Antibody drug conjugates of cleavable amino-alkyl and aryl maytansinoids

Bioorg Med Chem. 2018 May 15;26(9):2271-2279. doi: 10.1016/j.bmc.2018.02.025. Epub 2018 Feb 21.

Abstract

Natural products have been used for many medicinal purposes for centuries. Antibody drug conjugates (ADCs) have utilized this rich source of small molecule therapeutics to produce several clinically useful treatments. ADCs based on the natural product maytansine have been successful clinically. The authors further the utility of the anti-cancer natural product maytansine by developing efficacious payloads and linker-payloads for conjugating to antibodies. The success of our approach was realized in the EGFRvIII targeting ADC EGFRvIII-16. The ADC was able to regress tumors in 2 tumor models (U251/EGFRvIII and MMT/EGFRvIII). When compared to a positive control ADC, the efficacy observed was similar or improved while the isotype control ADCs had no effect.

Keywords: Antibody; Antibody drug conjugate; EGFRvIII; Maytansinoid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / immunology
  • Antineoplastic Agents / pharmacology*
  • CHO Cells
  • Cell Line, Tumor
  • Cricetulus
  • ErbB Receptors / immunology
  • Female
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Immunotoxins / chemistry
  • Immunotoxins / immunology
  • Immunotoxins / pharmacology*
  • Kinetics
  • Male
  • Maytansine / chemical synthesis
  • Maytansine / chemistry
  • Maytansine / pharmacology*
  • Mice
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Immunotoxins
  • epidermal growth factor receptor VIII
  • Maytansine
  • ErbB Receptors