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化学的に自己組み立てた抗体ナノリング (CSANs):抗CD3IgMバイオミテックの設計と特徴付け
Qing Li1, Christopher R So, Adrian Fegan
1Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Journal of the American Chemical Society
|November 17, 2010
まとめ
化学的に自己組み立てた抗体ナノリング (CSANs) は,標的の投与のために,IgMに類似する多価抗体を作成するための新しい方法を提供します. これらのナノリングは,伝統的なモノクローナル抗体とは異なり,T細胞の活性化を引き起こすことなく,CD3+白血病細胞に選択的に結合します.
科学分野:
- バイオテクノロジー バイオテクノロジー
- 免疫学 免疫学とは
- 構造生物学 構造生物学とは
背景:
- 既存の再結合抗体技術は,二価 (IgG) と四価 (IgA) の構造を達成することができます.
- より高いバレンシーは,通常,ナノ粒子への抗体結合によって達成されますが,IgMのようなバレンシー (デカバレンシー) を有する再結合抗体を生成する方法は欠けています.
研究 の 目的:
- IgMのようなバレンシーを持つ再結合抗体を作るための新しい方法論を開発する.
- キーナノリングサブユニットの結晶構造を特徴付ける.
- これらの多価ナノリングの生物学的活動と治療の可能性を評価する.
主な方法:
- 化学的に自己組み立てた抗体ナノリング (CSAN) を設計・製造しました.
- E. coli DHFRディマーとメトトレキサートディメリザーを含むナノリングサブユニットの結晶構造を決定しました.
- 融合タンパク質から8〜10の単鎖変数断片 (scFvs) を含む組み立てられたCSAN.
主要な成果:
- ナノリングサブユニットの結晶構造を報告した.
- 8-10 scFvs.までのバレンシーを持つCSANを成功裏に準備しました.
- CD3+白血病細胞に対する抗CD3CSANの選択的結合が実証されています.
- CSANsは,コレステロール,アクチン,およびタンパク質チロシンキナーゼを必要とするカヴェオリン独立経路を通じて内部化することが示されています.
- モノクローナル抗体と比較して,CSANによるT細胞受容体ダウンレギュレーションの有意な減少とT細胞増殖の欠如が観察されました.
- CSANで治療されたPBMCでは,モノクローナル抗体よりもCD25発現が低いことが判明しました.
結論:
- 2-8のバレンシーを持つ抗CD3CSANは,T細胞の活性化を誘導することなく,T細胞に標的を絞って投与するために使用できます.
- CSANは,有害な活性化効果を回避して,抗体結合ナノ粒子に潜在的な代替案を提供します.
- CSANプラットフォームは,他の多価単鎖変数フラグメントを作成するために適応可能です.
関連する概念動画
01:25Antibody Structure and Classes
Antibodies, also known as immunoglobulins, are produced by B cells in response to foreign substances, such as bacteria and viruses. These proteins are critical for recognizing and neutralizing these substances, protecting the body from potential harm.
The basic structure of an antibody consists of four protein chains: two identical heavy chains and two identical light chains. These chains are held together by disulfide bonds and other non-covalent interactions, forming a Y-shaped structure.
The basic structure of an antibody consists of four protein chains: two identical heavy chains and two identical light chains. These chains are held together by disulfide bonds and other non-covalent interactions, forming a Y-shaped structure.
01:10Antibody Structure
Overview
Antibodies, also known as immunoglobulins (Ig), are essential players of the adaptive immune system. These antigen-binding proteins are produced by B cells and make up 20 percent of the total blood plasma by weight. In mammals, antibodies fall into five different classes, which each elicits a different biological response upon antigen binding.
The Y-Shaped Structure of Antibodies Consists of Four Polypeptide Chains
Antibodies consist of four polypeptide chains: two identical heavy...
Antibodies, also known as immunoglobulins (Ig), are essential players of the adaptive immune system. These antigen-binding proteins are produced by B cells and make up 20 percent of the total blood plasma by weight. In mammals, antibodies fall into five different classes, which each elicits a different biological response upon antigen binding.
The Y-Shaped Structure of Antibodies Consists of Four Polypeptide Chains
Antibodies consist of four polypeptide chains: two identical heavy...
01:10Antibody Structure
Overview
Antibodies, also known as immunoglobulins (Ig), are essential players of the adaptive immune system. These antigen-binding proteins are produced by B cells and make up 20 percent of the total blood plasma by weight. In mammals, antibodies fall into five different classes, which each elicits a different biological response upon antigen binding.
The Y-Shaped Structure of Antibodies Consists of Four Polypeptide Chains
Antibodies consist of four polypeptide chains: two identical heavy...
Antibodies, also known as immunoglobulins (Ig), are essential players of the adaptive immune system. These antigen-binding proteins are produced by B cells and make up 20 percent of the total blood plasma by weight. In mammals, antibodies fall into five different classes, which each elicits a different biological response upon antigen binding.
The Y-Shaped Structure of Antibodies Consists of Four Polypeptide Chains
Antibodies consist of four polypeptide chains: two identical heavy...
01:31Immunoglobulin-like Cell Adhesion Molecules
Immunoglobulin-like cell adhesion molecules or Ig-CAMs are a versatile group of cell surface glycoproteins belonging to the immunoglobulin protein superfamily. Ig-CAMs possess the characteristic immunoglobulin protein domains and other domains such as the fibronectin type III domain. The Ig domains are glycosylated to varying degrees in different Ig-CAMs.
Ig-CAMs exhibit either homophilic binding (to other Ig-CAMs) or heterophilic binding (to other ligands such as integrins). While most Ig-CAMs...
Ig-CAMs exhibit either homophilic binding (to other Ig-CAMs) or heterophilic binding (to other ligands such as integrins). While most Ig-CAMs...