On December 3, 2018 Alpine Immune Sciences, Inc. (NASDAQ:ALPN), a leading immunotherapy company focused on developing innovative treatments for cancer, autoimmune/inflammatory, and other diseases, reported positive results from multiple preclinical studies which were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper)’s (ASH) (Free ASH Whitepaper) 60th Annual Meeting & Exposition in San Diego, CA (Press release, Alpine Immune Sciences, DEC 3, 2018, View Source [SID1234531837]). Oral and poster presentations described promising efficacy of ALPN-101 in preclinical models of acute graft versus host disease (GvHD) and hemophagocytic lymphohistiocytosis (HLH), while a poster presentation described the company’s transmembrane and secreted immunomodulatory protein (TIP/SIP) platform to enhance the activity of engineered T cell therapies for cancer. Additionally, Alpine strengthened its Scientific Advisory Board with the addition of Anne Davidson, MBBS, Professor, Center for Autoimmune, Musculoskeletal, and Hematopoietic Diseases, Feinstein Institute for Medical Research.
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
ALPN-101 Preclinical Study Results
Djamilatou Adom, PhD, from the Indiana University School of Medicine laboratory of Sophie Paczesny, MD PhD, and one of Alpine’s collaborators, presented an oral abstract titled, "ICOSL+ Plasmacytoid Dendritic Cells as Biomarker and Inducer of Graft-Versus-Host Disease" (publication #355), highlighting the novel role ICOS ligand (ICOSL) plays in acute GvHD and describing a strong correlation between ICOSL-positive plasmacytoid dendritic cells and the gastrointestinal manifestations of GvHD. In the investigators’ model of GvHD, ALPN-101 significantly improved survival.
"I’m excited about the potential of ALPN-101 in GvHD given its dual CD28/ICOS mechanism of action," said Dr. Paczesny, Professor of Immunology and Pediatrics at Indiana University School of Medicine and lead of the Biomarkers Stem Cell Transplantation Program. "Early biomarker development could identify patients at risk, specifically early quantification of ICOSL+ Plasmacytoid Dendritic Cells frequency may allow for identification of patients at risk of gastrointestinal and support ALPN-101 as an early intervention in this patient population."
In a poster titled, "Therapeutic Candidate ALPN-101, a Dual ICOS/CD28 Antagonist, Potently Suppresses Human/NSG Mouse Xenograft Graft vs. Host Disease (GvHD) in a Dose Ranging Study and Reduces Disease Activity in a Mouse Model of Hemophagocytic Lymphohistiocytosis (HLH)" (publication #2037), ALPN-101 was evaluated in a humanized model of GvHD and an experimental model of HLH. GvHD is a life-threatening disease reflecting immune-mediated attack of recipient tissue by donor T cells and is one of the leading causes of death following allogeneic stem cell transplantation. HLH is a rare, life-threatening inflammatory disease characterized by excessive T cell and macrophage activation. Results showed ALPN-101:
Humanized GvHD Model
Enhanced survival and suppressed disease activity in GvHD, even after administration of only a single dose.
Demonstrated superior efficacy to belatacept, an approved CD28 pathway inhibitor, in survival and disease activity, correlating with better suppression of activated T cells and circulating cytokines.
HLH Model
Reduced CD4+ T cell activation and liver inflammation
Did not appear to affect the activity of viral-specific T cells directed against lymphocytic choriomeningitis virus (LCMV), the virus used to induce the model.
The HLH data were generated in collaboration with the laboratory of Kim Nichols, MD, Director of the Cancer Predisposition Division at St. Jude Children’s Research Hospital. Dr. Nichols noted, "ALPN-101 clearly reduces inflammation in these models, but importantly the activity of viral-specific T cells was preserved, suggesting ALPN-101 may reduce pathogenic, but spare desired, immune responses."
"These results reinforce our confidence in ALPN-101 as a promising therapeutic candidate, not only in GvHD but multiple other autoimmune and/or inflammatory diseases," said Stanford Peng, M.D., Ph.D., Executive Vice President of Research and Development and Chief Medical Officer of Alpine. "We remain on track to initiate a Phase 1 study in the first quarter of 2019."
Transmembrane and Secreted Immunomodulatory Protein (TIP/SIP) Data Presented
A second poster, titled "’Switch’ Transmembrane Immunomodulatory Proteins (TIPs) Consisting of High-Affinity PD-1 Extracellular Domains (PD-1 vIgDs) and Costimulatory Intracellular Domains Potently Enhance the Activity of TCR-Engineered T Cells" (publication #2052), described for the first time an application of Alpine’s variant immunoglobulin domain (vIgD) platform to enhance the activity of engineered T cells (ECTs). Multiple formats were demonstrated, in which vIgDs expressed by TCR and/or CAR-T cells in either transmembrane or secreted forms enhanced their activity as determined by T cell proliferation, cytokine production, and/or target cell killing. Examples included CD86 costimulatory TIPs, PD-L2 checkpoint inhibitory SIPs, and PD-1 "switch" TIPs incorporating costimulatory intracellular signaling domains, using HPV-specific TCRs, as well as HER2- and CD19-specific CARs. Importantly, the success of this work relied upon Alpine’s development of a proprietary transduction vector to achieve high T cell transduction efficiencies.
Dr. Peng added, "Engineered T cell therapies continue to hold great promise but have seemed so far to demonstrate only modest efficacy in solid tumors, possibly due to an immunosuppressive and/or insufficiently immuno-stimulatory tumor environment. These data suggest Alpine’s TIPs and SIPs may represent a next-generation strategy to overcome such obstacles. We look forward to continuing to develop this potential."
Scientific Advisory Board Appointment
Dr. Anne Davidson, MBBS, Professor, Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases and Investigator at the Feinstein Institute for Medical Research, has been appointed to the Alpine Immune Sciences Scientific Advisory Board.
"We are pleased to have Anne join our ranks and lend her considerable expertise to the Alpine Scientific Advisory Board," said Andy Scharenberg, M.D., Chair of the Scientific Advisory Board. "She is a distinguished researcher and investigator, and her deep expertise in autoimmune disease processes will be valuable as Alpine works to advance its novel molecules in its autoimmune and inflammatory programs."
Dr. Davidson is a practicing rheumatologist at North Shore University Hospital and serves as program director of the Rheumatology Fellowship at Northwell Health. She has served on the medical advisory board for the S.L.E. Lupus Foundation and co-chairs a grant review committee for the Lupus Research Alliance. Her accolades include multiple grants from the National Institutes of Health, the Kirkland Scholar Award, the Dubois Award from the American College of Rheumatology, and the American College of Rheumatology Distinguished Investigator Award.
"I am pleased to join the Scientific Advisory Board at this pivotal time as Alpine advances its programs toward the clinic," said Dr. Davidson. "In particular, I am excited by what the ALPN-101 preclinical data has demonstrated to date, and I look forward to working with the team as Alpine explores this novel molecule’s potential application to a wide array of autoimmune disorders."