Session Type: Poster Session (Monday)
Session Time: 9:00AM-11:00AM
Background/Purpose: ALPN-101 is an Fc fusion protein of a human inducible T cell costimulator ligand (ICOSL) variant immunoglobulin domain (vIgDTM) designed to simultaneously inhibit the CD28 and ICOS costimulatory pathways. CD28 and ICOS each play a role in T cell activation and adaptive immunity which can contribute to autoimmune disease when dysregulated. ALPN-101 has previously been shown to have potent immunosuppressive activity in various in vitro and in vivo models of disease, including acute graft-versus host disease and multiple sclerosis. We report here in vitro analyses using PBMC from rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients and from healthy donors. ALPN-101 demonstrated superior suppression of human T cell activation and potent reduction of inflammatory mediators known to contribute to the pathogenesis of RA, PsA, and juvenile idiopathic arthritis (JIA). Additionally, the efficacy of ALPN-101 was confirmed in vivo in a mouse model of collagen-induced arthritis (CIA).
Methods: Healthy donor, RA, and PsA patient PBMC or Th17-skewed T cell cultures were stimulated with K562 cells expressing CD80, CD86, ICOSL, and anti-CD3 (OKT3) to evaluate the potency of ALPN-101 to suppress pro-inflammatory cytokine production. The activity of dual pathway inhibition by ALPN-101 was compared to the CD28-only inhibitor abatacept (CTLA-4-Fc) and to the ICOS pathway inhibitor prezalumab (AMG-557; anti-ICOSL, Creative Biolabs). ALPN-101 was tested in vivo vs. abatacept in a CIA model in which male DBA/1 mice were immunized with bovine collagen in Freund’s adjuvant on Days 0 and 18.
Results: Compared to abatacept, prezalumab, or combination abatacept + prezalumab, ALPN-101 demonstrated superior suppression of pro-inflammatory cytokine (i.e. TNF-α, IFN-γ, IL-1β, IL-2, IL-6, IL-17A, GM-CSF, RANKL, etc.) release from stimulated healthy and patient PBMCs (Fig. 1), and suppressed T cell proliferation in Th17-skewed cultures. The administration of ALPN-101 also consistently resulted in significant disease reduction in the mouse CIA model (including decreased paw inflammation, serum cytokines, and anti-collagen antibodies), matching or exceeding the activity of abatacept.
Conclusion: The immunosuppressive efficacy of dual CD28/ICOS antagonist ALPN-101 is superior to CD28 or ICOS costimulatory pathway inhibitors, administered individually or in combination, in human in vitro and/or mouse in vivo translational studies. The data suggest that ALPN-101 may significantly improve upon the clinical efficacy of currently approved therapeutics like abatacept for treatment of inflammatory diseases, including rheumatoid, psoriatic, and juvenile idiopathic arthritis. A Phase 1 clinical trial with ALPN-101 in healthy volunteers is underway, and trials in inflammatory arthritis and other inflammatory diseases are targeted to begin soon.
To cite this abstract in AMA style:Evans L, Dillon S, Lewis K, Bort S, Rickel E, Yang J, Wolfson M, Mudri S, Susmilch K, Levin S, MacNeil S, Rixon M, Hillson J, Peng S, Swiderek K. ALPN-101, a First-in-Class Dual ICOS/CD28 Antagonist, Suppresses Key Effector Mechanisms Underlying Rheumatoid and Psoriatic Arthritis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/alpn-101-a-first-in-class-dual-icos-cd28-antagonist-suppresses-key-effector-mechanisms-underlying-rheumatoid-and-psoriatic-arthritis/. Accessed October 20, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/alpn-101-a-first-in-class-dual-icos-cd28-antagonist-suppresses-key-effector-mechanisms-underlying-rheumatoid-and-psoriatic-arthritis/