimab and other anti-CD40 mAbs may TA B L E 3 Incidence of adverse events reported by >5% of RA patients results suggest that iscalimab is an attractive immunomodulation pharmacotherapy for patients undergoing allograft transplantation or suffering from selected autoimmune diseases. 11,12 These results suggest that iscalimab and other anti-CD40 mAbs may TA B L E 3 Incidence of adverse events reported by >5% of RA patients results suggest that iscalimab is an attractive immunomodulation pharmacotherapy for patients undergoing allograft transplantation or suffering from selected autoimmune diseases.…”

“…Doserange selection for HS was determined by the expected extent and duration of target engagement of whole blood (WB) B cells based on iscalimab in vitro binding data, 12 and in vivo PK/PD data in NHP. Doserange selection for HS was determined by the expected extent and duration of target engagement of whole blood (WB) B cells based on iscalimab in vitro binding data, 12 and in vivo PK/PD data in NHP.…”

“…[5][6][7] Additionally, CD40 pathway stimulation in macrophages and dendritic cells regulates their activation and differentiation as well as antigen presentation to T cells. 1,11,12 Iscalimab has been demonstrated to block TDAR, GC formation, and prolong kidney allograft survival in nonhuman primates (NHP) 1 as well as provide an alternative to calcineurin inhibitor treatment regimens in clinical transplantation. This notion is supported by studies showing that pathway blockade reduced autoimmune disease pathology and prolonged kidney allograft survival.…”

“…Iscalimab (CFZ533) is a fully human, aglycosylated immunoglobulin (Ig)G1, nondepleting anti-CD40 antibody that blocks CD154 binding to CD40 and downstream pathway activation. 1,11,12 Iscalimab has been demonstrated to block TDAR, GC formation, and prolong kidney allograft survival in nonhuman primates (NHP) 1 as well as provide an alternative to calcineurin inhibitor treatment regimens in clinical transplantation. 13 Furthermore, a recent study indicated that iscalimab provided clinical benefit in primary SS.…”