{
  "abstract": "CD154, also known as CD40 ligand, is a costimulatory molecule involved in humoral and adaptive immune responses upon pairing with its classical receptor, CD40. 1 The CD154/CD40 dyad is a key participant in the pathogenesis of many autoimmune diseases, including systemic lupus erythematosus (SLE). In SLE, the major cells at play, T and B lymphocytes, are shown to overexpress CD154 and CD40, respectively. Many therapeutic strategies directed against the CD154/CD40 couple have been deployed for the treatment of SLE and proved efficient in animal models and human studies. However, the incidence of thromboembolic complications in patients treated with these anti-CD154/CD40 antibodies halted their further clinical assessments and called for another class of therapies targeting these molecules.Thromboembolic complications observed in clinical trials of the above first-generation anti-CD154 mAbs are believed to result from platelet activation and aggregation following ligation of anti-CD154 mAb-sCD154 immune complexes to Fc gamma receptors located on platelets’ surface. To eliminate the potential for thromboembolic events, second-generation anti-CD40L and anti-CD40 antibodies have been engineered with inert or absent Fc tails to reduce platelet activation while retaining full target binding. These second-generation antibodies show promising results in recent clinical trials.1 Dapirolizumab pegol or CDP7657 is a humanized anti-CD154 Fab fragment conjugated with polyethylene glycol, replacing its Fc region. In the PHOENYCS GO study (n=321), dapirolizumab pegol was administered intravenously every four weeks.2 On the primary endpoint, measuring improvement of moderate-to-severe disease activity as assessed by achievement of British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) after 48 weeks, study participants receiving dapirolizumab pegol plus standard of care (SOC) had a statistically significant, 14.6% (95% confidence interval: 3.3, 25.8; p=0.0110) higher, response rate (49.5%) than those receiving SOC alone (34.6%). BI655064 is a humanized antagonistic non-depleting anti-CD40 mAb with Fc region with two mutations that prevent Fc-mediated antibody-dependent or complement-mediated cellular cytotoxicity and platelet activation. Two phase II clinical trials investigating the use of BI655064 in lupus nephritis have recently been completed. Results indicate a link between BI655064 treatment and a reduction in Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) total score in patients with lupus nephritis. Iscalimab (CFZ533) is a fully human blocking non-depleting anti-CD40 mAb also mutated at its Fc region and incapable of stimulating Fc gamma receptors which is under development for the treatment of primary Sjogren’s syndrome and lupus nephritis.References Allard CC, Salti S, Mourad W, et al. Implications of CD154 and its receptors in the pathogenesis and treatment of systemic lupus erythematosus. Cells. 2024;13(19). doi: 10.3390/cells13191621Clowse M, Isenberg D, Merrill J, et al. Dapirolizumab pegol demonstrated significant improvement in systemic lupus erythematosus disease activity: efficacy and safety results of a phase 3 trial [abstract]. Arthritis Rheumatol. 2025;76(suppl 9).Learning Objectives At the end of this presentation participants will be able to:Describe the CD154/CD40 pathway in SLEExplain the thrombotic complications of first-generation antibodies targeting the CD154/CD40 pathwayDiscuss the second-generation antibodies targeting the CD154/CD40 pathway under development in SLE",
  "authors": [
    {
      "affiliations": [
        "French National Reference Center for SLE, Sorbonne University, Paris, France"
      ],
      "name": "Zahir Amoura"
    }
  ],
  "title": "20 Co-stimulation blockade of CD40/CD40L in SLE and beyond",
  "uid": "a6fff155-41ed-5628-b37a-c4de574d17cc"
}