A first-in-class dual CD/ICOS antagonist
Our lead autoimmune/inflammation program is comprised of a novel single domain vIgD binding both ICOS and CD28 at higher affinity than wild-type molecules. ALPN-101 is designed to inhibit both the CD28 and ICOS pathways to potentially dampen an overactive immune response. Since it addresses potential deficiencies of single pathway blockade, we hypothesize it to be capable of delivering deeper clinical responses by blocking two key T cell costimulatory pathways with a single therapeutic.
Inducible T cell Costimulator (“ICOS”) is poorly expressed in naïve T cells, and rapidly induced upon activation. It appears to be a dominant costimulatory pathway in at least some effector or pathogenic T cells, particularly in the absence of CD28. Elevated levels of ICOS‑expressing T cells have been described in an increasing number of inflammatory diseases, correlating with disease activity., The ICOS pathway may therefore represent a major costimulatory pathway, nonredundant with CD28 and highly relevant to inflammatory diseases.
Cluster of Differentiation 28 (“CD28”) is the dominant costimulatory pathway in naïve, antigen-inexperienced T cells, and required for their activation. Therapeutic agents directed against the CD28 pathway alone, such as abatacept, have proven only partially effective or ineffective in some inflammatory diseases, and/or only induce only partial disease improvement in their approved indications. Therefore, an additional, non-CD28, costimulatory pathway(s) likely participates in activated, effector T cells, and may be particularly relevant to inflammatory disease pathogenesis.
Notably, ALPN-101 is not a bispecific antibody construct. A traditional bispecific would be constructed of one domain binding ICOS and one domain binding CD28. Instead, ALPN-101 makes use of a novel single domain engineered by our scientists using our proprietary scientific platform.
We have demonstrated ALPN-101’s superiority to FDA-approved therapies in several in vivo models of disease including GVHD and lupus. Details can be found in our scientific publications.
ALPN-101 completed enrollment of a Phase 1 healthy volunteer study in October 2019. Initial data were presented at the American Society of Hematology annual meeting in December 2019 and more data from this Phase 1 trial are expected in 2020. ‘BALANCE’, a Phase 1b/2 trial in acute GVHD, is open for enrollment.
Selected ALPN-101 Publications
 Wikenheiser & Stumhofer, Frontiers in Immunology, v7 n304. August 2016.
 e.g. Wang et al. Journal of Immunology, v172 n10. May 2004, pp 5917-5923.
 e.g. Choi, et al. Arthritis and Rheumatology, v67 n4. March 2015 pp 988-999
 e.g. Fonseca, et al. Arthritis and Rheumatology. (In press 10.1002/art.40424)
 McKnight, et al. Journal of Immunology, v152 n11. June 1994, pp 5220-5225
 e.g. Furie, et al, Arthritis & Rheumatology, v66 n2. January 2014, pp 379-389.
 e.g. Maxwell & Singh, Cochrane Database of Systematic Reviews, v2009 n4. October 2009.
Our scientific platform is well-positioned to create soluble inhibitory receptor agonists
Inhibitory Receptor Agonist
Uniquely suited to our platform
Inhibitory “checkpoint” receptors such as PD-1, CTLA-4, TIGIT, LAG-3, and BTLA reduce inflammation in several proposed ways, such as competing with activating ligands and/or initiating negative signaling within cells—essentially putting the brakes on the immune system. They are thought to play critical roles in inflammation since genetic flaws affecting their activity have been associated with many autoimmune and inflammatory conditions. Additionally, therapeutic interventions reducing or eliminating their activity result in autoimmunity and/or inflammation in preclinical models.
Agonizing one or more of these checkpoint receptors to press the brakes on the immune system, therefore, may be particularly effective in the treatment of multiple inflammatory disorders. True inhibitory receptor agonists, however, appear to have been generally difficult to generate reliably in drug-like formats.
Traditional approaches to make inhibitory receptor agonists have included monoclonal antibodies mAb or ligand-Fc fusion biologics, but to date, no such agonists have been approved for clinical use.
Our proprietary scientific platform may provide a particularly unique and advantageous means to achieve inhibitory receptor agonism, since it is based upon functional IgSF domains highly similar to naturally evolved checkpoint ligands. This potentially allows greater physiologic accessibility to the immune synapse and the ability to modulate specific interactions therein. We are investigating the ability of appropriately engineered vIgD inhibitory receptor agonists to target specifically pathogenic inflammatory cells, creating potent yet directed immunosuppressants.
 Dixon, et. al. Journal of Immunology v200 n6, March 2018. In Press.
 Carter, et al. European Journal of Immunology v32 n3 February 2002, pp 634-643