The in vivo and in vitro characterisation of an engineered human antibody to E-selectin

Anti-E-selectin is ineffective in the treatment of psoriasis: a randomized trial

“…CDP850 binds an epitope in the lectin/EGF region of E‐selectin and potently blocks the binding of CLA‐positive human lymphocytes to E‐selectin‐expressing cells in vitro . It also inhibits the tumour necrosis factor‐α‐mediated trafficking of leucocytes into human skin grafted on to SCID mice 15 . However, despite the theoretical potential of E‐selectin blockade as a selective and effective therapy for psoriasis, the results from our trial indicate that administration of CDP850, perhaps surprisingly, possesses little beneficial clinical efficacy in this condition.…”

“…Previous studies, in animal models, have shown that monoclonal antibodies to E‐selectin can block the recruitment of neutrophils and lymphocytes into sites of cutaneous inflammation. Using recombinant DNA techniques, a humanized monoclonal antibody (CDP850, previously known as SPLAT‐1), has been developed and found to possess a long circulating half‐life (greater than 14 days in humans) coupled with low immunogenicity 14,15 . CDP850 binds an epitope in the lectin/EGF region of E‐selectin and potently blocks the binding of CLA‐positive human lymphocytes to E‐selectin‐expressing cells in vitro .…”

“…As expression of E‐selectin is minimal on vascular endothelial cells in normal skin, an anti‐E‐selectin antibody should theoretically show little reactivity with the vasculature of uninflamed tissues. This feature of specificity, together with the recent molecular engineering of an adhesion‐blocking, humanized antibody with minimal effector functions (CDP850 previously designated SPLAT‐1), 14,15 suggests that such an antibody should be safe to administer to patients with psoriasis and may represent a highly specific form of immunomodulatory therapy. We thus performed a double‐blind, placebo‐controlled clinical study to investigate the safety profile and efficacy of CDP850 in the treatment of chronic plaque psoriasis.…”

The Fab Conformations in the Solution Structure of Human Immunoglobulin G4 (IgG4) Restrict Access to Its Fc Region

“…Other studies named Ser 222 as Ser 228 (22), Ser 229 (12), and Ser 241 (23). A mutant IgG4 with Pro 222 was generously supplied by Dr. Bryan Smith (UCB) (24). Both IgG4(Ser 222 ) and IgG4(Pro 222 ) were further purified by gel filtration to remove nonspecific aggregates using a Superose 6 10/300 column (GE Healthcare), concentrated using an Amicon Ultra spin concentrator (50-kDa-molecular mass cutoff), and dialyzed at 4 °C against the measurement buffer (see below).…”

P-Selectin Antagonism in Inflammatory Disease

“…Although no adverse reactions were observed in primates and this antibody was well tolerated in a randomized clinical trial, it failed to reduce the numbers of neutrophils and lymphocytes within the inflamed dermis of psoriasis patients and did not improve any disease symptoms [55,56]. Another (different) anti-E-selectin antibody was reported to reduce the inflammatory response when applied as a bolus injection immediately after experimental subarachnoid haemorrhage in mice [57].…”