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

Sullivan BA, Tsuji W, Kivitz A, Peng J, Arnold GE, Boedigheimer MJ, Chiu K, Green CL, Kaliyaperumal A, Wang C, Ferbas J, Chung JB - Lupus Sci Med (2016)

Bottom Line: AMG 557 demonstrated an acceptable safety profile.The 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.NCT02391259 and NCT00774943.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Sciences , Amgen Inc., One Amgen Center Drive , Thousand Oaks, California , USA.

ABSTRACT

Objectives: To 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).

Methods: Patients 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.

Results: AMG 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.

Conclusions: The 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 numbers: NCT02391259 and NCT00774943.

No MeSH data available.


Related in: MedlinePlus

Study schemas. Upper panel: single-ascending dose study. Subjects with mild, stable systemic lupus erythematosus (SLE) were randomised to receive placebo or AMG 557 at 1.8, 6, 18, 60, 140 and 210 mg subcutaneously (SC) or 18 mg intravenously (IV) in seven sequential rising-dose cohorts. Subjects were immunised with both a prime and boost consisting of a 1 mg intradermal injection of keyhole limpet haemocyanin (KLH) on days 2 and 29 (for 60 mg SC cohort), days 8 and 36 (for 140 and 210 mg SC cohorts), and days 15 and 43. Lower panel: multiple-ascending dose study. Subjects with mild, stable SLE were randomised to receive placebo or AMG 557 at 6, 18, 30, 45, 70, 140  or 210 mg subcutaneously in seven sequential rising-dose cohorts. Subjects were administered AMG 557 or placebo on days 1, 15, 29, 43, 57, 71 and 85. Subjects were immunised with KLH on days 57 and 85. EOS, end of study.
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LUPUS2016000146F1: Study schemas. Upper panel: single-ascending dose study. Subjects with mild, stable systemic lupus erythematosus (SLE) were randomised to receive placebo or AMG 557 at 1.8, 6, 18, 60, 140 and 210 mg subcutaneously (SC) or 18 mg intravenously (IV) in seven sequential rising-dose cohorts. Subjects were immunised with both a prime and boost consisting of a 1 mg intradermal injection of keyhole limpet haemocyanin (KLH) on days 2 and 29 (for 60 mg SC cohort), days 8 and 36 (for 140 and 210 mg SC cohorts), and days 15 and 43. Lower panel: multiple-ascending dose study. Subjects with mild, stable SLE were randomised to receive placebo or AMG 557 at 6, 18, 30, 45, 70, 140  or 210 mg subcutaneously in seven sequential rising-dose cohorts. Subjects were administered AMG 557 or placebo on days 1, 15, 29, 43, 57, 71 and 85. Subjects were immunised with KLH on days 57 and 85. EOS, end of study.

Mentions: The study designs and dose-escalation schedule are summarised in figure 1. The studies were carried out in accordance with the ethical principles set forth in the Declaration of Helsinki and the International Conference on Harmonization E6 Guidance for Good Clinical Practice. The sites and ethics committees that granted approval for these studies are listed in online supplementary appendix A.


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

Sullivan BA, Tsuji W, Kivitz A, Peng J, Arnold GE, Boedigheimer MJ, Chiu K, Green CL, Kaliyaperumal A, Wang C, Ferbas J, Chung JB - Lupus Sci Med (2016)

Study schemas. Upper panel: single-ascending dose study. Subjects with mild, stable systemic lupus erythematosus (SLE) were randomised to receive placebo or AMG 557 at 1.8, 6, 18, 60, 140 and 210 mg subcutaneously (SC) or 18 mg intravenously (IV) in seven sequential rising-dose cohorts. Subjects were immunised with both a prime and boost consisting of a 1 mg intradermal injection of keyhole limpet haemocyanin (KLH) on days 2 and 29 (for 60 mg SC cohort), days 8 and 36 (for 140 and 210 mg SC cohorts), and days 15 and 43. Lower panel: multiple-ascending dose study. Subjects with mild, stable SLE were randomised to receive placebo or AMG 557 at 6, 18, 30, 45, 70, 140  or 210 mg subcutaneously in seven sequential rising-dose cohorts. Subjects were administered AMG 557 or placebo on days 1, 15, 29, 43, 57, 71 and 85. Subjects were immunised with KLH on days 57 and 85. EOS, end of study.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836284&req=5

LUPUS2016000146F1: Study schemas. Upper panel: single-ascending dose study. Subjects with mild, stable systemic lupus erythematosus (SLE) were randomised to receive placebo or AMG 557 at 1.8, 6, 18, 60, 140 and 210 mg subcutaneously (SC) or 18 mg intravenously (IV) in seven sequential rising-dose cohorts. Subjects were immunised with both a prime and boost consisting of a 1 mg intradermal injection of keyhole limpet haemocyanin (KLH) on days 2 and 29 (for 60 mg SC cohort), days 8 and 36 (for 140 and 210 mg SC cohorts), and days 15 and 43. Lower panel: multiple-ascending dose study. Subjects with mild, stable SLE were randomised to receive placebo or AMG 557 at 6, 18, 30, 45, 70, 140  or 210 mg subcutaneously in seven sequential rising-dose cohorts. Subjects were administered AMG 557 or placebo on days 1, 15, 29, 43, 57, 71 and 85. Subjects were immunised with KLH on days 57 and 85. EOS, end of study.
Mentions: The study designs and dose-escalation schedule are summarised in figure 1. The studies were carried out in accordance with the ethical principles set forth in the Declaration of Helsinki and the International Conference on Harmonization E6 Guidance for Good Clinical Practice. The sites and ethics committees that granted approval for these studies are listed in online supplementary appendix A.

Bottom Line: AMG 557 demonstrated an acceptable safety profile.The 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.NCT02391259 and NCT00774943.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Sciences , Amgen Inc., One Amgen Center Drive , Thousand Oaks, California , USA.

ABSTRACT

Objectives: To 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).

Methods: Patients 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.

Results: AMG 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.

Conclusions: The 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 numbers: NCT02391259 and NCT00774943.

No MeSH data available.


Related in: MedlinePlus