Background/Purpose:   ABT-122 is a dual variable domain antibody which neutralizes both TNF and IL-17 and is in Phase II trials for rheumatoid arthritis (RA) and psoriatic arthritis.  Because anti-TNF treatment in RA patients has been reported to increase IL-10⁺CD4 T helper cells and Th17 cells, we evaluated whether the dual neutralization of TNF and IL-17 by ABT-122 would have additional effects on T cell cytokine production and T helper phenotypes in subjects receiving ABT-122.  

Methods:   In a Phase 1 study peripheral blood mononuclear cells (PBMCs) were taken from healthy volunteers at baseline, day 15, day 36 and day 57 following a single 1.5mg/kg dose of ABT-122 and cryopreserved. The PBMCs were thawed and either stimulated with anti-CD3/CD28 for 48hrs and supernatants evaluated for cytokine levels (Milliplex MAP technology) or stimulated with PMA/ionomycin for 4hrs and performed cytometric time of flight (CyTOF) analysis for T helper cell populations, including cytokine and transcription factor expression. Serum from 80 MTX-IR RA patients in a Phase II clinical trial with ABT-122 (60mg/EOW, 120mg/EOW, 120mg/EW) or anti-TNF (adalimumab, 40mg/EOW) was also evaluated for several cytokines that drive or are produced by T helper populations, including IL-23, IL-13, IFNγ, IL-22, IL-12, IL-10 and TGF-β (Myriad-RBM, Singulex, MSD or Milliplex).

Results:   The PBMC of healthy volunteers produced significantly lower levels of the cytokines IFNγ, IL-4, IL-2, GM-CSF, and IL-22 following ex vivo stimulation withanti-CD3/CD28 after a single dose of ABT-122 compared to pre-dose levels. In contrast, IL-1RA and IL-21 were significantly elevated in stimulated PBMC cultures, whereas IL-17A, IL-17F, IL-6, IL-1β and IL-10 levels were unchanged. To explore whether these alterations in cytokines reflect a shift in T helper cell populations, PBMCs from these Phase 1 studies were further evaluated with CyTOF. Decreases in IL-22+ T helper cells and increases in IL-21+ T helper cells were confirmed by the CyTOF analysis, but other ex vivo cytokine changes, including decreased IFNγ, IL4 and GM-CSF were not reflected in either proportion of cells or magnitude of expression. Similar to reports with anti-TNF in RA patients, there were increased percentages of Th17 cells following ABT-122 administration, but minimal changes in percentages of Th1, Th2 and Treg cells. From Phase 2 RA subjects, the levels of serum IL-23, a cytokine that promotes Th17 development, trended higher with ABT-122 compared to adalimumab treatment. Conversely, there was a significant increase in serum IL-10 levels, an immunoregulatory cytokine, with ABT-122 compared to adalimumab treatment, suggesting promotion of both Th17 and regulatory pathways with the dual neutralization.

Conclusion:   While circulating Th17 cells increase following administration of ABT-122, there appears to be a compensatory regulatory mechanism that restrains proinflammatory cytokine production following T cell receptor stimulation that may contribute to the dual mechanisms of action of ABT-122 in modulating pathogenic inflammation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/abt-122-an-anti-tnfanti-il-17-dual-variable-domain-antibody-alters-t-cell-responses-in-human-subjects/