抗体医薬はどうやって細胞質内の標的タンパク質に結合できるのか？

アルツハイマー病の治療戦略の一つに抗体医薬があります。脳内に蓄積するβアミロイドがあるADの原因という仮説があるので、βアミロイドに対する抗体でそれを除去できればアルツハイマー病が治療できるのではないかということだと思います。しかし、βアミロイドは細胞内に凝集するんじゃなかったっけ？どうして血中の抗体がそこにアクセスできるの？という疑問が湧きました。ChatGPT 4oに聞いてみました。以下は、その答え。そもそもβアミロイドタンパク質は細胞外に凝集するのだそうです。血液脳関門を抗体は通過できるのか？という疑問もあります。

The confusion here stems from the misunderstanding of where beta-amyloid (Aβ) accumulates in Alzheimer’s disease and how antibody-based therapies target these aggregates.

  1. Location of Beta-Amyloid Accumulation:
    In Alzheimer’s disease, beta-amyloid peptides primarily accumulate extracellularly, forming plaques in the brain tissue. These plaques are found in the space between neurons, not within the cytoplasm. Intracellular accumulation of beta-amyloid can also occur, but the large plaques that are characteristic of Alzheimer’s disease are extracellular.　https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10572082/
  2. Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans　
  3. MAbs. 2023; 15(1): 2261509. Published online 2023 Oct 12. doi: 10.1080/19420862.2023.2261509 PMCID: PMC10572082 PMID: 37823690　There are few treatments that slow neurodegeneration in Alzheimer’s disease (AD), and while therapeutic antibodies are being investigated in clinical trials for AD treatment, their access to the central nervous system is restricted by the blood–brain barrier.
  4. Mechanism of Antibody-Based Therapies:
    Antibody-based therapies for Alzheimer’s disease, such as monoclonal antibodies targeting beta-amyloid, work primarily by binding to the extracellular beta-amyloid plaques. These antibodies are designed to recognize and bind to specific forms of beta-amyloid, including the fibrillar forms that make up the plaques. Once the antibody binds to the beta-amyloid, it can recruit immune cells (such as microglia) to help clear the plaques through processes like phagocytosis.Additionally, some antibodies can bind to soluble beta-amyloid oligomers, which are smaller aggregates that are toxic to neurons. By binding to these soluble forms, the antibodies may prevent their aggregation into larger plaques or neutralize their toxic effects.
  5. Crossing the Blood-Brain Barrier:
    One of the challenges for antibody-based therapies is crossing the blood-brain barrier (BBB). However, some engineered antibodies or fragments of antibodies can cross the BBB to some extent, and once they are in the brain tissue, they can interact with the extracellular beta-amyloid.

To summarize, while antibodies generally do not enter cells and act intracellularly, they are effective in targeting the extracellular beta-amyloid plaques and soluble oligomers in Alzheimer’s disease. This extracellular targeting is sufficient for therapeutic purposes because the major pathological beta-amyloid aggregates are located outside of the neurons.

（ChatGPT 4o)

  1. Anti-amyloid-β Antibodies and Anti-tau Therapies for Alzheimer’s Disease: Recent Advances and Perspectives　2024 Volume 72 Issue 7 Pages 602-609　Chemical and Pharmaceutical Bulletin
  2. Immunotherapy for Alzheimer’s disease: targeting β-amyloid and beyond　Translational Neurodegeneration volume 11, Article number: 18 (2022)　Published: 18 March 2022

BBBを抗体が通過できない問題

 ~100% of biologic drugs do not cross the BBB　https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697739/

BBB restricts peripheral proteins and antibodies from entering the CNS. Protein passage through the BBB is mostly non-specific and is <0.1% of peripheral circulating proteins enter the CNS [, ]. Although neurodegenerative diseases are believed to cause dysfunctions of BBB with higher permeability, it has been demonstrated that the BBB integrity was well maintained, preventing passive BBB permeability of IgG injected peripherally in multiple AD mouse models, including PS2-amyloid precursor protein (APP), Tau transgenics, and APOE4 knock-in mice []. It was estimated that only 0.01% of the peripheral antibody molecules may enter the CNS [].　https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9759110/

アルツハイマー病の抗体薬

All currently approved DMTs for the treatment of AD are anti-amyloid monoclonal antibodies (mAbs). The two approved agents are aducanumab (Aduhelm®; Biogen, Cambridge, MA, USA), which received accelerated approval based on marked lowering of β-amyloid (Aβ) plaques as seen on amyloid positron emission tomography (PET) considered reasonably likely to predict clinical benefit [2]; and lecanemab (Leqembi®; Eisai Inc. and Biogen, Cambridge, MA, USA), which received accelerated approval based on a phase II study followed by standard approval based on clinical and biomarker data from a phase III study [3, 4].

Anti-Amyloid Monoclonal Antibodies for the Treatment of Alzheimer’s Disease Review Article Open access Published: 13 November 2023 Volume 38, pages 5–22, (2024)　https://link.springer.com/article/10.1007/s40259-023-00633-2

 

 

 

参考

  1. Blood-brain barrier permeable antibodies for Alzheimer’s potential therapeutic and diagnostic applications Ram Bhatt, Oscar Ramos First published: 16 June 2023 https://doi.org/10.1002/alz.061328　https://alz-journals.onlinelibrary.wiley.com/doi/abs/10.1002/alz.061328
  2. Targeting antibodies to the cytoplasm　MAbs. 2011 Jan-Feb; 3(1): 3–16. Published online 2011 Jan 1. doi: 10.4161/mabs.3.1.14110 PMCID: PMC3038006 Here, the various technologies to target intracellular proteins with antibodies are reviewed.