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Trispecific antigen binding proteins

A protein-binding and specific technology, used in hybrid immunoglobulins, anti-animal/human immunoglobulins, immunoglobulins, etc.

Pending Publication Date: 2020-12-22
CDR 生物科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These strategies do not address issues related to TAA expression on normal tissues or shedding of cell surface antigens that may create an "antigensink" that prevents therapeutic antibodies from reaching their intended tumor cell targets in vivo (see, For example Piccione et al. mAbs [monoclonal antibodies], 7(5):946-956, 2015; Herrmann et al. Blood [blood], 132(23):2484-2494, 2018)

Method used

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Examples

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example

[0211] Example 1 - Design, Expression and Purification of Exemplary Trispecific Antigen Binding Proteins

[0212] background

[0213] A major challenge in the development of trispecific antigen-binding protein therapeutics is the selection of molecular forms from among structurally diverse alternatives that can support a variety of different biological and pharmacological properties while maintaining the desirable attributes of developability. Such attributes include high thermal stability, high solubility, low tendency to aggregate, low viscosity, chemical stability and high level of expression (gram per liter titer).

[0214] Production of trispecific antigen-binding proteins by co-expression of multiple (three) light and heavy chains in a single host cell can be highly challenging due to low yields of the desired trispecific antigen-binding protein, And it is difficult to remove closely related mismatched contaminants. In IgG-based trispecific antigen-binding proteins, ...

example 2- 3

[0237] Example 2 - Ability of Trispecific Molecules and Bispecific Controls to Bind Their Targets

[0238] Binding ELISA assays were performed to determine whether the exemplary trispecific antigen binding proteins bound to their respective targets. The ability of the trispecific antibody CDR1-007 to bind its antigen was evaluated. Serial dilutions of CDR-007 to final concentrations ranging from 4 ng / mL to 10 μg / ml were tested in ELISA with human PD-L1 His-tag (nearside protein, #C315) recombinant human BCMA Fc chimera (produced in-house by transient expression in HEK293-6E cells) and the CD3εHis tag (proximity protein, #C578), each of which was coated on a 96-well plate. Trispecific antibodies were detected by goat anti-κ-LC antibody HRP (Thermo Fisher Scientific, #A18853). Figure 4A to Figure 4C Concentration-dependent binding of CDR1-007 was shown, confirming the ability of this trispecific antibody to bind three targets.

[0239] Additionally, the ability of trispecifi...

example 3-CD3

[0240] Example 3 - Ability of CD3 Binding Arm to Induce T Cell Proliferation

[0241] Antigen receptor molecules on human T lymphocytes are non-covalently associated with CD3 (T3) molecular complexes on the cell surface. Interference with this complex with anti-CD3 monoclonal antibodies may induce T cell activation, but this ability depends on certain properties, such as binding affinity, epitope, valency, antibody format, etc.

[0242] Linking different antigen-binding sites in fusion proteins to generate bispecific antibodies often exhibits reduced affinity for their target antigens compared to the parental antibody. Therefore, careful consideration should be given when evaluating the CD3-binding arms of T cell engagers to ensure functionality. One of the most common methods for assessing the ability of CD3 agonistic antibodies to activate T cells is to measure T cell proliferation after stimulation in vitro.

[0243] The CD3 binding arm design of the present invention was...

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Abstract

Trispecific antigen-binding proteins including: a first binding domain capable of binding to a cell surface protein of a tumor cell; a second binding domain capable of binding to a cell surface immunecheckpoint protein of the tumor cell; and a third binding domain capable of binding to a cell surface protein of an immune cell, are provided. Methods of making trispecific antigen-binding proteins are provided.

Description

technical field [0001] The present disclosure relates to compositions and methods of making trispecific antigen binding proteins. Background technique [0002] Bispecific T cell engagers activate T cells via CD3 and crosslink them to tumor-expressed antigens, thereby inducing immune synapse formation and tumor cell lysis. Bispecific T cell engagers have shown therapeutic efficacy in patients with liquid tumors; however, they do not benefit all patients. Antitumor immunity is limited by immunosuppression mediated by the PD-1 / PD-L1 pathway, and patients who do not benefit from existing bispecific T cell engagers may not respond because their T cells pass through PD The -1 / PD-L1 pathway is anergized. The use of monoclonal antibodies that block immune checkpoint molecules such as PD-L1 may help increase the baseline T cell-specific immune response that turns the immune system against tumors. However, disruption of the function of immune checkpoint molecules can lead to an imb...

Claims

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Application Information

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IPC IPC(8): C07K16/46C07K16/28C07K16/32A61P35/00
CPCC07K16/2803C07K16/2827C07K16/2878C07K16/32C07K2317/31C07K2317/52C07K2317/55C07K2317/565C07K2317/569C07K2317/62C07K2317/622C07K2317/64C07K2317/70C07K2317/73C07K2317/92C07K2317/94C07K2319/00A61K2039/507A61P35/00C07K16/2809G01N33/6854C07K16/30C07K2317/35C07K2317/24C07K2317/74C07K2317/76C07K2319/30G01N33/5011
Inventor 莱昂纳多·博拉斯多米尼克·埃舍尔克里斯蒂安·瓦尔德马·温格·莱斯纳法比安·沙伊费勒托马斯·施莱尔菲利普·罗伯特·瑞克雷
Owner CDR 生物科技股份有限公司
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