Which ADC pipeline layout is strong? Look at the first Sankyo

At present, 11 antibody-drug conjugates (ADCs) have been approved globally, and ADC drugs are gradually becoming a hot spot in the global oncology drug R&D and market in recent years.

Today’s ADC drug concept was born more than one hundred years ago.

1.

ADC drugs are composed of three parts: antibody, linker and drug carrier.

For drug loading, Daiichi Sankyo is based on the rich experience when Daiichi Pharmaceutical and Yakult Headquarters jointly developed the topoisomerase I inhibitor irinotecan hydrochloride (CPT11).

After confirming the drug loading, how to complete the design of the linker is the key to the performance of ADC drugs.

As the "big brother" of the ADC family, T-DXd has attracted the attention of AstraZeneca with its unique advantages, and signed an agreement in March 2019 to jointly develop and promote T-DXd globally.

T-DXd's research on HER2-positive metastatic breast cancer, DESTINY-Breast01, was first presented at the San Antonio Breast Cancer Symposium (SABCS) in 2019.

Similarly, T-DXd gastric cancer indication was also qualified as a breakthrough therapy recognized by the Center for Drug Evaluation (CDE) of the National Medical Products Administration of China in December 2020.

In February 2021, T-DXd won the "Prime Minister's Award" at the 9th Japan Technology Management and Innovation Ceremony.

2.

Dato-DXd is an antibody-conjugated drug (ADC) targeting TROP2 for the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC) with unchanged genome.

The latest clinical research data of the TROPION-PanTumor01 Phase I trial released at the ESMO Breast Cancer Conference (ESMO Breast21) held online on May 5-8, 2021 shows that Dato-DXd is used for metastatic three that progresses after treatment.

HER3-DXd is Daiichi Sankyo’s third blockbuster ADC product.

The HER3 gene belongs to the ERBB family of receptor tyrosines, including EGFR, HER2, HER3, and HER4.
HER2 must form a homodimer or heterodimer with other members of the family (such as HER3), and the study of the potential mechanism of HER3 target has shown that the activation of HER3 signal can promote cancer metastasis [2].

HER3 is expressed in the gastrointestinal tract, reproductive system, skin, nervous system, urinary tract and endocrine system of normal adults.
Overexpression of HER3 protein is associated with many cancers, including prostate cancer, bladder cancer and breast cancer.
Many R&D institutions have shifted their attention from the highly competitive HER2 to HER3, hoping that this target in the same family as HER2 can also serve as a new target for tumor treatment.

An oral report on the efficacy and safety of the Phase I trial of HER3-DXd in the treatment of locally advanced or metastatic TKI-resistant EGFR-mutant non-small cell lung cancer (NSCLC) patients at the upcoming ASCO 2021 meeting on June 4, 2021 Relevant data will also be released.
The preliminary data of this trial provides key information for the recently launched Phase II trial of HERTHENA-Lung01.
At present, there is no HER3 targeted therapy drug approved for marketing in the world, and HER3-DXd may become a "first-in class".

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references

[1] Lambert JM.
Antibody-Drug Conjugates (ADCs): Magic Bullets at Last!.
Mol Pharm.
2015;12(6):1701–1702.
doi:10.
1021/acs.
molpharmaceut.
5b00302

[2] F.
-C.
Bidard, CKY Ng, P.
Cottu, S.
Piscuoglio, et al.
Response to dual HER2 blockade in a patient with HER3-mutant metastatic breast cancer[J].
European Society for Medical Oncology:Oxford University Press, 2015.

[3]Building on our ADC success: the challenge and promise of R&D at Daiichi Sankyo

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