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Selecting for developability of polypeptide drugs in eukaryotic cell display systems

一种真核细胞、细胞的技术，应用在候选多肽药物的鉴定领域，能够解决缺乏等问题，达到晚期失败风险降低、改善可开发性特征的效果

Pending Publication Date: 2020-07-24
AIENTAS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite this, there is a lack of peptide drug discovery methods that easily integrate exploitability screening into candidate drug selection early in the process, especially aspects such as drug solubility and avoidance of non-specific binding.

Method used

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  • Selecting for developability of polypeptide drugs in eukaryotic cell display systems
  • Selecting for developability of polypeptide drugs in eukaryotic cell display systems
  • Selecting for developability of polypeptide drugs in eukaryotic cell display systems

Examples

Experimental program
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example 1

[0708] Example 1. Construction of targeting vectors for soluble expression and cell surface display of IgG formatted antibodies

[0709] To enable the display of binder molecules (including antibodies) on the surface of higher eukaryotic cells and their subsequent genetic selection, vectors can be used to target the binder genes to specific locations in the host genome. Vectors may encode selectable markers to enable selection of stable cell lines and such selectable markers may encode conferring resistance to blasticidin, G418 / Geneticin, hygromycin, puromycin (puromycin) or zeocin resistance gene. Targeting vectors may contain exogenous promoters that drive the expression of genes encoding selectable markers. Alternatively, the transgene can be integrated into the cellular DNA at a location downstream of an endogenous promoter so that correctly integrated transgenes can be preferentially selected. Targeting vectors will also encode homology arms to allow homologous recomb...

example 2

[0712] Example 2. Comparison of Surface Presentation Levels of 3 Pairs of Antibodies on Parental Clones and Developability Enhanced Clones

[0713] We examined three pairs of antibodies in which the original parent antibody had poor developability characteristics and its re-engineered daughter molecule that was altered to improve its self-interaction and cross-interaction properties. The panel includes CNTO607 (monoclonal antibody against interleukin IL-13) and its modified counterpart CNTO607 W100A 14 . CNTO607 is poorly soluble at neutral pH, precipitates in PBS buffer at high concentrations and shows self-interactions, as measured in an affinity-capture self-interaction nanoparticle spectroscopy (AC-SINS) assay 39 . Structural determination of CNTO697 reveals a hydrophobic patch in the heavy chain CDR3. VH CDR3 mutation W100A improves antibody solubility and cross-interaction chromatography (CIC) characteristics 47 . CIC measures binding to human serum polyclonal ant...

example 4

[0742] Example 4. Enrichment of "exploitability-enhancing" anti-NGF antibodies based on surface presentation levels

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Abstract

Use of the surface presentation level of binders (e.g., antibodies, receptors) on cultured higher eukaryotic cells in vitro as a predictive indicator of developability characteristics, e.g., solubility, of the binders. Display libraries of higher eukaryotic cells, e.g., mammalian cells, adapted for use in screening surface-displayed binders for developability and affinity of target binding. High-throughput screening of display libraries with in-built selection for developability including binder solubility, capability to be formulated at high concentrations, low propensity for non-specific binding, and half-life. Enrichment of populations of binders for developability characteristics and / or other qualities such as target binding and affinity, by controlling cell surface presentation of binders from an inducible promoter operably linked to binder-encoding DNA.

Description

technical field [0001] The present invention relates to the identification of candidate polypeptide drugs that possess desirable developability characteristics, such as solubility, ability to be formulated at high concentrations, low propensity for non-specific binding, and optimal half-life. The invention further relates to screening for binding agents by drug discovery, including antibody discovery. Background technique [0002] Antibodies have proven to be an extremely successful class of drugs, with more than 70 therapeutic antibodies approved to date and many more in the development pipeline. However, the production and formulation of polypeptide drugs (such as antibodies) is in many respects more complex and laborious than small molecule drugs. Many factors affect the feasibility of developing a polypeptide drug, such as an antibody, and whether a lead candidate antibody will be successfully developed into a drug that is not only effective, but also manufacturable, st...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/10
CPCC12N15/1037C12N15/102
Inventor J·麦考夫迪R·佩雷拉M·R·戴森K·帕特赫本J·L·锡尔加宁
Owner AIENTAS LTD
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