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.

One of the pharmaceutical companies in these oncology research and development has attracted the attention of everyone with three unique ADC drugs.

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 Co.

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.

Daiichi Sankyo is desperately expanding its runway on the road of ADC drug research and development.
In addition to T-DXd targeting HER2, Dato-DXd, another ADC product targeting TROP2, also joined hands with AstraZeneca again because of its excellent product characteristics.
, Reached a global cooperation with Daiichi Sankyo on ADC therapy Dato-DXd in 2020.

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) whose genome has not changed.
TROP2 is also a new type of pan-cancer target discovered in the past two years.

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.
The initial objective response rate (ORR) of patients with negative breast cancer (TNBC) was 43%, and the disease control rate was 95%.
The initial results of the study are encouraging.

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 2021 ASCO annual 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 that has been approved for marketing in the world, and HER3-DXd may become "first-in class".
( Cyber ​​Blue )

Note: The original text has been deleted

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

https:// 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.
The Nobel laureate German scientist Paul Ehrlich once put forward the idea of ​​“Magic bullets”: If cytotoxic drugs are installed in specific On the carrier targeted to tumor cells, it is possible to accurately kill cancer cells without harming normal cells [1].
However, there are many technical difficulties in the design and preparation of ADCs: which antibody and toxic drug can be selected to suppress side effects while ensuring the effect, how to ensure that the drug loaded on the antibody is stable and does not fall off in advance, and so on.
In 2000, the world's first ADC drug Mylotarg was launched.
However, in subsequent confirmatory clinical trials, Mylotarg was terminated early because of its failure to extend the survival period and doubts about its safety.
Therefore, although the theory is good, it is difficult to translate clinically.

1.
Rely on "magic bullets" to open up a new situation

One of the pharmaceutical companies in these oncology research and development has attracted the attention of everyone with three unique ADC drugs.
It is through the merger of the century-old Japanese pharmaceutical company Sankyo and Daiichi Pharmaceutical that he is firmly among the top three Japanese pharmaceutical companies.
Daiichi Sankyo Co.
, Ltd.
(Daiichi Sankyo).

ADC drugs are composed of three parts: antibody, linker and drug carrier.
The nuances of these three components reflect the company's strength in research and development, and will directly affect the efficacy of ADC drugs.

For drug loading, Daiichi Sankyo is based on the rich experience when Daiichi Pharmaceutical Co.
, Ltd.
and Yakult Headquarters jointly developed the topoisomerase I inhibitor irinotecan hydrochloride (CPT11).
After evaluating various compounds synthesized in the company in-house, Anticancer drugs that inhibit topoisomerase I have surfaced.

After confirming the drug loading, how to complete the design of the linker is the key to the performance of ADC drugs.
The reason why Daiichi Sankyo, as a latecomer, was able to successfully develop T-DXd in ADC research is mainly because it fully designed the linker.
In the process of synthesizing and evaluating hundreds of linkers, the Daiichi Sankyo R&D team found that linkers are difficult to cleave in the blood.
If they enter cells, they can be cleaved by the enzymes in them to release the drug.
The drug carrier is also fat-soluble, so after being separated from the antibody in the cancer cell, it can be discharged outside the cell through the cell membrane formed by lipids, and play a role known as the bystander effect to kill surrounding cancer cells.
Nevertheless, the half-life of the drug-loaded blood is relatively short, so adverse reactions are not prone to occur.

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.
After the conference, the research results were quickly published in the top journal "New England Journal of Medicine" and accelerated in December 2019 Approved by the FDA for the treatment of HER2-positive metastatic breast cancer.
Followed by the DESTINY-Gastric01 study for HER2-positive advanced gastric cancer, the results of the trial were announced at the 2020 American Society of Clinical Oncology (ASCO) meeting and republished in the New England Journal of Medicine, January 2021 in the United States Approved a new indication for gastric cancer, becoming the world's first ADC drug for targeting HER2-positive metastatic gastric cancer.

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.
At the same time, T-DXd was selected as one of the two major developments in "ASCO Annual Clinical Progress: Molecular Analysis Driven Progress in GI Tumors" in the "Clinical Cancer Progress 2021" report.
The clinical development project of T-DXd is being carried out on a global scale, and clinical trials in lung cancer, bowel cancer and other fields are in full swing!

2.
Actively promote multiple pipelines

Daiichi Sankyo is desperately expanding its runway on the road of ADC drug research and development.
In addition to T-DXd targeting HER2, Dato-DXd, another ADC product targeting TROP2, also joined hands with AstraZeneca again because of its excellent product characteristics.
, Reached a global cooperation with Daiichi Sankyo on ADC therapy Dato-DXd in 2020.

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) whose genome has not changed.
TROP2 is also a new type of pan-cancer target discovered in the past two years.

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.
The initial objective response rate (ORR) of patients with negative breast cancer (TNBC) was 43%, and the disease control rate was 95%.
The initial results of the study are encouraging.

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 2021 ASCO annual 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 that has been approved for marketing in the world, and HER3-DXd may become "first-in class".
( Cyber ​​Blue )

Note: The original text has been deleted

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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