Therapeutics/pharmacology

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Novel Immunomodulatory Proteins Generated via Directed Evolution of Variant Igsf Domains

Wednesday, June 14
6:15 PM - 7:45 PM

The immunoglobulin superfamily (IgSF) is a large, diverse family of proteins expressed on immune cells extensively targeted for treatment of cancers and autoimmune diseases. Most of the therapeutic strategies targeting this family have focused on high affinity antibodies binding a single receptor. Moreover, wild-type IgSF receptors typically exhibit low affinities for their counter-structures, limiting their utility in therapeutic modulation of immune responses. We have developed a novel variant Ig domain (vIgD™) platform using directed evolution and yeast display to affinity mature human IgSF extracellular domains. In this platform, libraries of mutagenized IgSF domains are selected for enhanced or altered affinity to specific recombinant proteins. Fc fusion proteins incorporating these evolved immunomodulatory IgSF domains are then tested in vitro for their ability to either agonize or antagonize T cell responses. Multiple novel vIgD™ fusion proteins have been generated which significantly attenuate or accentuate T cell activation in vitro as assessed by proliferation and cytokine production. Lead molecules also exhibited in vivo efficacy in the human PBMC-NSG™ GVHD mouse model. Efficacy in vitro and in vivo was superior to wild-type IgSF domains due to the induced alterations in affinity for cognate ligand and through specifically directed changes in their ability to bind additional counter-structures. Our results demonstrate that vIgDs™ evolved to acquire unique biochemical properties significantly enhance therapeutic utility as immunomodulatory agents. This vIgD™ therapeutic platform has broad potential to enhance the activity of biologics in treatment of autoimmune diseases, cancer, and other disorders.

Katherine E. Lewis

Sr. Principal Scientist
Alpine Immune Sciences, Inc.

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    Lawrence S. Evans

    Alpine Immune Sciences, Inc.

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      Steven D. Levin

      Alpine Immune Sciences, Inc.

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        Erika Rickel

        Alpine Immune Sciences, Inc.

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          Martin F. Wolfson

          Alpine Immune Sciences, Inc.

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            Susan Bort

            Alpine Immune Sciences, Inc.

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              Stacey R. Dillon

              Alpine Immune Sciences, Inc.

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                Michael G. Kornacker

                Alpine Immune Sciences, Inc.

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                  Ryan M. Swanson

                  Alpine Immune Sciences, Inc.

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                    Stanford L. Peng

                    Alpine Immune Sciences, Inc.

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