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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

Mean (SD) AMG 557 serum concentration–time profiles following single-ascending dose (SAD) (A) and multiple-ascending dose (MAD) (B) administration AMG 557 in subjects with systemic lupus erythematosus. The dose levels are indicated in the legend, with the number of values per symbol in parentheses. The lower limit of quantitation (LLOQ) of 15 ng/mL is indicated as a dashed horizontal line on each graph. IV, intravenous; SC, subcutaneous.
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LUPUS2016000146F2: Mean (SD) AMG 557 serum concentration–time profiles following single-ascending dose (SAD) (A) and multiple-ascending dose (MAD) (B) administration AMG 557 in subjects with systemic lupus erythematosus. The dose levels are indicated in the legend, with the number of values per symbol in parentheses. The lower limit of quantitation (LLOQ) of 15 ng/mL is indicated as a dashed horizontal line on each graph. IV, intravenous; SC, subcutaneous.

Mentions: Serum AMG 557 exposure (Cmax and area under the curve (AUC)) increased greater than dose-proportionally at lower doses after either single or multiple subcutaneous doses (figure 2 and table 2). However, an approximately dose-proportional increase in exposure was observed at higher doses (≥140 mg for SAD;≥70 mg for MAD). Maximum concentration of AMG 557 was reached in 3–7 days (tmax) after subcutaneous administration (table 2). Bioavailability after subcutaneous dosing was estimated to be 57%. Moderate accumulation was observed at steady state (seventh dose), with median accumulation ratios being approximately 2–4. A total of 6% (N=2/36, SAD) and 24% (N=10/42, MAD) of AMG 557-treated subjects tested positive for postbaseline anti-AMG 557 binding antibodies, although anti-AMG 557 antibodies were present in 9% (5/56) of subjects at baseline in the MAD study, which may be due to cross-reactivity in the assay. The specificity of the anti-AMG 557 assay was determined by addition of 100 µg/mL of excess unlabelled drug to the samples that tested positive in the assay. If the addition of the excess drug quenched the positive signal in the assay, they are considered specific to the drug. There was no apparent impact of anti-AMG 557 antibodies on serum AMG 557 concentrations. No subjects tested positive for neutralising anti-AMG 557 antibodies.


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)

Mean (SD) AMG 557 serum concentration–time profiles following single-ascending dose (SAD) (A) and multiple-ascending dose (MAD) (B) administration AMG 557 in subjects with systemic lupus erythematosus. The dose levels are indicated in the legend, with the number of values per symbol in parentheses. The lower limit of quantitation (LLOQ) of 15 ng/mL is indicated as a dashed horizontal line on each graph. IV, intravenous; SC, subcutaneous.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

LUPUS2016000146F2: Mean (SD) AMG 557 serum concentration–time profiles following single-ascending dose (SAD) (A) and multiple-ascending dose (MAD) (B) administration AMG 557 in subjects with systemic lupus erythematosus. The dose levels are indicated in the legend, with the number of values per symbol in parentheses. The lower limit of quantitation (LLOQ) of 15 ng/mL is indicated as a dashed horizontal line on each graph. IV, intravenous; SC, subcutaneous.
Mentions: Serum AMG 557 exposure (Cmax and area under the curve (AUC)) increased greater than dose-proportionally at lower doses after either single or multiple subcutaneous doses (figure 2 and table 2). However, an approximately dose-proportional increase in exposure was observed at higher doses (≥140 mg for SAD;≥70 mg for MAD). Maximum concentration of AMG 557 was reached in 3–7 days (tmax) after subcutaneous administration (table 2). Bioavailability after subcutaneous dosing was estimated to be 57%. Moderate accumulation was observed at steady state (seventh dose), with median accumulation ratios being approximately 2–4. A total of 6% (N=2/36, SAD) and 24% (N=10/42, MAD) of AMG 557-treated subjects tested positive for postbaseline anti-AMG 557 binding antibodies, although anti-AMG 557 antibodies were present in 9% (5/56) of subjects at baseline in the MAD study, which may be due to cross-reactivity in the assay. The specificity of the anti-AMG 557 assay was determined by addition of 100 µg/mL of excess unlabelled drug to the samples that tested positive in the assay. If the addition of the excess drug quenched the positive signal in the assay, they are considered specific to the drug. There was no apparent impact of anti-AMG 557 antibodies on serum AMG 557 concentrations. No subjects tested positive for neutralising anti-AMG 557 antibodies.

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