RRC ID |
63017
|
著者 |
Huetter J, Gritzan U, Gutcher I, Doecke WD, Luetke-Eversloh MV, Golfier S, Roider HG, Frisk AL, Hunter J, Pow A, Drake A, Levine Z, Levy O, Azulay M, Barbiro I, Cojocaru G, Vaknin I, Kreft B, Roese L.
|
タイトル |
Characterization of BAY 1905254, an Immune Checkpoint Inhibitor Targeting the Immunoglobulin-Like Domain Containing Receptor 2 (ILDR2).
|
ジャーナル |
Cancer Immunol Res
|
Abstract |
The immunoglobulin-like domain containing receptor 2 (ILDR2), a type I transmembrane protein belonging to the B7 family of immunomodulatory receptors, has been described to induce an immunosuppressive effect on T-cell responses. Besides its expression in several nonlymphoid tissue types, we found that ILDR2 was also expressed in fibroblastic reticular cells (FRC) in the stromal part of the lymph node. These immunoregulatory cells were located in the T-cell zone and were essential for the recruitment of naïve T cells and activated dendritic cells to the lymph nodes. Previously, it has been shown that an ILDR2-Fc fusion protein exhibits immunomodulatory effects in several models of autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and type I diabetes. Herein, we report the generation and characterization of a human/mouse/monkey cross-reactive anti-ILDR2 hIgG2 antibody, BAY 1905254, developed to block the immunosuppressive activity of ILDR2 for cancer immunotherapy. BAY 1905254 was shown to promote T-cell activation in vitro and enhance antigen-specific T-cell proliferation and cytotoxicity in vivo in mice. BAY 1905254 also showed potent efficacy in various syngeneic mouse cancer models, and the efficacy was found to correlate with increasing mutational load in the cancer models used. Additive or even synergistic antitumor effects were observed when BAY 1905254 was administered in combination with anti-PD-L1, an immunogenic cell death-inducing chemotherapeutic, or with tumor antigen immunization. Taken together, our data showed that BAY 1905254 is a potential drug candidate for cancer immunotherapy, supporting its further evaluation.
|
巻・号 |
8(7)
|
ページ |
895-911
|
公開日 |
2020-7-1
|
DOI |
10.1158/2326-6066.CIR-19-0321
|
PII |
2326-6066.CIR-19-0321
|
PMID |
32312711
|
MeSH |
Animals
Antineoplastic Agents, Immunological / pharmacology*
B7-H1 Antigen / antagonists & inhibitors
B7-H1 Antigen / immunology
CD8-Positive T-Lymphocytes / immunology*
Cell Line, Tumor
Disease Models, Animal
Female
Humans
Immune Tolerance
Immunoglobulin G / immunology
Immunoglobulin G / pharmacology*
Immunotherapy / methods
Leukocytes, Mononuclear / immunology
Lymphocyte Activation / immunology*
Membrane Proteins / antagonists & inhibitors
Membrane Proteins / immunology*
Mice
Mice, Inbred C57BL
Mice, Knockout
Neoplasms / drug therapy*
Neoplasms / immunology
Neoplasms / metabolism
|
IF |
8.728
|
リソース情報 |
ヒト・動物細胞 |
MBT-2(RCB0544)
293T(RCB2202) |