Recent progress in linker technology for antibody-drug conjugates: Methods for connection and release

Shino Manabe

doi:10.1007/978-4-431-56880-3_5

Recent progress in linker technology for antibody-drug conjugates: Methods for connection and release

Research output: Chapter in Book/Report/Conference proceeding › Chapter

Abstract

Linkers connect antibodies to payloads in antibody-drug conjugates (ADCs). The choice of linker controls the conjugation-site and antibody-drug ratios as well as the releasing mechanism and the rate of release. In order to optimize the efficacy of ADCs, improvements in linker technology, especially site-selective conjugation methods, are being explored. Site-specific conjugation methods involving non-natural amino acid incorporation, glycan utilization, and enzymatic addition methodologies are discussed in this chapter. In addition to conjugation methodology, payload-releasing strategy is a very important consideration for delivering maximum focused toxicity to the vicinity of the tumor cells. Although protease-cathepsin-cleavable dipeptide Val-Cit sequence is currently the most common choice for an enzymatic cleavable linker, novel approaches for releasing payloads, such as light stimulation and chemical reaction, have been reported. In this chapter, advances in development of linker technology will be reviewed.

Original language	English
Title of host publication	Cancer Drug Delivery Systems Based on the Tumor Microenvironment
Publisher	Springer Japan
Pages	93-123
Number of pages	31
ISBN (Electronic)	9784431568803
ISBN (Print)	9784431568780
DOIs	https://doi.org/10.1007/978-4-431-56880-3_5
Publication status	Published - 2020 Jan 1
Externally published	Yes

Keywords

1,6-elimitation reaction
Anti-IL-7R antibody
Anti-insoluble fibrin (IF) antibody
Bio-orthogonal reaction
Cancer stromal targeting (CAST) therapy
Cathepsin
Diketopiperazine-releasing spacer
Drug-to-antibody ratio (DAR)
Endo-β-N-acetylglucosaminidase
Enhanced permeability and retention (EPR) effect
Formylglycine-generating enzyme
Galactosyl transferase
Glycan
Inverse-electron-demand Diels-Alder reaction
Linker
Maleimide
Matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS)
Monomethyl auristatin E (MMAE)
MS imaging
Nucleophilic aromatic substitution (SAr)
p-aminobenzyl carbamate
Plasmin
Polyethylene glycol (PEG)
Sialyl transferase
SN-38
Sortase A
Strain-promoted azide-alkyne cycloaddition reaction
Therapeutic index
THIOMAB
Transglutaminase
Val-Cit
β-glucuronidase-cleavable linker

ASJC Scopus subject areas

Medicine(all)
Biochemistry, Genetics and Molecular Biology(all)
Engineering(all)

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title = "Recent progress in linker technology for antibody-drug conjugates: Methods for connection and release",

abstract = "Linkers connect antibodies to payloads in antibody-drug conjugates (ADCs). The choice of linker controls the conjugation-site and antibody-drug ratios as well as the releasing mechanism and the rate of release. In order to optimize the efficacy of ADCs, improvements in linker technology, especially site-selective conjugation methods, are being explored. Site-specific conjugation methods involving non-natural amino acid incorporation, glycan utilization, and enzymatic addition methodologies are discussed in this chapter. In addition to conjugation methodology, payload-releasing strategy is a very important consideration for delivering maximum focused toxicity to the vicinity of the tumor cells. Although protease-cathepsin-cleavable dipeptide Val-Cit sequence is currently the most common choice for an enzymatic cleavable linker, novel approaches for releasing payloads, such as light stimulation and chemical reaction, have been reported. In this chapter, advances in development of linker technology will be reviewed.",

keywords = "1,6-elimitation reaction, Anti-IL-7R antibody, Anti-insoluble fibrin (IF) antibody, Bio-orthogonal reaction, Cancer stromal targeting (CAST) therapy, Cathepsin, Diketopiperazine-releasing spacer, Drug-to-antibody ratio (DAR), Endo-β-N-acetylglucosaminidase, Enhanced permeability and retention (EPR) effect, Formylglycine-generating enzyme, Galactosyl transferase, Glycan, Inverse-electron-demand Diels-Alder reaction, Linker, Maleimide, Matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS), Monomethyl auristatin E (MMAE), MS imaging, Nucleophilic aromatic substitution (SAr), p-aminobenzyl carbamate, Plasmin, Polyethylene glycol (PEG), Sialyl transferase, SN-38, Sortase A, Strain-promoted azide-alkyne cycloaddition reaction, Therapeutic index, THIOMAB, Transglutaminase, Val-Cit, β-glucuronidase-cleavable linker",

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doi = "10.1007/978-4-431-56880-3_5",

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AB - Linkers connect antibodies to payloads in antibody-drug conjugates (ADCs). The choice of linker controls the conjugation-site and antibody-drug ratios as well as the releasing mechanism and the rate of release. In order to optimize the efficacy of ADCs, improvements in linker technology, especially site-selective conjugation methods, are being explored. Site-specific conjugation methods involving non-natural amino acid incorporation, glycan utilization, and enzymatic addition methodologies are discussed in this chapter. In addition to conjugation methodology, payload-releasing strategy is a very important consideration for delivering maximum focused toxicity to the vicinity of the tumor cells. Although protease-cathepsin-cleavable dipeptide Val-Cit sequence is currently the most common choice for an enzymatic cleavable linker, novel approaches for releasing payloads, such as light stimulation and chemical reaction, have been reported. In this chapter, advances in development of linker technology will be reviewed.

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KW - Anti-insoluble fibrin (IF) antibody

KW - Bio-orthogonal reaction

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