モノクローナル抗体製剤の進歩 免疫原性 完全マウス型抗体 1st 世代 キメラ型抗体 2nd 世代 ヒト化抗体 3rd 世代 完全ヒト型抗体

Presentation on theme: "モノクローナル抗体製剤の進歩 免疫原性 完全マウス型抗体 1st 世代 キメラ型抗体 2nd 世代 ヒト化抗体 3rd 世代 完全ヒト型抗体"— Presentation transcript:

1 モノクローナル抗体製剤の進歩 免疫原性 完全マウス型抗体 1st 世代 キメラ型抗体 2nd 世代 ヒト化抗体 3rd 世代 完全ヒト型抗体
免疫原性高度 100% マウス 例： ibritumomab マウス可変領域 マウス定常領域 ヒト可変領域 ヒト定常領域 免疫原性あり ~30% マウス 例： rituximab abciximab 免疫原性低度 ~5-10% マウス 例： trastuzumab bevacizumab 免疫原性なし 例： adalimumab panitumumab Ref 1/ Foltz 2013/ pg 2225/ figure 2 Ref 2/ Nelson 2010/ pg771/ table 1 & pg 768/ box 1 免疫原性 完全マウス型抗体 1st 世代 キメラ型抗体 2nd 世代 ヒト化抗体 3rd 世代 完全ヒト型抗体 4th 世代 The first therapeutic monoclonal antibodies were developed in mice. These fully mouse antibodies are recognised by the human immune system as foreign and are immunogenic. Immunogenicity against the therapeutic antibody leads to destruction of the antibody and can also result in hypersensitivity or allergic reaction. Second and third generation monoclonal antibodies incorporate all or some of the mouse variable region but retain a human constant region. Such fusion proteins have decreased immunogenicity in comparison to the fully mouse antibody. Current biotechnology practices enable the creation of fully human antibodies for use as therapeutics. These have the lowest potential for immunogenicity and are the gold standard in development today. 1 Catapano, A. a. (2013). The safety of therapeutic monoclonal antibodies: Implications for cardiovascular disease and targeting the PCSK9 pathway. Atherosclerosis, 1-11. 1. Foltz I et al. Circulation 2013 Jun 4;127(22): ; 2. Nelson AL et al. Nature Reviews Drug Discovery 2010 Oct;9(10): 　この2つの文献より作図

2 バイオテクノロジーの進歩が、マウスにヒト化抗体および 完全ヒト型抗体を産生させることを可能にした
野生型マウス* ヒト化抗体 マウスの可変鎖の一部（CDR）（赤）と完全ヒト型抗体骨格（青）が融合する B細胞 抗体発現 トランスジェニックマウス** 完全ヒト型抗体¶ 抗体骨格配列の多様性が生じる B細胞 抗体発現 Key Points: Several technologies exist for producing humanized (>97% human sequence) or “fully” human (100% human sequence) antibodies In this diagram, a common technique is shown whereby mice are the host for producing humanized or human antibodies For the production of a humanized antibody such as bococizumab, wild type mice were immunized with fully human PCSK9 protein, thereby inducing the mice to produce an antibody that fully recognizes the human version of PCSK9 A technique known as ‘CDR grafting’ was then employed which essentially entails splicing the CDRs from the antibody produced in response to the human PCSK9 onto a 100% human framework. For production of “fully” human antibodies, an alternative strategy can be used by generating transgenic or ‘humanized’ mice that express ‘fully’ human IgG antibodies. Here, when the mice are immunized with the protein of interest, such as PCSK9, the mice produce human IgGs against the protein. The main difference between these two protocols is that with humanized antibodies, the engineering steps takes place at the tail end by allowing for selection of CDRs that have the strongest binding and grafting them onto the desired IgG framework. For the production of ‘fully’ human antibodies, the engineering step takes place at the front end by creation of the transgenic mice that are able to express human IgGs. It is also important to note that one of the natural ways antibody diversity is generated in the immune response is due to somatic hypermutation - an adaptive process whereby gene rearrangements and gene mutations result in a diverse repertoire of antibodies with varying affinities for a particular target. In other words, due to this natural process, “fully” human antibodies are not technically fully human since they would inevitably differ from the germline IgG sequences encoded in the DNA. ヒト化抗体、完全ヒト型抗体は、マウスの免疫系で産生される Liang H et al. J Pharmacol Exp Ther. 2012;340(2):

3 バイオテクノロジーの進歩が、マウスにヒト化抗体および 完全ヒト型抗体を産生させることを可能にした
野生型マウス* ヒト化抗体 マウスの可変鎖の一部（CDR）（赤）と完全ヒト型抗体骨格（青）が融合する B細胞 抗体発現 トランスジェニックマウス** 完全ヒト型抗体¶ 抗体骨格配列の多様性が生じる B細胞 抗体発現 Key Points: Several technologies exist for producing humanized (>97% human sequence) or “fully” human (100% human sequence) antibodies In this diagram, a common technique is shown whereby mice are the host for producing humanized or human antibodies For the production of a humanized antibody such as bococizumab, wild type mice were immunized with fully human PCSK9 protein, thereby inducing the mice to produce an antibody that fully recognizes the human version of PCSK9 A technique known as ‘CDR grafting’ was then employed which essentially entails splicing the CDRs from the antibody produced in response to the human PCSK9 onto a 100% human framework. For production of “fully” human antibodies, an alternative strategy can be used by generating transgenic or ‘humanized’ mice that express ‘fully’ human IgG antibodies. Here, when the mice are immunized with the protein of interest, such as PCSK9, the mice produce human IgGs against the protein. The main difference between these two protocols is that with humanized antibodies, the engineering steps takes place at the tail end by allowing for selection of CDRs that have the strongest binding and grafting them onto the desired IgG framework. For the production of ‘fully’ human antibodies, the engineering step takes place at the front end by creation of the transgenic mice that are able to express human IgGs. It is also important to note that one of the natural ways antibody diversity is generated in the immune response is due to somatic hypermutation - an adaptive process whereby gene rearrangements and gene mutations result in a diverse repertoire of antibodies with varying affinities for a particular target. In other words, due to this natural process, “fully” human antibodies are not technically fully human since they would inevitably differ from the germline IgG sequences encoded in the DNA. ヒト化抗体、完全ヒト型抗体は、マウスの免疫系で産生される Liang H et al. J Pharmacol Exp Ther. 2012;340(2):