Nonclinical Safety Assessment of CFZ533, a Fc-Silent Anti-CD40 Antibody, in Cynomolgus Monkeys

Abstract

CFZ533 is a pathway blocking, nondepleting anti-CD40 antibody that is in clinical development for inhibition of transplant organ rejection and therapy for autoimmune diseases. A 26-week GLP toxicity study in sexually mature Cynomolgus monkeys was conducted in order to support chronic application of CFZ533. CFZ533 was subcutaneously administered at doses up to 150 mg/kg/week and was safe and generally well tolerated. CFZ533 showed no adverse effects for cardiovascular, respiratory, and neurobehavioral endpoints, and no changes were observed for blood lymphocyte and platelet counts or blood coagulation markers. In line with the nondepleting nature of CFZ533, CD20+ B cells in the blood were only marginally reduced. A complete suppression of germinal center (GC) development in lymph nodes and spleen was the most prominent result of post-mortem histological investigations. This was corroborated by an abrogated T-dependent antibody response (TDAR) to the antigen Keyhole Limpet Hemocyanin (KLH) as well as an absence of anti-drug antibodies (ADAs) in the absence of B cell depletion as seen with immunophenotyping and histology. When serum levels of CFZ533 in recovery animals dropped levels necessary for full CD40 occupancy on B cells, all animals were able to mount a TDAR to KLH. All histological changes also reverted to normal appearance after recovery. In summary, CFZ533 was shown to be well tolerated and safe in the 26-week toxicity study with a distinct pharmacodynamic profile in histology and immune function.

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

“…These results are consistent with observations in nonclinical toxicology studies for iscalimab studies, 11 as well as clinical studies in kidney transplantation and primary SS, where iscalimab has been dosed for up to 2 years. These results are consistent with observations in nonclinical toxicology studies for iscalimab studies, 11 as well as clinical studies in kidney transplantation and primary SS, where iscalimab has been dosed for up to 2 years.…”

“…need to access affected tissue in sufficient concentrations to enable full pathway blockade 11. In this study, almost complete CD40 RO on WB B cells was achieved at iscalimab plasma concentrations from 0.3 to 0.4 µg/mL, which are levels sufficient for suppression of ex vivo rCD154-induced activation markers in WB.…”

“…[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.…”

“…[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.…”

“…need to access affected tissue in sufficient concentrations to enable full pathway blockade 11. Previously published data indicated that ≈10-fold higher concentrations of iscalimab in plasma were associated with complete suppression of lymph node GCs in cynomolgus monkeys 11. Previously published data indicated that ≈10-fold higher concentrations of iscalimab in plasma were associated with complete suppression of lymph node GCs in cynomolgus monkeys 11.…”