Preparation of trastuzumab-DM1 conjugate with a high drug-to-antibody ratio for breast cancer therapy

Abstract

Antibody-drug conjugates (ADCs) are important in active tumor-targeting therapy. However, improving the efficiency of payload delivery to tumors without affecting the tumor-targeting ability of the antigen-binding fragment (Fab) structure remains a challenge. In this study, a Fab-nondestructive ADC loaded with maytansine (DM1) (T-NPLG-DM135) was prepared with drug-to-antibody ratio (DAR) of up to 35 by utilizing the carboxyl groups on the side-chain of poly(L-glutamic acid) (PLG) as the payload binding sites. The use of the Fc-III-4C peptide and the preparation condition of aqueous environment were conducive to avoiding the impact of the Fab structure of monoclonal antibodies on tumor-targeting capability. T-NPLG-DM135 was recognized and rapidly internalized by HER2-expressing SKBR-3 tumor cells, with a 3.8-fold increase in accumulation compared to that of the non-tumor-targeting IgG-NPLG-DM135. T-NPLG-DM135 also showed excellent tumor inhibition and its therapeutic effect improved as the DAR increased. The successful development of T-NPLG-DM135 demonstrates the potential of this approach for future ADC design and development.