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694 NC410 is a novel immunomedicine for the treatment of solid tumors
  1. Linjie Tian1,
  2. M Ines Pascoal Ramos2,
  3. Emma de Ruiter2,
  4. Ana Paucarmayta1,
  5. Eline Elshof2,
  6. Stefan Willems2,
  7. Chang Song1,
  8. Zachary Cusumano1,
  9. Jason Bosiacki1,
  10. Linda Liu1,
  11. Solomon Langermann1,
  12. Linde Meyaard2 and
  13. Dallas Flies1
  1. 1NextCure, Inc., Beltsville, MD, USA
  2. 2University Medical Center, Utrecht, Utrecht, Netherlands


Background Abnormalities in the extracellular matrix of tumor microenvironments support tumor progression, lead to immune dysfunction, and provide a target for cancer therapeutics. Collagens are a primary component of the extracellular matrix. Abnormal levels of collagen and of the collagen-domain containing complement component 1q (C1q) in tumor microenvironments has been proposed to disrupt anti-tumor immunity. LAIR-1 is an adhesion molecule and inhibitory receptor expressed on the cell surface of several immune cell subsets. LAIR-1 binding to collagen-like domains present in collagens and C1q inhibit immune cell function. LAIR-2 is a soluble homolog of LAIR-1 that binds to and outcompetes LAIR-1 binding to collagens and C1q and serves as a natural decoy to promote immune function.

Methods Taking advantage of a natural decoy system, we designed a protein biologic, NC410, composed of LAIR-2 fused with a functional IgG1 Fc domain to target collagen-rich tumors and promote immune activation, infiltration and effector function.

Results NC410 has increased avidity due to Fc mediated dimerization, and blocks LAIR-1 interactions with ligands, and LAIR-1 signaling. In vivo administration of NC410 in humanized tumor models reduced tumor growth in a dose dependent fashion. NC410 increased the numbers of infiltrating human CD8+ and CD4+ T cells in the tumor, which is associated with increased levels of chemokines in the local tumor environment. Effector function was also enhanced, as denoted by increased levels of IFN-gamma and Granzyme B in the local tumor environment. In addition, NC410 increased specific collagen degradative products in the serum of humanized tumor-bearing mice, suggesting NC410 may promote tumor microenvironment remodeling and immune accessibility to further promote anti-tumor immunity.

Conclusions These data support NC410 as a novel therapeutic for targeting collagen-rich tumors and enabling normalization of the tumor-immune microenvironment. FIH studies have recently been initiated with NC410.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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