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Novel immune checkpoint inhibitors

An immune checkpoint, inhibitory technology, applied in the field of prognostic biomarkers, can solve the problems of high treatment cost and toxicity, little patient benefit, no benefit, etc.

Pending Publication Date: 2021-07-23
YALE UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the majority of patients treated with checkpoint inhibitors benefit little or no benefit, and these treatments are costly and may have some associated toxicities

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0156] Lymphocyte activation gene 3 protein (LAG3) is a cell surface T-cell inhibitory protein and is thought to function by interacting with major histocompatibility complex class II (MHC-II). However, in various experimental settings, this interaction was not required for LAG3-induced inhibitory function, suggesting the existence of other functional LAG3 ligands. Using a genome-scale receptor array system, we identified fibrinogen-like protein 1 (FGL1), a liver-enriched soluble protein with mitogenic and metabolic functions in hepatocytes, as a LAG3-binding partner.

[0157] Using immunoglobulin (Ig) Fc-tagged LAG3 extracellular domain fusion proteins, the genome-scale receptor array platform (RAP) was used to search for novel LAG3-binding proteins ( figure 1 a). RAP is a semi-automated large-scale gene expression system in which individual human cDNAs encoding transmembrane and soluble proteins can be transiently overexpressed on the surface of 293T cells (Yao, S. et al. B...

Embodiment 2

[0159] The interaction appears to be conserved between human and mouse species ( figure 1 d and figure 1 e). FGL1 / LAG3 interaction can be detected by flow cytometry ( figure 2 b) and Octet biolayer interferometry at about 1.5nM Kd ( figure 1 d) Validation performed to demonstrate high affinity interactions. The slow off-rates in both mouse and human binding suggest possible stability of this interaction ( figure 1 c and figure 1 f). Other FGL1 homologues involved in regulating Treg function, including FGL2, as well as several angiopoietin-related family members, were not shown to interact with LAG3 (data not shown), suggesting that the FGL1 / LAG3 interaction is highly specific.

[0160] We worked to determine the binding domain of FGL1 to LAG3 and whether this affects MHC-II interaction. FGL1 consists of a helix-coil domain (CCD) and a fibrinogen-like domain (FD) (Yamamoto, T. et al. Molecular cloning and initial characterization of a novel fibrinogen-related gene, HFRE...

Embodiment 3

[0163] In a competition assay, it was further determined whether existing monoclonal anti-LAG3 antibodies blocked the FGL1-LAG3 interaction. Human LAG3-expressing CHO cells were treated with fluorescently labeled FGL1 (1 ug / ml FGL-A647) in the presence or absence of anti-LAG3 antibody (10 ug / ml anti-LAG3-A488 antibody; R&D Systems) or with anti-CD3 antibody Primary T cells activated to induce LAG3 expression were stained to determine whether they compete with FGL1 for binding to LAG3. Binding of FGL1 was not reduced in the presence of anti-LAG3 antibodies (data not shown) and thus did not appear to interfere with the FGL1:LAG3 interaction.

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Abstract

The present invention relates to the identification of fibrinogen like protein 1 (FGL1) as a prognostic biomarker for responsiveness to an immune checkpoint inhibitor in a cancer patient. More specifically it relates to methods of treating cancer in a human patient comprising administering an immune checkpoint inhibitory antibody specifically inhibiting the interaction of fibrinogen-like protein 1 (FGL1) with lymphocyte-activation gene 3 protein (LAG3), wherein the cancer is an FGL1 expressing cancer. Further, the invention relates to methods for assessing susceptibility or predicting the responsiveness to the treatment with an immune checkpoint inhibitory antibody specifically inhibiting the interaction of FGL1 with LAG3 in a cancer patient, comprising detecting FGL1 expression in a sample from said patient and to a kit for selecting a cancer patient that would benefit from an immune checkpoint inhibitory antibody specifically inhibiting the interaction of FGL1 with LAG3. The immune checkpoint inhibitory antibody that specifically inhibits the interaction between FGL1 and LAG3 may be an antibody directed against human FGL1 or an antibody directed against human LAG3, optionally in combination with other immune checkpoint inhibitory antibodies, such as an anti-PD1 or an anti-PD-L1 antibody.

Description

technical field [0001] The present invention relates to the identification of fibrinogen-like protein 1 (FGL1 ) as a target for the treatment of cancer patients and as a prognostic biomarker for predicting the responsiveness of this cancer patient to immune checkpoint inhibitors. More specifically, the invention relates to a method of treating cancer in a human patient comprising administering an antibody that specifically inhibits the interaction of fibrinogen-like protein 1 (FGL1) with lymphocyte activation gene 3 protein (LAG3), and / or or an antibody that specifically binds to FGL1, wherein the cancer is preferably a cancer expressing FGL1. Furthermore, the present invention relates to a method for assessing sensitivity to or predicting responsiveness to treatment with an immune checkpoint inhibitory antibody in a cancer patient, said method comprising detecting FGL1 expression in a sample from said patient . The present invention also relates to kits for selecting cancer...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C40B30/04G01N33/574
CPCG01N33/574G01N33/57492G01N2333/70596G01N2800/52C40B30/04G01N2500/02A61P35/00A61K45/06A61K2039/507C07K16/2803C07K16/36G01N33/68G01N2496/00
Inventor D·A·布莱尔陈列平王俊T·郑
Owner YALE UNIV
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