Abstract
Antibody–drug conjugates (ADCs) take the advantage of monoclonal antibodies to selectively deliver highly potent cytotoxic drugs to tumor cells, which have become a powerful measure for cancer treatment in recent years. To develop a more effective therapy for human epidermal growth factor receptor 2 (HER2)-positive cancer, we explored a novel ADCs composed of anti-HER2 scFv–HSA fusion antibodies conjugates with a potent cytotoxic drug DM1. The resulting ADCs, T-SA1–DM1 and T-SA2–DM1 (drug-to-antibody ratio in the range of 3.2–3.5) displayed efficient inhibition in the growth of HER2-positive tumor cell lines and the half-maximal inhibitory concentration on SKBR-3 and SKOV3 cells were both at the nanomolar levels in vitro. In HER2-positive human ovarian cancer xenograft models, T-SA1–DM1 and T-SA2–DM1 also showed remarkable antitumor activity. Importantly, three out of six mice exhibited complete remission without regrowth in the high-dose group of T-SA1–DM1. On the basis of the analysis of luminescence imaging, anti-HER2 scFv–HSA fusion antibodies, especially T-SA1, showed strong and rapid tumor tissue penetrability and distribution compared with trastuzumab. Collectively, the novel type of ADCs is effective and selective targeting to HER2-positive cancer, and may be a promising antitumor drug candidate for further studies.
Highlights
Antibody–drug conjugates (ADCs), combining an antibody with high cytotoxic small-molecule compounds via a linker, are a new class of highly potent anti-cancer drugs
To improve tumor tissue penetration and therapeutic efficacy, we developed a novel type of ADCs composed of anti-Human epidermal growth factor receptor 2 (HER2) scFv– Human serum albumin (HSA) fusion antibodies conjugated with the potent cytotoxic drug
On the basis of their characteristics, two ADCs complexes T-SA1–DM1 and T-SA2–DM1 were prepared, which were composed of scFv–HSA fusion antibodies conjugated with maytansine derivative DM1 on the sites of lysine residues via MCC linker
Summary
Antibody–drug conjugates (ADCs), combining an antibody with high cytotoxic small-molecule compounds via a linker, are a new class of highly potent anti-cancer drugs. Antibody drugs include trastuzumab (Herceptin, Genentech),[17,18,19] pertuzumab (Perjeta, Genentech)[20,21] as well as T-DM1 (Kadcyla, Genentech).[22,23] In addition, there are two classes of small-molecule tyrosine kinase inhibitors targeting HER2, including lapatinib (Tykerb, Novartis)[24,25,26] and afatinib (Giotrif, Boehringer Ingelheim).[27]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
