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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

ICOSL target occupancy and the pharmacokinetics/pharmacodynamic relationship. (A) ICOSL target occupancy on circulating B cells from the multiple-ascending dose (MAD) study is shown by dose and visit (placebo: 0 mg and AMG 557: 6, 18, 30, 45, 70, 140 and 210 mg). Means from each applicable visit from day 1 to day 253 are graphed and coloured in chronological order within each dose group along with and 95% CIs. The baseline 95% CI of all data points is shown as a grey band. (B) The relationship between AMG 557 serum concentration and ICOSL target occupancy on circulating B cells from the combined single-ascending dose and MAD studies. ICOSL target occupancy is shown on the y-axis, and AMG 557 serum concentration on the x-axis. The observed data are shown as solid black symbols, and the model-predicted median and 80% prediction interval are shown as a solid line and blue shaded area. (C) Relationship between AMG 557 trough concentration at steady state with AMG 557 dose. The model-estimated IC99 (with 95% CI) for the AMG 557 target occupancy is shown as a coloured bar.
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LUPUS2016000146F3: ICOSL target occupancy and the pharmacokinetics/pharmacodynamic relationship. (A) ICOSL target occupancy on circulating B cells from the multiple-ascending dose (MAD) study is shown by dose and visit (placebo: 0 mg and AMG 557: 6, 18, 30, 45, 70, 140 and 210 mg). Means from each applicable visit from day 1 to day 253 are graphed and coloured in chronological order within each dose group along with and 95% CIs. The baseline 95% CI of all data points is shown as a grey band. (B) The relationship between AMG 557 serum concentration and ICOSL target occupancy on circulating B cells from the combined single-ascending dose and MAD studies. ICOSL target occupancy is shown on the y-axis, and AMG 557 serum concentration on the x-axis. The observed data are shown as solid black symbols, and the model-predicted median and 80% prediction interval are shown as a solid line and blue shaded area. (C) Relationship between AMG 557 trough concentration at steady state with AMG 557 dose. The model-estimated IC99 (with 95% CI) for the AMG 557 target occupancy is shown as a coloured bar.

Mentions: Relative target occupancy was assessed on B cells in the peripheral blood using a semiquantitative flow cytometric assay in both studies. Overall, the degree of ICOSL target occupancy by AMG 557 was found to be dose-related and reversible, sustaining maximal levels in the higher dose groups in the MAD study (figure 3A). Similar results were observed with the SAD study. There was a dose-related increase in total ICOSL levels on peripheral B cells and a dose-related decrease in free ICOSL on peripheral B cells (data not shown), consistent with preclinical studies of a mouse surrogate anti-ICOSL antibody.42 The relative RO in figure 3A was calculated using baseline-free and total ICOSL as a comparator. The relative RO was at times ‘negative’ due to a fall in total ICOSL levels and a rise in free ICOSL levels after the last dose beyond measured baseline levels, resulting in a negative number using the equation as described in ‘Materials and methods’. This is a consequence of the fluctuating levels of ICOSL and the variability of the assay.


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)

ICOSL target occupancy and the pharmacokinetics/pharmacodynamic relationship. (A) ICOSL target occupancy on circulating B cells from the multiple-ascending dose (MAD) study is shown by dose and visit (placebo: 0 mg and AMG 557: 6, 18, 30, 45, 70, 140 and 210 mg). Means from each applicable visit from day 1 to day 253 are graphed and coloured in chronological order within each dose group along with and 95% CIs. The baseline 95% CI of all data points is shown as a grey band. (B) The relationship between AMG 557 serum concentration and ICOSL target occupancy on circulating B cells from the combined single-ascending dose and MAD studies. ICOSL target occupancy is shown on the y-axis, and AMG 557 serum concentration on the x-axis. The observed data are shown as solid black symbols, and the model-predicted median and 80% prediction interval are shown as a solid line and blue shaded area. (C) Relationship between AMG 557 trough concentration at steady state with AMG 557 dose. The model-estimated IC99 (with 95% CI) for the AMG 557 target occupancy is shown as a coloured bar.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4836284&req=5

LUPUS2016000146F3: ICOSL target occupancy and the pharmacokinetics/pharmacodynamic relationship. (A) ICOSL target occupancy on circulating B cells from the multiple-ascending dose (MAD) study is shown by dose and visit (placebo: 0 mg and AMG 557: 6, 18, 30, 45, 70, 140 and 210 mg). Means from each applicable visit from day 1 to day 253 are graphed and coloured in chronological order within each dose group along with and 95% CIs. The baseline 95% CI of all data points is shown as a grey band. (B) The relationship between AMG 557 serum concentration and ICOSL target occupancy on circulating B cells from the combined single-ascending dose and MAD studies. ICOSL target occupancy is shown on the y-axis, and AMG 557 serum concentration on the x-axis. The observed data are shown as solid black symbols, and the model-predicted median and 80% prediction interval are shown as a solid line and blue shaded area. (C) Relationship between AMG 557 trough concentration at steady state with AMG 557 dose. The model-estimated IC99 (with 95% CI) for the AMG 557 target occupancy is shown as a coloured bar.
Mentions: Relative target occupancy was assessed on B cells in the peripheral blood using a semiquantitative flow cytometric assay in both studies. Overall, the degree of ICOSL target occupancy by AMG 557 was found to be dose-related and reversible, sustaining maximal levels in the higher dose groups in the MAD study (figure 3A). Similar results were observed with the SAD study. There was a dose-related increase in total ICOSL levels on peripheral B cells and a dose-related decrease in free ICOSL on peripheral B cells (data not shown), consistent with preclinical studies of a mouse surrogate anti-ICOSL antibody.42 The relative RO in figure 3A was calculated using baseline-free and total ICOSL as a comparator. The relative RO was at times ‘negative’ due to a fall in total ICOSL levels and a rise in free ICOSL levels after the last dose beyond measured baseline levels, resulting in a negative number using the equation as described in ‘Materials and methods’. This is a consequence of the fluctuating levels of ICOSL and the variability of the assay.

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