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MULTIVALENT IgM- AND IgA-Fc-BASED BINDING MOLECULES

A technology for binding molecules and polypeptides, applied in the field of multivalent binding molecules based on IgM-Fc and IgA-Fc, which can solve problems such as untested signal transduction ability

Pending Publication Date: 2021-05-25
IGM BIOSCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In another study, human PD-L1 ectodomain was fused to wild-type human IgM constant region and expressed with or without human J chain and tested in vitro flow cytometry and plate-based immunoassays, However, the ability of the construct to induce signal transduction in PD-1 expressing cells was not tested (Ammann, JU. et al., Eur. J. Immunol 42:1354-1356 (2012)

Method used

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  • MULTIVALENT IgM- AND IgA-Fc-BASED BINDING MOLECULES
  • MULTIVALENT IgM- AND IgA-Fc-BASED BINDING MOLECULES
  • MULTIVALENT IgM- AND IgA-Fc-BASED BINDING MOLECULES

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0174] Example 1: Construction of multivalent PD-L1-IgM fusion protein

[0175] Two DNA constructs encoding PD-L1-IgM fusion protein subunits were constructed by commercial suppliers. The schematic is provided as Figure 3A and Figure 3B .

[0176] The first construct included DNA encoding the signal peptide, the V1 and C2 domains of human PD-L1 (amino acids 1 to 238 of UniProtKB / Swiss-Prot: Q9NZQ7.1 presented herein as SEQ ID NO: 8), so Said DNA was fused to DNA encoding the Cμ2, Cμ3, Cμ4 and tail (tp) domains of the human IgM constant region modified with P311A and P313S amino acid substitutions in the Cμ3 domain to reduce or eliminate complement mediation. induced cytotoxicity (see P PCT Publication No. WO 2018 / 187702, which is hereby incorporated by reference in its entirety). The amino acid sequence of the precursor fusion protein encoded by the construct is presented herein as SEQ ID NO: 11, and the amino acid sequence of the mature fusion protein encoded by the con...

Embodiment 2

[0180] Example 2: Activation of PD-1 expressing T cells by PD-L1-IgM and PD-L1-H-IgM

[0181] The ability of the hexameric and pentameric forms of the PD-L1-IgM and PD-L1-H-IgM fusion proteins to activate PD-1 expressing T cells was assessed as follows. Reporter Jurkat T cells that produce light upon activation by PD-1 were obtained from DiscoverX ( PD-1 assay, catalog number 93-1104C19) was purchased and used according to the manufacturer's instructions. In these cells, the full-length PD-1 receptor is engineered with a small β-gal fragment fused to its C-terminus, and the SH2 domain of SHP-1 is engineered with a complementary β-gal fragment (EA). These constructs were stably expressed in Jurkat cells. After PD-L1 engages PD-1 on the surface of these cells, the PD-1 fusion protein is phosphorylated, resulting in the recruitment of the SHP-1 fusion protein, which generates active β-gal enzyme. This active enzyme hydrolyzes the substrate to produce chemiluminescence as a me...

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Abstract

This disclosure provides IgM-and IgA-derived binding molecules comprising binding polypeptides, e.g., receptor ectodomains, ligands, or receptor-binding fragments thereof, and the like, fused to multimerizing IgM or IgA constant regions.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 62 / 749,429, filed October 23, 2018, which is incorporated herein by reference in its entirety. [0003] sequence listing [0004] This application contains a Sequence Listing that has been filed electronically in ASCII format and is hereby incorporated by reference herein in its entirety. The ASCII copy was created on October 23, 2019, named 09789-021WO1-Sequence-Listing, and is 190,396 bytes in size. Background technique [0005] Multimerizable antibodies and antibody-like molecules such as IgA and IgM antibodies have emerged as promising drug candidates in fields such as immuno-oncology and infectious diseases, allowing for improved specificity, improved avidity, and the ability to bind multiple binding targets. 参见例如美国专利第9,951,134、10,400,038和9,938,347号,美国专利申请公布第US20190100597A1、US20180118814A1、US20180118816A1、US20190185570A1和US201802...

Claims

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Application Information

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IPC IPC(8): A61K39/395C07K16/28C07K14/705
CPCC07K14/705C12N15/62C07K2319/00C07K2317/528C07K2317/52C07K2319/30C07K16/00C07K14/70578C07K14/70532C07K14/70521C07K14/70503C12N15/85C12N5/0636C07K16/2827C07K16/2803C07K16/2818C07K16/2863A61P37/06C07K2317/734C07K2317/622C12N2510/00A61K2039/505C07K2317/31
Inventor R·巴利加P·辛顿D·吴B·基特
Owner IGM BIOSCI
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