Toward a Ferrous Iron-Cleavable Linker for Antibody–Drug Conjugates

• DOI: 10.1021/acs.molpharmaceut.8b00242
• Publication Date: 2018-03-23T15:22:28Z
• Authors: Benjamin Spangler; Toni Kline; Jeffrey Hanson; Xiaofan Li; Sihong Zhou; James A. Wells; Aaron K. Sato; Adam R. Renslo
• Keywords: Linker; Conjugate; Internalization; Antibody-drug conjugate; Moiety; Cancer Immunotherapy

Antibody–drug conjugates (ADCs) are antigen-targeted therapeutics that employ antibodies to deliver potent, cytotoxic effectors cells with potentially high specificity. While promising clinical results have been achieved, significant pitfalls remain including internalization of ADCs in nontargeted expressing target antigen, which can limit therapeutic windows. Novel ADC linkers cleaved selectively cancer but not normal could minimize collateral damage caused by uptake tissues. Here, we describe a prototypical linker based on an Fe(II)-reactive 1,2,4-trioxolane scaffold (TRX) itself has demonstrated tumor-selective activity preclinical models. We prepared TRX-linked site-selective conjugation two sites trastuzumab and compared their Her2 positive negative controls established chemistry. Our confirm the TRX moiety efficiently releases its payload following uptake, affording picomolar potencies antigen-positive cells. also identified destabilizing interaction between these initial nearby antibody residues suggest approach improve upon designs.