Inducible T-cell co-stimulator ligand (ICOSL) blockade leads to selective inhibition of anti-KLH IgG responses in subjects with systemic lupus erythematosus

Abstract

ObjectivesTo evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single-dose and multiple-dose administration of AMG 557, a human anti-inducible T cell co-stimulator ligand (ICOSL) monoclonal antibody, in subjects with systemic lupus erythematosus (SLE).MethodsPatients with mild, stable SLE (n=112) were enrolled in two clinical trials to evaluate the effects of single (1.8–210 mg subcutaneous or 18 mg intravenous) and multiple (6 –210 mg subcutaneous every other week (Q2W)×7) doses of AMG 557. Subjects received two 1 mg intradermal injections 28 days apart of keyhole limpet haemocyanin (KLH), a neoantigen, to assess PD effects of AMG 557. Safety, PK, target occupancy, anti-KLH antibody responses, lymphocyte subset analyses and SLE-associated biomarkers and clinical outcomes were assessed.ResultsAMG 557 demonstrated an acceptable safety profile. The PK properties were consistent with an antibody directed against a cell surface target, with non-linear PK observed at lower concentrations and linear PK at higher concentrations. Target occupancy by AMG 557 was dose dependent and reversible, and maximal occupancy was achieved in the setting of this trial. Anti-AMG 557 antibodies were observed, but none were neutralising and without impact on drug levels. A significant reduction in the anti-KLH IgG response was observed with AMG 557 administration without discernible changes in the anti-KLH IgM response or on the overall IgG levels. No discernible changes were seen in lymphocyte subsets or in SLE-related biomarkers and clinical measures.ConclusionsThe selective reduction in anti-KLH IgG demonstrates a PD effect of AMG 557 in subjects with SLE consistent with the biology of the ICOS pathway and supports further studies of AMG 557 as a potential therapeutic for autoimmune diseases.Trial registration numbersNCT02391259 and NCT00774943.

Emerging Treatment Models in Rheumatology: IgG4‐Related Disease: Insights Into Human Immunology and Targeted Therapies

“…Targeting certain surface markers that are specific for T FH cells and only expressed after antigen activation are currently being explored in SLE and Sjögren’s syndrome with AMG-557, a neutralizing mAb directed against the inducible T cell co-stimulatory ligand (ICOS-L). 66 , 67 Further studies on T FH cells in IgG4-RD are needed before the pursuit of such therapeutic strategies could be justified.…”

Immunopathogenesis of granulomas in chronic autoinflammatory diseases

“…168 A monoclonal antibody targeting ICOSL, AMG-557, has been developed and is currently undergoing the first trial in systemic lupus erythematosus. 169 While treatment targeting the ICOS/ICOSL pathway is still under development, it is a potential target of interest for granulomatous inflammatory diseases, because ICOS/ICOSL is an implicated pathway in both sarcoidosis and Crohn's disease. Moreover, targeting this costimulatory pathway affects both T- and B-cell activation without their cellular depletion.…”

“…Moreover, targeting this costimulatory pathway affects both T- and B-cell activation without their cellular depletion. 169 …”

“…Moreover, targeting this costimulatory pathway affects both T-and B-cell activation without their cellular depletion. 169 Finally, alternative approaches to target B cells are promising therapeutics. Currently, belimumab, a monoclonal antibody targeting BAFF, is currently implemented in the treatment of systemic lupus erythematosus.…”

Novel innate and adaptive lymphocytes: The new players in the pathogenesis of inflammatory upper airway diseases

“…Anti-TSLP (AMG157), anti-IL-33 and anti-IL-25 antibody Inhibiting transcription factors such as GATA-3 (SB010) CRTH2 antagonist (BI 671800) IL-4Ra monoclonal antibody (Dupilumab) IL-5 monoclonal antibody (Mepolizumab) 6,[110][111][112][113][114] Th22 cells Anti-IL-22 monoclonal antibody (ILV-094) IL-12/IL-23p40 antagonist (Ustekinumab) Avoiding diesel exhaust particle [115][116][117] Th9 cells Anti-IL-9 monoclonal antibody (MEDI-528) Anti-TNFa antibody (Infliximab) Anti-IL-25 antibody [119][120][121] Tfh cells Anti-ICOS ligand antibody (AMG557) Anti-IL-21 antibody (NNC0114-0006) Anti-CXCL13 antibody (VX5) Anti-PD-1 antibody (BMS-936558) Small molecules targeting STAT3 (ISIS-STAT3Rx/AZD9150) CTLA4-IgFc fusion protein (Abatacept) [122][123][124][125][126] Bregs Ex vivo expanded autologous Bregs transfer…”