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Cancer immunotherapy by NC410, a LAIR-2 Fc protein blocking human LAIR-collagen interaction.
- Source :
-
ELife [Elife] 2021 Jun 14; Vol. 10. Date of Electronic Publication: 2021 Jun 14. - Publication Year :
- 2021
-
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 <superscript>+</superscript> immune cells are localized. Our findings show that NC410 might be a novel strategy for cancer immunotherapy for immune-excluded tumors.<br />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).<br /> (© 2021, Ramos et al.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 2050-084X
- Volume :
- 10
- Database :
- MEDLINE
- Journal :
- ELife
- Publication Type :
- Academic Journal
- Accession number :
- 34121658
- Full Text :
- https://doi.org/10.7554/eLife.62927