Background/Purpose: ALPN-101 is an Fc fusion protein of a human inducible T cell costimulator ligand (ICOSL) variant immunoglobulin domain (vIgD^TM) 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.

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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/