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Current ADC Linker Chemistry.

Nareshkumar Jain1, Sean W Smith2, Sanjeevani Ghone2

  • 1The Chemistry Research Solution, LLC, 360 George Patterson Blvd., Suite 101E, Bristol, Pennsylvania, 19007, USA. njain@tcrs-us.com.

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|March 12, 2015
PubMed
Summary
This summary is machine-generated.

Antibody-drug conjugates (ADCs) are advancing, with many utilizing cysteine or lysine conjugation. Site-specific conjugation methods are emerging to create more homogeneous ADCs for improved linker design.

Keywords:
ADCADC clinical candidatesantibody-drug conjugatesbioconjugateslinker chemistry

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Area of Science:

  • Biotechnology
  • Pharmaceutical Sciences
  • Medicinal Chemistry

Background:

  • The clinical landscape of antibody-drug conjugates (ADCs) is expanding, with established drugs like ADCETRIS® and Kadcyla® paving the way.
  • Currently, 40 ADCs are in clinical development, but only 34 have disclosed structures, predominantly using cysteine (24) or lysine (10) conjugation to monoclonal antibodies (mAbs).
  • Heterogeneity in traditional conjugation methods leads to significant research into homogeneous ADC production.

Purpose of the Study:

  • To highlight the growing importance of ADCs in clinical development.
  • To discuss the limitations of current cysteine and lysine conjugation strategies.
  • To explore the potential of site-specific conjugation for creating homogeneous ADCs and advancing linker technology.

Main Methods:

  • Review of disclosed ADC structures in clinical development.
  • Analysis of conjugation strategies employed in existing and emerging ADCs.
  • Discussion of site-specific conjugation techniques, including genetic engineering for cysteine or non-natural amino acid incorporation.

Main Results:

  • A significant number of ADCs in development rely on conjugation to antibody cysteines or lysines.
  • Heterogeneity remains a challenge with current conjugation approaches.
  • Site-specific conjugation offers a pathway to homogeneous ADCs.

Conclusions:

  • Site-specific conjugation, through genetic engineering or non-natural amino acids, is crucial for producing homogeneous ADCs.
  • These advanced methods enable novel bio-orthogonal chemistries, expanding linker diversity.
  • This innovation is expected to drive the development of next-generation ADCs with improved therapeutic properties.