Characterization of BAY 1905254, an Immune Checkpoint Inhibitor Targeting the Immunoglobulin-Like Domain Containing Receptor 2 (ILDR2)

Huetter, Julia; Gritzan, Uwe; Gutcher, Ilona; Doecke, Wolf‐Dietrich; Luetke-Eversloh, Merlin V.; Golfier, Sven; Roider, Helge G.; Frisk, Anna-Lena; Hunter, John; Pow, Andrew; Drake, Andrew; Levine, Zurit; Levy, Ofer; Azulay, Meir; Barbiro, Inbal; Cojocaru, Gady; Vaknin, Ilan; Kreft, Bertolt; Roese, Lars

doi:10.1158/2326-6066.cir-19-0321

Cited by 9 publications

(9 citation statements)

References 44 publications

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“…55 Ildr2 evinces immunomodulatory activity, wherein administration of Ildr2 as a fusion protein (ILDR2-Fc) rebalances immune homeostasis, which leads to an amelioration of autoimmune disease states in mouse models of rheumatoid arthritis, type I diabetes, and relapsing-remitting multiple sclerosis. [55][56]57 Recently, an Ildr2 blocking antibody , BAY 1905254, was generated to block the immunosuppressive activity of Ildr2 for cancer immunotherapy. 57 BAY 1905254 promotes T-cell activation in vitro and enhances antigen-specific T-cell proliferation and cytotoxicity in vivo, and is currently in phase I clinical trials.…”

Section: Discussionmentioning

confidence: 99%

“…[55][56]57 Recently, an Ildr2 blocking antibody , BAY 1905254, was generated to block the immunosuppressive activity of Ildr2 for cancer immunotherapy. 57 BAY 1905254 promotes T-cell activation in vitro and enhances antigen-specific T-cell proliferation and cytotoxicity in vivo, and is currently in phase I clinical trials. 57 Ildr2 presents an unexplored niche in podocyte biology centered around the function of podocytes in immune cell modulation.…”

Section: Discussionmentioning

confidence: 99%

“…57 BAY 1905254 promotes T-cell activation in vitro and enhances antigen-specific T-cell proliferation and cytotoxicity in vivo , and is currently in phase I clinical trials. 57 Ildr2 presents an unexplored niche in podocyte biology centered around the function of podocytes in immune cell modulation. Yet, the ability for immune cells such as T-cells to interreact with podocytes is challenged by the podocyte cellular environment and the GBM.…”

Section: Discussionmentioning

confidence: 99%

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Mapping of the podocin proximity-dependent proteome reveals novel components of the kidney podocyte foot process

Gerlach

Imseis

Cooper

et al. 2022

Preprint

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The unique architecture of glomerular podocytes is integral to kidney filtration. Interdigitating foot processes extend from the podocyte cell body, wrap around fenestrated capillaries, and form specialized junctional complexes termed slit diaphragms to create a molecular sieve. However, the full complement of proteins which maintain foot process integrity, and how this localized proteome changes with disease, remains to be elucidated. Proximity-dependent biotin identification (BioID) enables the identification of spatially localized proteomes. To this end, we developed a novel in vivo BioID knock-in mouse model. We utilized the slit diaphragm protein podocin (Nphs2) to create a podocin-BioID fusion. Podocin-BioID localizes to the slit diaphragm and biotin injection leads to podocyte-specific protein biotinylation. We isolated the biotinylated proteins and performed mass spectrometry to identify proximal interactors. Gene ontology analysis of 54 proteins specifically enriched in our podocin-BioID sample revealed cell junctions, actin binding, and cytoskeleton organization as top terms. Known foot process components were identified and we further uncovered two novel proteins: the tricellular junctional protein Ildr2 and the CDC42 and N-WASP interactor Fnbp1l. We confirmed Ildr2 and Fnbp1l are expressed by podocytes and partially colocalize with podocin. Finally, we investigated how this proteome changes with age and uncovered a significant increase in Ildr2. This was confirmed by immunofluorescence on human kidney samples and suggests altered junctional composition may preserve podocyte integrity. Together, these assays have led to new insights into podocyte biology and supports the efficacy of utilizing BioID in vivo to interrogate spatially localized proteomes in health, aging, and disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Mapping of the podocin proximity-dependent proteome reveals novel components of the kidney podocyte foot process

Gerlach

Imseis

Cooper

et al. 2022

Preprint

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“…They presented that the antibody targeting ILDR2, BAY 1905254, enhances activation of T lymphocytes and induces responses of antigen-specific T lymphocytes in vivo via inhibiting the immunosuppressive role of ILDR2. Consequently, BAY 1905254 can induce anti-tumor immune responses in vivo, as monotherapy or in combination with docetaxel and anti-PD-L1 in various syngeneic tumor models [ 172 ]. To date, no studies have reported on the role of ILDR2 in pathological states and the clinical significance of ILDR2 expression in GC.…”

Section: Ig-like Domain-containing Receptor 2 (Ildr2)mentioning

confidence: 99%

The Positive and Negative Immunoregulatory Role of B7 Family: Promising Novel Targets in Gastric Cancer Treatment

Bolandi

Derakhshani

Hemmat

et al. 2021

IJMS

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Gastric cancer (GC), with a heterogeneous nature, is the third leading cause of death worldwide. Over the past few decades, stable reductions in the incidence of GC have been observed. However, due to the poor response to common treatments and late diagnosis, this cancer is still considered one of the lethal cancers. Emerging methods such as immunotherapy with immune checkpoint inhibitors (ICIs) have transformed the landscape of treatment for GC patients. There are presently eleven known members of the B7 family as immune checkpoint molecules: B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1, CD274), B7-DC (PDCD1LG2, PD-L2, CD273), B7-H2 (B7RP1, ICOS-L, CD275), B7-H3 (CD276), B7-H4 (B7x, B7S1, Vtcn1), B7-H5 (VISTA, Gi24, DD1α, Dies1 SISP1), B7-H6 (NCR3LG1), B7-H7 (HHLA2), and Ig-like domain-containing receptor 2 (ILDR2). Interaction of the B7 family of immune-regulatory ligands with the corresponding receptors resulted in the induction and inhibition of T cell responses by sending co-stimulatory and co-inhibitory signals, respectively. Manipulation of the signals provided by the B7 family has significant potential in the management of GC.

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“…LSR has previously been shown to play a role in clearance of lipids by removing apo-B containing lipoproteins in conjunction with the LDL receptor [9]. Recently, increased expression of nuclear LSR was shown to be associated with poor outcomes in breast cancer [10], while an anti-ILDR2 antibody promoted T cell activation leading to anti-tumor effects [11]. Thus, the ILDR family of proteins displays multifunctional and diverse roles in mammalian tissues.…”

Section: Introductionmentioning

confidence: 99%

Ildr1 gene deletion protects against diet-induced obesity and hyperglycemia

et al. 2022

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Objective Immunoglobulin-like Domain-Containing Receptor 1 (ILDR1) is expressed on nutrient sensing cholecystokinin-positive enteroendocrine cells of the gastrointestinal tract and it has the unique ability to induce fat-mediated CCK secretion. However, the role of ILDR1 in CCK-mediated regulation of satiety is unknown. In this study, we examined the effects of ILDR1 on food intake and metabolic activity using mice with genetically-deleted Ildr1. Methods The expression of ILDR1 in murine tissues and the measurement of adipocyte cell size were evaluated by light and fluorescence confocal microscopy. The effects of Ildr1 deletion on mouse metabolism were quantitated using CLAMS chambers and by targeted metabolomics assays of multiple tissues. Hormone levels were measured by ELISA. The effects of Ildr1 gene deletion on glucose and insulin levels were determined using in vivo oral glucose tolerance, meal tolerance, and insulin tolerance tests, as well as ex vivo islet perifusion. Results ILDR1 is expressed in a wide range of tissues. Analysis of metabolic data revealed that although Ildr1-/- mice consumed more food than wild-type littermates, they gained less weight on a high fat diet and exhibited increased metabolic activity. Adipocytes in Ildr1-/- mice were significantly smaller than in wild-type mice fed either low or high fat diets. ILDR1 was expressed in both alpha and beta cells of pancreatic islets. Based on oral glucose and mixed meal tolerance tests, Ildr1-/- mice were more effective at lowering post-prandial glucose levels, had improved insulin sensitivity, and glucose-regulated insulin secretion was enhanced in mice lacking ILDR1. Conclusion Ildr1 loss significantly modified metabolic activity in these mutant mice. While Ildr1 gene deletion increased high fat food intake, it reduced weight gain and improved glucose tolerance. These findings indicate that ILDR1 modulates metabolic responses to feeding in mice.

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Characterization of BAY 1905254, an Immune Checkpoint Inhibitor Targeting the Immunoglobulin-Like Domain Containing Receptor 2 (ILDR2)

Abstract: have ownership interest as shares in Bayer AG; Zurit Levine and Ofer Levy have ownership interest as shares in Compugen Ltd.

Cited by 9 publications

References 44 publications

Mapping of the podocin proximity-dependent proteome reveals novel components of the kidney podocyte foot process

Mapping of the podocin proximity-dependent proteome reveals novel components of the kidney podocyte foot process

The Positive and Negative Immunoregulatory Role of B7 Family: Promising Novel Targets in Gastric Cancer Treatment

Ildr1 gene deletion protects against diet-induced obesity and hyperglycemia

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