First-in-human trial of the safety, pharmacokinetics and immunogenicity of a PEGylated anti-CD40L antibody fragment (CDP7657) in healthy individuals and patients with systemic lupus erythematosus

Abstract

Single doses of CDP7657 showed predictable PK in healthy individuals and patients with SLE and were well tolerated, with no safety signals of concern. These findings support further investigation of CDP7657 as a therapy for SLE.

Repeated administration of dapirolizumab pegol in a randomised phase I study is well tolerated and accompanied by improvements in several composite measures of systemic lupus erythematosus disease activity and changes in whole blood transcriptomic profiles

“…These safety findings are comparable with those from a previous single-dose, double-blind, first-in-human, phase I study of dapirolizumab pegol (NCT01093911). 29 None of the study subjects experienced any dose limiting toxicities and no thromboembolic events were reported 29…”

Anti-PEG antibodies in the clinic: Current issues and beyond PEGylation

“…This result explains why PEGylated nonhuman enzymes, e.g., uricase and asparaginase, have been reported to present the most severe issues resulting from anti-PEG Abs, whereas others are relatively safer. [49, 51, 52] Another key finding from this study is that the degree of modification is a crucial factor determining PEG-protein conjugate immunogenicity, as more PEG chains on a protein elicited weaker antibody responses, possibly due to better masking of immunogenic epitopes. Finally, it has been determined that anti-PEG Ab binds to 6–7 ethylene glycol repeating units.…”

“…Anti-PEG Abs have also been found in pre-treatment sera or untreated controls in clinical trials. [16–18, 46, 49, 51] The mechanism of anti-PEG Ab generation in individuals who have never received PEGylated therapeutics has not been clearly studied yet. However it is likely to be related with the increased daily exposure to PEG-containing household, hygiene and cosmetic products.…”

Update on Biologic Therapies for Systemic Lupus Erythematosus

“…After the underlying mechanism for thromboembolic events associated with anti-CD40L antibody therapy was found to be platelet activation via the IgG (FcγRIIa) receptor [112], further research led to the development of CDP7657, a PEGylated monovalent Fab' anti-CD40L fragment lacking a Fc domain, which does not induce thrombosis but still improves renal disease in lupus-prone mice [113]. Predictable PK and acceptable tolerability of CDP7657 in healthy individuals and in SLE patients were seen in a phase I RCT, supporting its further clinical development [114].…”