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Latest Research and Development of ADCs for HER2 Cancer Therapy

Published on 06th March

One of the limitation of traditional chemotherapy in the treatment of cancer is dose-limiting toxicity caused by the exposure of non-tumor cells to cytotoxic agents.

Molecular targeted drugs, including specific kinase inhibitors and antibodies may help overcome this limitation. Antibody–drug conjugate or ADC offer a rational strategy for improving efficacy and reducing systemic adverse events.[1]

Antibody-drug Conjugates deliver potent cytotoxic agents directly to tumor cells and drastically improving the therapeutic index of chemotherapeutic agents.

The clinical failure of early ADCs in the 1980s and ’90s have led to improvements in ADC technology, and resulted in the approval of four novel Antibody-drug Conjugates.  While these novel agents are successful in treating patients, further advances in ADC technology are required to streamline their clinical efficacy and reduce toxicity.

[fam-] Trastuzumab deruxtecan (DS-8201a),  a next-generation ADC being developed by Daiichi Sankyo, is expected to satisfies requirements based on currently available evidence.

Designed using Daiichi Sankyo’s proprietary ADC technology, [fam-] trastuzumab deruxtecan is comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. This investigational agent targets and delivers chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.[2]

DS-8201a has several innovative features: a highly potent novel payload with a high drug-to-antibody ratio (DAR), good homogeneity, a tumor-selective cleavable linker, stable linker-payload in circulation, and a short systemic half-life cytotoxic agent in vivo.

In addition, the released cytotoxic payload could exert a bystander effect.

With respect to its preclinical profiles, the investigational agent may provide a valuable therapy with a great potential against HER2-expressing cancers in clinical settings. In a phase I trial, DS-8201a has shown acceptable safety profiles with potential therapeutic efficacy, with the wide therapeutic index.

In a new review article, published in J-STAGE | Chemical and Pharmaceutical Bulletin, Takashi Nakada, Kiyoshi Sugihara, Takahiro Jikoh, Yuki Abe, Toshinori Agatsuma discuss the latest research and development of ADCs.

Reference
[1] Nakada T, Sugihara K, Takahiro Jikoh T, Yuki Abe, Agatsuma T. The Latest Research and Development into the Antibody–Drug Conjugate, [fam-] Trastuzumab Deruxtecan (DS-8201a), for HER2 Cancer Therapy. J-STAGE | Chemical and Pharmaceutical Bulletin | Volume 67 (2019) 3 [Article]
[2] Hofland P. Encouraging Preliminary Results in Treatment of Colorectal Cancer with Trastuzumab Deruxtecan. ADC Review | J. Antibody-drug Conjugates. October 21, 2018 [Article]


Last Editorial Review: March 6, 2019

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