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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

Pharmacodynamic effect of AMG 557—inhibition of the anti-keyhole limpet haemocyanin (KLH) IgG response. Anti-IgM and anti-IgG responses are shown for the placebo subjects and the aggregate AMG 557-treated subjects from the single-ascending dose (SAD) (A and B) and multiple-ascending dose (MAD) (C and D) studies. Data are shown for all four graphs by time following the first KLH immunisation on the x-axis and baseline-adjusted anti-KLH IgM (A and C) and anti-KLH IgG (B and D) values. The second KLH immunisation was administered approximately four weeks later (arrow). The fold change over baseline is shown on the right y-axis and the baseline-adjusted value (median fluorescence intensity (MFI) for IgM and concentration for IgG) is shown on the left y-axis; the dashed line indicates a fold change of 1. All AMG 557 doses were pooled for comparison to the placebo group. The number of values per symbol is indicated at the top of each graph. The plots show the mean±SEM.
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LUPUS2016000146F4: Pharmacodynamic effect of AMG 557—inhibition of the anti-keyhole limpet haemocyanin (KLH) IgG response. Anti-IgM and anti-IgG responses are shown for the placebo subjects and the aggregate AMG 557-treated subjects from the single-ascending dose (SAD) (A and B) and multiple-ascending dose (MAD) (C and D) studies. Data are shown for all four graphs by time following the first KLH immunisation on the x-axis and baseline-adjusted anti-KLH IgM (A and C) and anti-KLH IgG (B and D) values. The second KLH immunisation was administered approximately four weeks later (arrow). The fold change over baseline is shown on the right y-axis and the baseline-adjusted value (median fluorescence intensity (MFI) for IgM and concentration for IgG) is shown on the left y-axis; the dashed line indicates a fold change of 1. All AMG 557 doses were pooled for comparison to the placebo group. The number of values per symbol is indicated at the top of each graph. The plots show the mean±SEM.

Mentions: No statistically significant changes were seen in the anti-KLH IgM responses in either study (figure 4A,C). No statistically significant changes to anti-KLH IgG antibodies were observed in the SAD study (figure 4B). In the MAD study, the anti-KLH IgG antibody responses throughout the study period were significantly lower in the combined AMG 557-treated subjects compared with the combined placebo subjects from all the cohorts (p=0.0044) (figure 4D). Individual dose cohorts of AMG 557, compared with placebo, did not reach statistical significance. Also, 9 of the 56 subjects were found to have detectable levels (>250 ng/mL) of anti-KLH IgG antibodies prior to the first immunisation in the study, potentially confounding the assessment of primary and secondary responses to KLH in the study. A post hoc analysis was conducted excluding these subjects (figure 5), showing a clearer visual trend of a dose response. The reduction in KLH-specific IgG and lack of impact on the KLH-specific IgM was consistent with human and mouse genetic studies and in studies of pharmacological blockade in mice.11131442 An analysis of the relationship between the AUC) for AMG 557 serum concentrations and AUC for the anti-KLH IgG response is shown in figure 5C. This approach takes into account the impact of magnitude and duration of ICOSL blockade. Collectively, these analyses show a general dose response with maximal inhibition of the anti-KLH IgG response occurring at around 70 mg.


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)

Pharmacodynamic effect of AMG 557—inhibition of the anti-keyhole limpet haemocyanin (KLH) IgG response. Anti-IgM and anti-IgG responses are shown for the placebo subjects and the aggregate AMG 557-treated subjects from the single-ascending dose (SAD) (A and B) and multiple-ascending dose (MAD) (C and D) studies. Data are shown for all four graphs by time following the first KLH immunisation on the x-axis and baseline-adjusted anti-KLH IgM (A and C) and anti-KLH IgG (B and D) values. The second KLH immunisation was administered approximately four weeks later (arrow). The fold change over baseline is shown on the right y-axis and the baseline-adjusted value (median fluorescence intensity (MFI) for IgM and concentration for IgG) is shown on the left y-axis; the dashed line indicates a fold change of 1. All AMG 557 doses were pooled for comparison to the placebo group. The number of values per symbol is indicated at the top of each graph. The plots show the mean±SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

LUPUS2016000146F4: Pharmacodynamic effect of AMG 557—inhibition of the anti-keyhole limpet haemocyanin (KLH) IgG response. Anti-IgM and anti-IgG responses are shown for the placebo subjects and the aggregate AMG 557-treated subjects from the single-ascending dose (SAD) (A and B) and multiple-ascending dose (MAD) (C and D) studies. Data are shown for all four graphs by time following the first KLH immunisation on the x-axis and baseline-adjusted anti-KLH IgM (A and C) and anti-KLH IgG (B and D) values. The second KLH immunisation was administered approximately four weeks later (arrow). The fold change over baseline is shown on the right y-axis and the baseline-adjusted value (median fluorescence intensity (MFI) for IgM and concentration for IgG) is shown on the left y-axis; the dashed line indicates a fold change of 1. All AMG 557 doses were pooled for comparison to the placebo group. The number of values per symbol is indicated at the top of each graph. The plots show the mean±SEM.
Mentions: No statistically significant changes were seen in the anti-KLH IgM responses in either study (figure 4A,C). No statistically significant changes to anti-KLH IgG antibodies were observed in the SAD study (figure 4B). In the MAD study, the anti-KLH IgG antibody responses throughout the study period were significantly lower in the combined AMG 557-treated subjects compared with the combined placebo subjects from all the cohorts (p=0.0044) (figure 4D). Individual dose cohorts of AMG 557, compared with placebo, did not reach statistical significance. Also, 9 of the 56 subjects were found to have detectable levels (>250 ng/mL) of anti-KLH IgG antibodies prior to the first immunisation in the study, potentially confounding the assessment of primary and secondary responses to KLH in the study. A post hoc analysis was conducted excluding these subjects (figure 5), showing a clearer visual trend of a dose response. The reduction in KLH-specific IgG and lack of impact on the KLH-specific IgM was consistent with human and mouse genetic studies and in studies of pharmacological blockade in mice.11131442 An analysis of the relationship between the AUC) for AMG 557 serum concentrations and AUC for the anti-KLH IgG response is shown in figure 5C. This approach takes into account the impact of magnitude and duration of ICOSL blockade. Collectively, these analyses show a general dose response with maximal inhibition of the anti-KLH IgG response occurring at around 70 mg.

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