1. Cancer immunotherapy by NC410, a LAIR-2 Fc protein blocking human LAIR-collagen interaction.
- Author
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Ramos MIP, Tian L, de Ruiter EJ, Song C, Paucarmayta A, Singh A, Elshof E, Vijver SV, Shaik J, Bosiacki J, Cusumano Z, Jensen C, Willumsen N, Karsdal MA, Liu L, Langermann S, Willems S, Flies D, and Meyaard L
- Subjects
- Animals, Antineoplastic Agents, Immunological, Cell Line, Tumor, Computational Biology, Humans, Immunoglobulin G genetics, Immunoglobulin G metabolism, Mice, Neoplasms therapy, Xenograft Model Antitumor Assays, Collagen metabolism, Immunoglobulin Fc Fragments genetics, Immunoglobulin Fc Fragments metabolism, Immunotherapy methods, Receptors, Immunologic genetics, Receptors, Immunologic metabolism, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism
- Abstract
Collagens are a primary component of the extracellular matrix and are functional ligands for the inhibitory immune receptor leukocyte-associated immunoglobulin-like receptor (LAIR)-1. LAIR-2 is a secreted protein that can act as a decoy receptor by binding collagen with higher affinity than LAIR-1. We propose that collagens promote immune evasion by interacting with LAIR-1 expressed on immune cells, and that LAIR-2 releases LAIR-1-mediated immune suppression. Analysis of public human datasets shows that collagens, LAIR-1 and LAIR-2 have unique and overlapping associations with survival in certain tumors. We designed a dimeric LAIR-2 with a functional IgG1 Fc tail, NC410, and showed that NC410 increases human T cell expansion and effector function in vivo in a mouse xenogeneic-graft versus-host disease model. In humanized mouse tumor models, NC410 reduces tumor growth that is dependent on T cells. Immunohistochemical analysis of human tumors shows that NC410 binds to collagen-rich areas where LAIR-1
+ immune cells are localized. Our findings show that NC410 might be a novel strategy for cancer immunotherapy for immune-excluded tumors., Competing Interests: MR, Ed, CS, AP, AS, EE, SV, JS, JB, ZC, CJ, NW, MK, LL, SL, SW, DF, LM No competing interests declared, LT LT, CS, AP, JS, JB, ZC, LL, SL and DF are employees from Nextcure. Nextcure holds a patent on NC410. (PCT/US20 17/0453 10)., (© 2021, Ramos et al.)- Published
- 2021
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