N-terminal selective conjugation method widens the therapeutic window of antibody–drug conjugates by improving tolerability and stability. Issue 1 (1st January 2021)

• Record Type: Journal Article
• Authors: Ko, Min Ji; Song, Daehae; Kim, Juhee; Kim, Jae Yong; Eom, Jaehyun; Sung, Byungje; Son, Yong-Gyu; Kim, Young Min; Lee, Sang Hoon; You, Weon-Kyoo; Jung, Jinwon
• Is Part Of: MAbs. Volume 13:Issue 1(2021)
• Publication Date: 2021-01-01
• Subjects: Antibody–drug conjugate -- N-terminal conjugation -- therapeutic window -- toxicity -- stability -- trastuzumab -- monomethyl auristatin-F; Monoclonal antibodies -- Therapeutic use -- Periodicals; Monoclonal antibodies -- Periodicals; Antibodies, Monoclonal -- Periodicals; 616.0798
• DOI: 10.1080/19420862.2021.1914885
• Languages: English
• ISSNs: 1942-0862

Abstract

ABSTRACT: Antibody–drug conjugates (ADCs) are targeted therapeutic agents that treat cancers by selective delivery of highly potent cytotoxic drugs to tumor cells via cancer-specific antibodies. However, their clinical benefit is limited by off-target toxicity and narrow therapeutic windows. To overcome these limitations, we have applied reductive alkylation to develop a new type of ADC that has cytotoxic drugs conjugated to the N-terminal of an antibody through amine bonds introduced via reductive alkylation reactions (NTERM). To test whether the NTERM-conjugated ADCs can widen therapeutic windows, we synthesized three different ADCs by conjugating trastuzumab and monomethyl auristatin-F using three different methods, and compared their stability, efficacy, and toxicity. The NTERM-conjugated ADC was more stable in vitro and in vivo than the thiol-conjugated and the lysine-conjugated ADCs. The NTERM-conjugated ADC showed lower toxicity compared to other ADCs, whereas its efficacy was comparable to that of the thiol-conjugated ADC and better than that of the lysine-conjugated ADC. These results suggest that the NTERM conjugation method could widen the therapeutic window of ADCs by enhancing its stability and reducing toxicity.