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Antibodies specific to human nectin-2

A connexin and antibody technology, applied in the direction of animal/human protein, anti-animal/human immunoglobulin, antibody, etc.

Pending Publication Date: 2021-08-24
YISSUM RES DEV CO OF THE HEBREWUNIVERSITY OF JERUSALEM LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] There is an unmet need to provide additional and more effective, specific, safe and / or stable agents that can boost cells of the immune system to attack tumor or virus-infected cells alone or in combination with other agents

Method used

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  • Antibodies specific to human nectin-2
  • Antibodies specific to human nectin-2
  • Antibodies specific to human nectin-2

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0311] Example 1. High expression of connexin-2 mRNA correlates with poor survival probability in patients with various cancers

[0312] The correlation between connexin-2 mRNA expression and survival probability was studied on the data from the TCGA website and analyzed using the oncolnc.org website (https: / / doi.org / 10.7717 / peerj-cs.67) . For low-grade gliomas ( Figure 1A ; p=5.22E-5), renal clear cell carcinoma ( Figure 1B ; p=0.00037) and lung adenocarcinoma ( Figure 1C ; p=0.0319) patients, this correlation is indicated by the arrow in Figure 1 .

Embodiment 2

[0313] Example 2. Connexin-2 binds and affects immune cells through specific receptors

[0314] Schematic representation of receptors expressed on immune cells and their corresponding affinities for connexin-2 expressed on tumors or on antigen-presenting cells (APCs) ( figure 2 ). TIGIT is associated with co-inhibitory receptors on immune cells such as T and NK cells; DNAM-1 (also known as CD226) is associated with activating receptors on immune cells such as T cells, and CD112R (also known as PVRIG ) is associated with co-inhibitory receptors on lymphoid immune cells (such as T and NK cells); connexin-2 (CD112) is an inhibitory ligand of immune cells, mainly through its binding to CD112R. According to the present invention, anti-connexin-2 mAb can block the interaction of connexin-2 with its ligands CD112R and / or TIGIT and enhance the activation of immune cells.

Embodiment 3

[0315] Example 3. Analysis of the binding and blocking characteristics of anti-connexin-2 mAbs

[0316] Connexin-2 clones did not bind to parental 8866 cells (EBV positive Burkitt lymphoma) that do not express connexin-2. Figure 3A Shows the association of anti-connexin-2 antibody clones with MDA-MB-231 (breast adenocarcinoma) cells endogenously expressing connexin-2 (black bars) or 8866-human connexin-2 overexpressing connexin-2 Binding of cells (gray bars). All mAbs used 30ul / well hybridoma supernatant. Goat anti-mouse 647 Ab diluted 1:250 was used for detection. Figure 3B The results of FACS analysis of CD112R-Fc (extracellular domain of CD112R fused to Fc region of human IgG1) bound to 8866-human connexin 2 cells are shown. Of the antibodies produced, three clones (#9, 11 and 13) partially blocked these interactions, while one clone (#7) completely blocked them. Figure 3C Results of FACS analysis of DNAM-1-Fc bound to 8866-human connexin 2 cells are shown. Except f...

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Abstract

The present dislosure provides monoclonal antibodies that recognize human Nectin-2 ( Nectin-2, Poliovirus Receptor-Related Protein-2, Poliovirus Receptor-Like 2, CDI12, or PRR-2, is a single pass transmembrane glycoprotein with two Ig-like C2-type domains and an Ig-like V-type domain) with high affinity and specificity and inhibit its binding to TIGIT and / or CD112R. The antibodies recognize the Nectin-2 protein (CD112), prevent its binding to T cell immunoreceptor with Ig and ITIM domains (TIGIT) and CD112R (PVRIG) and inhibit suppressive activity on lymphocytes such as natural killer (NK) cells and T-cells. The disclosure further provides pharmaceutical and methods for use in cancer immunotherapy and in diagnosis. The disclosure finally further provides chimeric antigen receptor (CAR) comprising scFv antibody binding to Nectin-2.

Description

technical field [0001] The present invention belongs to the field of immunotherapy and relates to antibodies and fragments thereof binding to human protein connexin-2 (CD112), polynucleotide sequences encoding these antibodies and fragments and cells producing them. The invention also relates to therapeutic and diagnostic compositions comprising these antibodies and fragments, and methods of using them for the treatment and diagnosis of diseases, especially cancer. Background technique [0002] Cancer immunotherapy is used to generate and enhance an anti-tumor immune response, for example by treatment with antibodies specific to antigens on tumor cells, by treatment using fusions of antigen-presenting cells and tumor cells, or by specific activation of anti-tumor T cells . The ability to recruit immune cells, such as T cells, against tumor cells in patients offers a treatment modality to combat cancer types and metastases that until now were considered incurable. [0003] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P3/02A61P43/00C07K16/28
CPCC07K16/2803C07K16/2809C07K16/2896A61P3/02A61P43/00C07K2317/622C07K2317/73C07K2317/76Y02A50/30C07K14/70517C07K14/70521C07K14/70578C07K14/7051C12N5/0636A61K35/17A61P35/00A61P31/12C07K2317/92A61K2039/505C07K2319/02C12N2510/00C07K16/2818C07K2317/74C07K2319/03G01N33/57492
Inventor 奥夫尔·曼德尔波姆平沙斯·楚克尔曼斯提潘·约尼奇蒂哈娜·莱纳克罗维斯保拉·库坎布里克
Owner YISSUM RES DEV CO OF THE HEBREWUNIVERSITY OF JERUSALEM LTD
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