Background/Purpose:

The interaction of inducible costimulator (ICOS) with its ligand, B7-related protein-1 (B7RP-1 or ICOSL), plays a role in T cell differentiation, cytokine production, and T cell dependent help for B cells.  Blockade of the B7RP-1/ICOS pathway may be efficacious in treating SLE and other autoimmune diseases.  AMG 557 is a human IgG2 monoclonal antibody that binds to B7RP-1, inhibiting its interaction with ICOS.  Safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple dose administration of AMG 557 were assessed in SLE subjects.   

Methods:

Fifty-six subjects with mild, stable SLE received multiple doses of AMG 557 or placebo in a 3:1 ratio ranging from 6 mg to 210 mg SC (every 2 weeks x 7 doses).  Subjects received an intradermal injection of the neoantigen keyhole limpet hemocyanin (KLH) on days 57 and 85 (1 mg, Biosyn^TM).    Adverse events, safety laboratory tests and disease activity were assessed. Serum AMG 557 concentrations and anti-AMG 557 binding and neutralizing antibodies were measured during the study.  B7RP-1 target occupancy (TO) and an immunophenotyping panel selected for SLE and the ICOS pathway were measured in whole blood (WB) by flow cytometry. Serum protein and WB RNA biomarkers associated with SLE were measured by ELISA and microarray, respectively.  Measurement of serum anti-KLH IgG and IgM antibodies was conducted by a flow cytometric bead array assay.

Results:

The tolerability of multiple doses of AMG 557 up to 210 mg SC was acceptable.  Most adverse events were grade 1 and 2 and no grade 3 adverse events were attributed to AMG 557.  Serious adverse events were reported for 5 subjects (12%) who received AMG 557 and 2 subjects (14%) who received placebo.  Serum AMG 557 exposure increased greater than dose‑proportionally from 6 – 70 mg SC and approximately dose‑proportionally from 70 – 210 mg SC.  No subjects tested positive for neutralizing anti‑AMG 557 antibodies.  Mean TO was greater than 50% in the 18 mg dose group (and above) and was greater than 90% from days 71 – 141 in the 140 mg group and from days 5 – 169 in the 210 mg group.  A significant reduction in anti‑KLH IgG response was observed in the subjects treated with AMG 557 compared to subjects treated with placebo (p = 0.0044).  No difference in anti‑KLH IgM response was observed between the AMG 557 and placebo groups.  A consistent effect of AMG 557 on SLE disease activity or SLE biomarkers was not observed. 

Conclusion:

Multiple doses of AMG 557 up to 210 mg SC demonstrated an acceptable safety profile.  AMG 557 showed dose-proportional PK above the 70 mg dose level.  Binding of AMG 557 to B7RP-1 was dose-related, reversible, and reached maximum observed levels in the 140 mg SC and greater dose groups.  Significant and selective reduction in the anti‑KLH IgG response was observed with AMG 557 treatment, without reduction in the anti-KLH IgM response, demonstrating a pharmacodynamic effect of multiple doses of AMG 557 in subjects with SLE and consistent with the biology of the ICOS pathway.  No impact on disease activity was observed in these mild, stable SLE patients.  These data support further evaluation of AMG 557 in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/administration-of-amg-557-a-human-anti-b7rp-1-icosl-antibody-leads-to-the-selective-inhibition-of-anti-klh-igg-responses-in-subjects-with-sle-results-of-a-phase-1-randomized-double-blind/