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Antagonistic PD-1, PD-L1 and LAG-3 binding proteins

A PD-L1 and binding protein technology, applied in the direction of anti-animal/human immunoglobulin, immunoglobulin, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, etc.

Pending Publication Date: 2020-11-27
ケイレスアーゲー
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of these trials did not perform preclinical head-to-head comparisons to predict the most effective treatments due to the inability to obtain large numbers of antibodies against different immune checkpoints in one laboratory

Method used

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  • Antagonistic PD-1, PD-L1 and LAG-3 binding proteins
  • Antagonistic PD-1, PD-L1 and LAG-3 binding proteins
  • Antagonistic PD-1, PD-L1 and LAG-3 binding proteins

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Experimental program
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Effect test

Embodiment approach

[0305] In the following, different aspects of the invention will be defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as preferred or advantageous may be combined with any other feature or features indicated as preferred or advantageous.

[0306] In a first aspect, the invention provides an antagonistic antigen binding protein that specifically binds PD-1, wherein said antigen binding protein competes for binding to PD-1 with an antibody, said antibody

[0307] (i) comprising the amino acid sequence heavy chain variable region of SEQ ID NO: 2; and the amino acid sequence light chain variable region of SEQ ID NO: 3; or

[0308] (ii) comprising the amino acid sequence of SEQ ID NO:11 heavy chain variable region; and the amino acid sequence of SEQ ID NO:12 light chain variable region.

[0309] Preferably, the present invention provides an antagonistic ant...

Embodiment 1

[0682] Example 1: Selection of scFv on activated human T lymphocytes

[0683] Our goal is to generate a library of human antibodies against immune checkpoints (ICs). Since many ICs are expressed on the surface of T lymphocytes and their expression increases when T cells are exposed to antigen-dependent or antigen-independent stimuli, we sought to use unfractionated human peripheral blood mononuclear cells (hPBMC) To screen a library of human single-chain antibody fragments (scFvs). To optimize the selection process, we first assessed the kinetics and expression levels of ten different ICs (shown in Table 1) after activation with anti-CD3 / CD28 beads in vitro. As shown in Table 1, peak expression measured by flow cytometry analysis varied among the different immunomodulators, however, most stimulators reached maximally displayed levels after 96 hours of stimulation (see Table 1). After 96 hours of stimulation, all ICs were well expressed in more than 50% of the gated populatio...

Embodiment 2

[0687] Example 2: Determination of scFv binders by next generation sequencing

[0688] To identify individual phage clones selected by the combined in vitro / in vitro approach, we sequenced the VH region of the IC-specific library by massively parallel sequencing on the MiSeqIllumina platform (see Materials and methods section for details). To ensure efficient enrichment of target-specific phage, starting from the immunome library (cycle 1), we performed two subsequent rounds of selection (cycle 2 and cycle 3) on Fc-fusion recombinant proteins. Sequence analysis of the entire selection sequence showed that enrichment had indeed occurred after cycle 2, but a higher level of enrichment (i.e.: at least 10-fold) was obtained after the third cycle ( figure 1 ). Analysis of the parallel sequencing data allowed us to remove all selected VH sequences that were shared, possibly due to the enrichment of Fc binders shared by the 10 biochemical baits. Similarly, non-specifically bioenric...

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Abstract

The present invention relates to antagonistic antigen binding proteins, a nucleic acid encoding the antagonistic binding protein, a recombinant expression vector comprising the nucleic acid molecule,a host cell comprising the vector, a method of making the antagonistic antigen binding protein, an antagonistic binding protein produced by the method and a pharmaceutical composition comprising the antagonistic binding protein, the nucleic acid or the vector. The present invention further relates to a kit comprising the pharmaceutical composition and use of the antagonistic binding protein in thetreatment of cancer and / or chronic infectious diseases.

Description

[0001] The present invention relates to an antagonistic antigen binding protein, a nucleic acid encoding the antagonistic binding protein, a recombinant expression vector comprising the nucleic acid molecule, a host cell comprising the vector, a method for preparing the antagonistic antigen binding protein, and an antagonistic antigen binding protein produced by the method. Binding proteins and pharmaceutical compositions comprising antagonist binding proteins, nucleic acids or vectors. The present invention also relates to a kit comprising the pharmaceutical composition and the use of the antagonistic binding protein in the treatment of cancer and / or chronic infectious diseases. [0002] Background of the invention [0003] Activation and proliferation of immune cells involved in antitumor responses are regulated by multiple stimulatory and inhibitory pathways. Monoclonal antibodies (mAbs) can target a variety of stimulatory and inhibitory pathways, and these mAbs can inhibit ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28A61K39/00
CPCC07K16/2803C07K16/2818C07K16/2827C07K2317/21C07K2317/622C07K2317/73C07K2317/76C07K2317/92A61K2039/505A61P35/00C07K2317/565
Inventor 阿尔弗雷多·尼科西亚尼古拉·赞布拉诺埃马努埃莱·萨索克劳迪娅·德洛伦佐
Owner ケイレスアーゲー
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