A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity

Abstract

The CD40/CD40L axis plays a central role in the generation of humoral immune responses and is an attractive target for treating autoimmune diseases in the clinic. Here, we report the generation and clinical results of a CD40L binding protein, VIB4920, which lacks an Fc domain, therefore avoiding platelet-related safety issues observed with earlier monoclonal antibody therapeutics that targeted CD40L. VIB4920 blocked downstream CD40 signaling events, resulting in inhibition of human B cell activation and plasma cell differentiation, and did not induce platelet aggregation in preclinical studies. In a phase 1 study in healthy volunteers, VIB4920 suppressed antigen-specific IgG in a dose-dependent fashion after priming and boosting with the T-dependent antigen, KLH. Furthermore, VIB4920 significantly reduced circulating Ki67+ dividing B cells, class-switched memory B cells, and a plasma cell gene signature after immunization. In a phase 1b proof-of-concept study in patients with rheumatoid arthritis, VIB4920 significantly decreased disease activity, achieving low disease activity or clinical remission in more than 50% of patients in the two higher-dose groups. Dose-dependent decreases in rheumatoid factor autoantibodies and Vectra DA biomarker score provide additional evidence that VIB4920 effectively blocked the CD40/CD40L pathway. VIB4920 demonstrated a good overall safety profile in both clinical studies. Together, these data demonstrate the potential of VIB4920 to significantly affect autoimmune disease and humoral immune activation and to support further evaluation of this molecule in inflammatory conditions.

The enhanced immunopharmacology of VIB4920, a novel Tn3 fusion protein and CD40L antagonist, and assessment of its safety profile in cynomolgus monkeys

“…The pharmacological effect of VIB4920 was demonstrated in vivo through the dose‐dependent inhibition of antigen‐specific immune responses and the effects on B cells. VIB4920 showed a favourable safety and PK profile in our studies supporting the clinical investigation of VIB4920 in ongoing trials of autoimmune disease (NCT02151110; NCT02780388; Albulescu, ; Karnell et al, ).…”

“…VIB4920 effectively inhibited the KLH‐specific IgG and IgM antibody responses to secondary immunisation in all three studies. This finding was subsequently reproduced in the Phase 1a clinical study in healthy volunteers (Karnell et al, ). A recent Keystone Symposia talk (Ettinger, ) featured our cynomolgus study showing that VIB4920 inhibited the primary IgM response to KLH.…”

“…In our studies, none of the animals presented with a thromboembolic event. There were no adverse VIB4920‐related changes in any of the specialised clinical pathology parameters designed to detect evidence of thromboembolic events, nor was thrombosis noted in the clinical studies with VIB4920 (Karnell et al, ), further supporting the hypothesis that molecules lacking an intact Fc region (such as VIB4920) do not directly or indirectly (via interaction with ADA) induce such events.…”

“…VIB4920 has recently completed clinical studies for the evaluation of PK and efficacy (Karnell et al, ). In other clinical trials, single dose administration of CDP7657, an anti‐CD40L PEG‐Fab (dapirolizumab pegol), showed a t ½ of 6.25–16.1 days across the dose groups of 0.5–5 mg·kg −1 for healthy individuals and a t ½ of 8.59–14.6 days across the dose groups of 5–60 mg·kg −1 for patients with SLE (Tocoian et al, ).…”

“…Preclinical pharmacology studies have demonstrated that VIB4920 binds specifically to human CD40L with high affinity. In both in vitro functional platelet assessment systems and in vivo, no platelet activation occurred following VIB4920 administration suggesting that VIB4920 does not induce platelet‐mediated thrombogenic activity in humans (Karnell et al, ). VIB4920 may act as an immune modulator and therefore has potential therapeutic activity for a range of autoimmune diseases through CD40/CD40L blockade, including rheumatoid arthritis, systemic lupus erythematosus, primary Sjögren's syndrome, and idiopathic thrombocytopenic purpura.…”