ABSTRACT
ADCs based on the natural product maytansine have been successfully employed clinically. In a previous report, ADCs based on hydrophilic non-cell permeable maytansinoids was presented. The authors in this report further explore the maytansine scaffold to develop tubulin inhibitors capable of cell permeation. The research resulted in amino-benzoyl-maytansinoid payloads that were further elaborated with linkers for conjugating to antibodies. This approach was applied to MUC16 tumor targeting antibodies for ovarian cancers. A positive control ADC was evaluated alongside the amino-benzoyl-maytansinoid ADC and the efficacy observed was equivalent while the isotype control ADCs had no effect.
Subject(s)
Immunoconjugates/metabolism , Maytansine/chemistry , Tubulin Modulators/chemistry , Animals , Cell Line , Cell Line, Tumor , Cell Survival/drug effects , Female , Humans , Immunoconjugates/chemistry , Immunoconjugates/pharmacology , Immunoconjugates/therapeutic use , Maytansine/metabolism , Mice, SCID , Neoplasms/drug therapy , Neoplasms/pathology , Structure-Activity Relationship , Transplantation, Heterologous , Tubulin Modulators/metabolismABSTRACT
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.
