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Development and application of immunomodulator

A sequence and antibody technology, applied in the field of binding programmed death ligand 1 antibody

Pending Publication Date: 2022-06-17
CHENGDU CONMED BIOSCI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Although immune checkpoint therapy has achieved durable remission in some patients, currently marketed immune checkpoint inhibitors (including CTLA-4, PD-1 or PD-L1 monoclonal antibodies) only respond to about 15%-40% of patients. It is effective for the patients (Ribas, A. and J.D. Wolchok, Cancer immunotherapy using checkpoint blockade. Science, 2018.359(6382): p.1350-1355)

Method used

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  • Development and application of immunomodulator
  • Development and application of immunomodulator
  • Development and application of immunomodulator

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0180] Example 1. PD-L1 humanized antibody

[0181] The PD-L1 antibody is derived from the mouse hybridoma clone PDL1-3F2 obtained from immunized animals, and its antibody variable region sequence is as follows:

[0182] The amino acid sequence of the light chain variable region of PDL1-3F2 is shown in SEQ ID NO.1, its CDR1, CDR2 and CDR3 are shown in SEQ ID NO.2, 3, and 4, respectively, and its encoding nucleic acid is shown in SEQ ID NO.5 Show.

[0183] CDR1CDR2 RASQSISNNLH WYQQKSHESPRLLIK YASQSIS GIPSRFSGSGSGT--FR3------------->CDR3

[0184] DFTLSINSVETEDFGMYFC QQSKSWPFTF GSGTRLEIK

[0185]Nucleic acid sequence

[0186] GATATTGTGCTAGCTCAGTCTCCAGCCACCCTGTCTGTGACTcCAGGAGATAGCGTCAGTCTTTCCTGCAGGGCCAGCCAAAGTATTAGCAACAACCTACACTGGTATCAACAAAAATCACATGAGTCTCCAAGGCTTCTCATCAAGTATGCTTCCCAGTCCATCTCTGGGATCCCCTCTAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACTCTCAGTATCAACAGTGTGGAGACTGAAGATTTTGGAATGTATTTCTGTCAACAGAGTAAAAGCTGGCCATTCACGTTCGGCTCGGGGACAAGGTTGGAAATAAAA

[0187] The amino acid sequen...

Embodiment 2

[0218] Example 2. Binding and blocking activity of PD-L1 humanized antibody

[0219] 1. ELISA detection of humanized antibody binding to human PD-L1

[0220] 1 μg / ml human PD-L1 protein (Sinobiological #10084-H08H) was coated on a 96-well microtiter plate at 4°C overnight. After blocking with 2% milk, 100 μl of the recombinantly expressed PD-L1 humanized antibody prepared in Example 1 was added to each well, and incubated at room temperature for 1 hour; after washing three times with PBST and PBS, 100 μl of HRP-labeled antibody was added to each well. Human IgG F(ab)' 2 Secondary antibody, incubated at room temperature for 60 minutes. After washing three times with PBST and PBS, 100 μl of TMB substrate was added to each well for 10 minutes at 37° C. After color development, the reaction was terminated with 50 μl of 2M sulfuric acid solution per well, and the absorbance was read at a wavelength of 450 nm. The control antibody atezolizumab was synthesized according to the pub...

Embodiment 3

[0234] Example 3. Affinity determination of humanized antibody and PD-L1

[0235] 10 μg / ml of human PD-L1 recombinant protein was coupled to a CM5 chip (GEhealthcare) by amino coupling reagent, the flow rate was 10 μl / min, and the amount of antigen coupling was controlled by Biacore T200 to about 200RU. After the chip was rinsed with buffer until the baseline was stable, the PD-L1 antibody prepared in Example 1 with gradient dilution (from 10 μg / ml, 2-fold dilution for 7 gradients) was flowed through the chip at a flow rate of 30 μl / min, and the binding was set. Time 350 seconds, dissociation time 600 seconds. A 1:1 binding model was fitted with Biacore T200 evaluation software to obtain kinetic constants (Table 4).

[0236] Table 4. Affinity of PD-L1 humanized antibody and PD-L1 recombinant protein

[0237]

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PUM

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Abstract

The present disclosure relates to the development and use of an immunomodulator that is an antibody or antigen-binding portion thereof that binds to PD-L1. The PD-L1 antibody has high blocking activity on combination of PD-L1 and PD-1, a novel bifunctional antibody formed by the PD-L1 antibody and TGFBR2 can release the anti-tumor activity of T cells by blocking interaction of PD-L1 and PD-1, meanwhile, immunosuppression caused by activation of a smad signal channel by TGF-beta in a tumor microenvironment is effectively blocked, and the anti-tumor activity of the T cells is improved. The induction of effective and lasting anti-tumor immune response in the tumor which is not reacted originally is facilitated.

Description

technical field [0001] The present disclosure relates to the development of an immunomodulatory agent and its application, in particular to an antibody that binds programmed death ligand 1 (PD-L1) and its application. Background technique [0002] PD-L1 is a cell surface glycoprotein that is one of two known ligands for programmed death 1 (PD-1), which is thought to play an important role in immune regulation and maintenance of peripheral tolerance. Expression of PD-L1 has been observed on the surface of many immune cells, including untreated lymphocytes and activated B and T cells, monocytes and dendritic cells (ibid.). In addition, PD-L1 mRNA is expressed by non-lymphoid tissues (including vascular endothelial cells, epithelial cells, myocytes) as well as in tonsil and placental tissues. [0003] Although immune checkpoint therapy has achieved durable responses in a subset of patients, currently marketed immune checkpoint inhibitors (including CTLA-4, PD-1 or PD-L1 mAbs) ...

Claims

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Application Information

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IPC IPC(8): C07K16/28C07K19/00C12N15/13C12N15/62A61K45/00A61K47/68A61K51/10A61P31/12A61P31/14A61P31/18A61P31/20A61P35/00A61P37/02
CPCC07K16/2827A61K47/6849A61K47/6879A61K45/00A61K51/109A61K51/1027A61P35/00A61P37/02A61P31/12A61P31/18A61P31/20A61P31/14C07K2317/565C07K2317/56C07K2319/00
Inventor 徐刚陈博王常玉陈绪虹
Owner CHENGDU CONMED BIOSCI CO LTD
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