Date: Sunday, October 21, 2018
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: CD28 and Inducible T-cell Costimulator (ICOS) are two related costimulatory molecules within the immunoglobulin superfamily (IgSF) expressed on T cells and interacting with CD80/CD86 and ICOS ligand (ICOSL), respectively. Both play critical roles in T cell activation and adaptive immunity, but when dysregulated can contribute to autoimmunity. We used our proprietary platform to create a variant Ig domain (vIgD™), an engineered version of ICOSL capable of binding both ICOS and CD28 and blocking the interaction of these costimulatory molecules with their respective receptors. This ICOSL vIgD was fused to a human Fc lacking effector function (i.e. FcR binding and complement fixation) to create the therapeutic candidate ALPN-101, which has previously been shown to have potent immunosuppressive activity in vitro. We report here in vivo activity data in mouse models of autoimmune disease supporting the potent immunosuppressive activity of ALPN-101.
Methods: ALPN-101 was evaluated for immunosuppressive activity in multiple mouse models, including the collagen-induced arthritis (CIA) model with either prophylactic or therapeutic dosing. ALPN-101 was dosed a maximum of 4 times either prior to or just after disease onset. Comparator molecules were administered at molar equivalent doses in regimens matching ALPN-101.
Results: ALPN-101, when given either prophylactically or therapeutically, significantly attenuated disease activity in the collagen-induced arthritis model. ALPN-101 mediated significant disease reduction in CIA, matching or exceeding CD28-only or ICOS-only inhibitors. Similar effects were observed in additional disease models.
Conclusion: Efficacy in vivo of ALPN-101 is superior to wild-type ICOSL domains or CD28-only inhibitors. The increased efficacy of ALPN-101 was made possible by engineering the wild-type ICOSL IgSF to create a vIgD with altered affinity between ICOSL and ICOS and through specifically-directed alterations in ICOSL/CD28 binding. Preclinical development of ALPN-101 is underway to support clinical studies of this potentially first-in-class dual ICOS and CD28 inhibitor.
To cite this abstract in AMA style:Dillon S, Lewis K, Evans L, Swanson R, Yang J, Wolfson M, Seaberg M, Susmilch K, Mudri S, Rixon M, Peng S, Swiderek K. Alpn-101, a Dual ICOS/CD28 Antagonist, Potently Suppresses Disease in Multiple Mouse Models of Autoimmunity [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/alpn-101-a-dual-icos-cd28-antagonist-potently-suppresses-disease-in-multiple-mouse-models-of-autoimmunity/. Accessed October 27, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/alpn-101-a-dual-icos-cd28-antagonist-potently-suppresses-disease-in-multiple-mouse-models-of-autoimmunity/