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DS-8201 (Enhertu): A Potential ADC Drug
Targeting HER2
Enhertu (fam-Trastuzumab deruxtecan-nxki) is a HER2-targeting ADC
drug jointly developed by AstraZeneca and Daiichi Sankyo, also known as
DS-8201 or T-DXd. It is for the treatment of solid tumors with HER2+/Low
expression/mutation. DS-8201 is prepared by conjugating a humanized
anti-HER2 antibody (IgG1) and a topoisomerase I inhibitor through an
enzymatically cleavable tetrapeptide linker (GGFG). It is currently the
only ADC drug with a drug-antibody ratio (DAR) of 8:1, the highest theoretical
value, with the advantages of precise targeting, high efficiency and low toxicity.
Figure 1 Schematic diagram of DS8201 structure
DS-8201, as the benchmark for the improvement of a new generation of ADC,
has demonstrated its excellent therapeutic ability in different tumors. Sales
growth in 2022 was excellent, with full-year revenue of US$1.238 billion, a
year-on-year increase of 191% (US$426 million in 2021). With its full-line
advancement in the field of breast cancer (HER2+, HER2+/Low/HER2 Mutant,
Triple-negative BC), and the development of other tumor treatment areas
(mNSCLC, GC), DS-8201 has the potential to be a blockbuster in the ADC
market (Figure 2)[1].
Huateng Pharma https://us.huatengsci.com
Figure 2. Forecast global sales volume of approved ADCs
(Source: https://www.nature.com/articles/d41573-021-00054-2)
Novel Mechanism of Action of DS-8201
The conjugation method of DS-8201 is to open the disulfide bond between the
antibody chains through the reducing agent TCEP·
HCl, and link the
Linker-Payload to the exposed cysteine residue, resulting in a conjugate with
high DAR value. This coupling method may affect the structure of the antibody,
thereby further affecting the function of the antibody. Through ELISA
experiments, it was found that the Kd value of DS-8201 was 7.3 ng/mL, and
the Kd value of Trastuzumab was 7.8 ng/mL, indicating that the high DAR
value did not affect the binding activity of DS-8201a and HER2 too much
(Figure 3A).
The primary mechanism of action of trastuzumab involves ADCC as well as
downregulation of phosphorylated Akt (pAkt) levels and inhibition of cell
proliferation. Experiments show that DS-8201 still retains the same
mechanism of action as Trastuzumab. DS-8201 showed ADCC activity in
SK-BR-3 cells mediated by human peripheral blood mononuclear cells
(PBMC), with a maximum ADCC activity of 48.6% and an EC50 of 3.8 ng/mL
(Figure 3B), similar to Trastuzumab.
Regarding the inhibition of Akt phosphorylation level, DS-8201 induced the
downregulation of intracellular pAkt (Ser473) in SK-BR-3 cells in a
dose-dependent manner, and the control IgG ADC did not affect the
phosphorylation level of Akt under the same conditions (Figure 3C ).
Trastuzumab reduced Akt phosphorylation by about 70%, suggesting that DXd
conjugation may enhance the downregulation of pAkt by unconjugated
Huateng Pharma https://us.huatengsci.com
Trastuzumab. These data indicate that DS-8201 retains the function of
Trastuzumab after DXd conjugation. On the other hand, DS-8201 (10 mg/mL)
can induce phosphorylation of Chk1 and histone H2A.X (DNA damage Marker)
and cleavage of PARP (apoptosis Marker), and anti-HER2 Ab at 10 mg/mL
does not cause any changes in target proteins at corresponding time points.
These results suggest that DS-8201 induces DNA damage and apoptosis in
the same manner as DXd. Thus, DS-8201 exhibits HER2-specific cell growth
inhibition and antitumor activity through a novel mechanism of action.
Figure 3. Mechanism of action of DS-8201
DS-8201 Global Approval Timeline and Indications
On December 20, 2019, the FDA approved DS-8201 (Enhertu,
fam-trastuzumab deruxtecan-nxki) for the treatment of adult patients with
HER2-positive unresectable or metastatic breast cancer who have received
two or more anti-HER2 therapies in the presence of metastases.
On January 15, 2021, the FDA approved DS-8201 for the treatment of patients
with locally advanced or metastatic HER2-positive gastric or gastroesophageal
junction (GEJ) adenocarcinoma who have received prior trastuzumab therapy,
the first ADC drug approved for HER2-positive gastric cancer.
On May 4, 2022, the FDA approved DS-8201 for the second-line treatment of
adult patients with unresectable or metastatic HER-2-positive breast cancer
who have received at least one or more prior anti-HER-2 therapy.
Huateng Pharma https://us.huatengsci.com
On August 5, 2022, the FDA approved DS-8201 by intravenous infusion for the
treatment of patients with unresectable or metastatic HER2 low-expressing
breast cancer. This is the first therapy approved for patients with a subtype of
HER2 low-expressing breast cancer, a newly defined subtype of
HER2-negative breast cancer.
On August 11, 2022, the FDA granted accelerated approval for DS8201 for the
treatment of adult patients with unresectable or metastatic non-small cell lung
cancer (NSCLC) who were detected by an FDA-approved test to harbor a
HER2 mutation and who had received prior systemic therapy. Notably, this
approval marks another "first" as it is the first FDA-approved drug for patients
with HER2 mutation-positive non-small cell lung cancer.
On February 24, 2023, the National Medical Products Administration (NMPA)
announced that DS-8201 (Enhertu) (fam-Trastuzumab deruxtecan-nxki) for
injection has been officially approved in China. According to public information,
Enhertu has been granted marketing authorization for patients with
unresectable or metastatic HER2-positive adult breast cancer who have been
treated with one or more anti-HER2 drugs in the past. This is the first time that
Enhertu has been approved in China.
The Bystander Effect of DS-8201
In the current DS-8201 data, we can often see a word called "bystander
effect", Daiichi Sankyo attributed a major reason for the success of DS-8201
to small molecular toxins have a bystander effect.
So what exactly is the bystander effect? To put it simply, the expression
marker in tumor tissues is generally uneven. For example, for some tumor
cells with low expression or no expression at all, the end of ADC cannot play a
targeting effect, so it cannot enter the cell to release payload to perform the
killing function. These cells wait for an opportunity to move, and malignantly
proliferate again, and the tumor will continue to grow. At this time, if the
payload has a bystander effect, that is, after the cell is killed by lysis and
release in the positive target cell, it can also enter the tumor cells next to the
low expression or no expression, and kill this part of the cells, the killing of the
tumor tissue will be relatively clean and thorough.
Huateng Pharma https://us.huatengsci.com
Figure 4 DS-8201 directly kills tumor cells and neighboring tumor cells through the
"bystander effect."
(Source: Gastric Cancer. May 2021.)
There are different opinions about the bystander effect of ADC, but the data
show that DS-8201 can kill HER2-negative cells near HER2-positive tumors,
and the specific mechanism is speculated to be due to the excellent drug
properties of Dxd.In vitro experiments, only DS-8201 can kill HER2-negative
tumor cells, and the other two ADCs can only kill HER2-positive tumor cells.
Figure 5 DS-8201 bystander effect
(Source: References[8])
Huateng Pharma https://us.huatengsci.com
In mice inoculated with a mixture of HER2-positive and negative cells, only
DS-8201 reduced the fluorescence of HER2-negative cells and inhibited tumor
growth.
This inhibitory effect on negative cells had no effect on HER2-negative tumors
inoculated remotely.
Clinical Data of DS-8201
DS-8201 has been approved for marketing in different regions of the
world for 7 indications: HER2 mutant non-small cell lung cancer, HER2 low
expression breast cancer, gastroesophageal junction adenocarcinoma, HER2
positive gastric cancer, gastric cancer, breast cancer, HER2 positive breast
cancer. In addition to breast cancer, gastric cancer, and lung cancer
indications, DS-8201 is also exploring the possibility of treating colorectal
cancer, pancreatic cancer, and biliary tract cancer. Below is a brief overview of
the clinical data of DS-8201 in HER2-positive breast cancer, HER2-low
expression breast cancer, stomach cancer, lung cancer, and colorectal
cancer.
HER2-positive breast cancer: According to data from a Phase 3 clinical trial
of DS-8201 in December 2022 (DESTINY-Breast03), in patients with
HER2-positive unresectable and/or metastatic breast cancer treated with
trastuzumab and paclitaxanes in the past compared to T-DM1, DS-8201
showed a statistically significant and clinically significant improvement in
overall survival (OS). DS-8201 reduced the risk of death by 36% compared to
T-DM1.
Compared with T-DM1, DS-8201 significantly prolongs the median
progression-free survival time of patients by 22 months, and has statistically
significant and clinically meaningful benefits in terms of progression-free
survival (PFS). The confirmed objective response rate (ORR) in the DS-8201
arm was 78.5%, with 21.1% of patients in complete response (CR). The
median duration of response (DoR) for DS-8201 was 36.6 months.
HER2-low expression breast cancer: In patients with positive HR and low
expression of HER2, DS-8201 reduced the risk of disease progression or
death by 49% compared with chemotherapy, with a median progression-free
survival (PFS) of 10.1 months in the DS-8201 group and 5.4 months in the
chemotherapy group. Patients had a 49% lower risk of disease progression or
death, with a median progression-free survival (PFS) of 10.1 months in the
DS-8201 group and 5.4 months in the chemotherapy group.
Lung cancer: ORR of all patients was 57.7%, 1.9% of patients (1 case)
achieved complete remission, 55.8% of patients (29 cases) achieved partial
Huateng Pharma https://us.huatengsci.com
remission; median duration of response (DOR) was 8.7 months. The data
show that DS-8201 has a stable effect on lung cancer.
Gastric cancer: The overall survival (OS) of the DS-8201 experimental group
was 12.5 months, the objective response rate (ORR) was 40.5%, the median
PFS of DS-8201 was 5.6 months, the median DOR was 11.3 months, and the
mortality rate was reduced up 41%.
Colorectal cancer: Median treatment response was 3.5 months; 38.5% of
patients continued DS-8201 treatment. Confirmed ORR in cohort A (HER2
positive) was 45.3%, including 1 complete response and 23 partial responses.
The objective response rate of patients who had previously received
anti-HER2 therapy was 43.8%. The disease control rate was 83.0%; the
median PFS was 6.9 months; the median OS was not reached. No responses
were observed in cohorts B or C.
Conclusion
Three HER2 ADCs have been approved for sale worldwide, including Kadcyla,
Enhertu and Aidixi, of which Aidixi is the only domestic HER2 ADC product.
Enhertu is the star product of HER2 ADC products, which is very powerful. It
can almost double the PFS of patients with metastatic breast cancer with low
expression of HER2, subvert the treatment of breast cancer patients, change
the competitive landscape of HER2 ADC, and improve the approval standard
of HER2 ADC drugs. It forced Ambrx to suspend internal development of the
HER2 ADC drug ARX788.
However, Enhertu is expensive and has security issues, and it remains to be
seen whether the HER2 ADC developed later will be able to match or solve
security issues.
Huateng Pharma is a leading CDMO for PEG derivatives and pharmaceutical
intermediates which can meet customers’ needs from lab research to pilot
plant to large sacle commercial production. We are dedicated to being your
most reliable partner to provide chemical synthesis and high-quality PEG
linkers for ADC drugs.
References:
[1]. do Pazo, C., K. Nawaz, and R.M. Webster, The oncology market for
antibody-drug conjugates. Nat Rev Drug Discov, 2021. 20(8): p. 583-584.
[2]. Walsh, S.J., et al., General dual functionalisation of biomacromolecules via a
cysteine bridging strategy. Org Biomol Chem, 2020. 18(22): p. 4224-4230.
[3].. Clynes, R.A., et al.,Inhibitory Fc receptors modulate in vivo cytotoxicity
against tumor targets. Nat Med, 2000. 6(4): p. 443-6.
Huateng Pharma https://us.huatengsci.com
[4].. Yakes, F.M., et al., Herceptin-induced inhibition of phosphatidylinositol-3 kinase and
Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor
action. Cancer Res, 2002. 62(14): p. 4132-41.
[5].. Xiao, Z., et al., Chk1 mediates S and G2 arrests through Cdc25A degradation in
response to DNA-damaging agents. J Biol Chem, 2003. 278(24): p. 21767-73.
[6].. Furuta, T., et al., Phosphorylation of histone H2AX and activation of Mre11, Rad50,
and Nbs1 in response to replication-dependent DNA double-strand breaks induced by
mammalian DNA topoisomerase I cleavage complexes. J Biol Chem, 2003. 278(22): p.
20303-12.
[7]. Kaufmann, S.H., et al., Specific proteolytic cleavage of poly(ADP-ribose) polymerase:
an early marker of chemotherapy-induced apoptosis. Cancer Res, 1993. 53(17): p.
3976-85.
[8]. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor
receptor 2 antibody–drug conjugate, in tumors with human epidermal growth factor
receptor 2 heterogeneity
Related articles:
[1].Bystander Effects of Antibody-Drug Conjugates
[2].Trodelvy: Any Chance Against Dato-DXd and Enhertu?
[3].ADC Linker - Development and Challenges

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DS-8201 (Enhertu) A Potential ADC Drug Targeting HER2.pdf

  • 1. Huateng Pharma https://us.huatengsci.com DS-8201 (Enhertu): A Potential ADC Drug Targeting HER2 Enhertu (fam-Trastuzumab deruxtecan-nxki) is a HER2-targeting ADC drug jointly developed by AstraZeneca and Daiichi Sankyo, also known as DS-8201 or T-DXd. It is for the treatment of solid tumors with HER2+/Low expression/mutation. DS-8201 is prepared by conjugating a humanized anti-HER2 antibody (IgG1) and a topoisomerase I inhibitor through an enzymatically cleavable tetrapeptide linker (GGFG). It is currently the only ADC drug with a drug-antibody ratio (DAR) of 8:1, the highest theoretical value, with the advantages of precise targeting, high efficiency and low toxicity. Figure 1 Schematic diagram of DS8201 structure DS-8201, as the benchmark for the improvement of a new generation of ADC, has demonstrated its excellent therapeutic ability in different tumors. Sales growth in 2022 was excellent, with full-year revenue of US$1.238 billion, a year-on-year increase of 191% (US$426 million in 2021). With its full-line advancement in the field of breast cancer (HER2+, HER2+/Low/HER2 Mutant, Triple-negative BC), and the development of other tumor treatment areas (mNSCLC, GC), DS-8201 has the potential to be a blockbuster in the ADC market (Figure 2)[1].
  • 2. Huateng Pharma https://us.huatengsci.com Figure 2. Forecast global sales volume of approved ADCs (Source: https://www.nature.com/articles/d41573-021-00054-2) Novel Mechanism of Action of DS-8201 The conjugation method of DS-8201 is to open the disulfide bond between the antibody chains through the reducing agent TCEP· HCl, and link the Linker-Payload to the exposed cysteine residue, resulting in a conjugate with high DAR value. This coupling method may affect the structure of the antibody, thereby further affecting the function of the antibody. Through ELISA experiments, it was found that the Kd value of DS-8201 was 7.3 ng/mL, and the Kd value of Trastuzumab was 7.8 ng/mL, indicating that the high DAR value did not affect the binding activity of DS-8201a and HER2 too much (Figure 3A). The primary mechanism of action of trastuzumab involves ADCC as well as downregulation of phosphorylated Akt (pAkt) levels and inhibition of cell proliferation. Experiments show that DS-8201 still retains the same mechanism of action as Trastuzumab. DS-8201 showed ADCC activity in SK-BR-3 cells mediated by human peripheral blood mononuclear cells (PBMC), with a maximum ADCC activity of 48.6% and an EC50 of 3.8 ng/mL (Figure 3B), similar to Trastuzumab. Regarding the inhibition of Akt phosphorylation level, DS-8201 induced the downregulation of intracellular pAkt (Ser473) in SK-BR-3 cells in a dose-dependent manner, and the control IgG ADC did not affect the phosphorylation level of Akt under the same conditions (Figure 3C ). Trastuzumab reduced Akt phosphorylation by about 70%, suggesting that DXd conjugation may enhance the downregulation of pAkt by unconjugated
  • 3. Huateng Pharma https://us.huatengsci.com Trastuzumab. These data indicate that DS-8201 retains the function of Trastuzumab after DXd conjugation. On the other hand, DS-8201 (10 mg/mL) can induce phosphorylation of Chk1 and histone H2A.X (DNA damage Marker) and cleavage of PARP (apoptosis Marker), and anti-HER2 Ab at 10 mg/mL does not cause any changes in target proteins at corresponding time points. These results suggest that DS-8201 induces DNA damage and apoptosis in the same manner as DXd. Thus, DS-8201 exhibits HER2-specific cell growth inhibition and antitumor activity through a novel mechanism of action. Figure 3. Mechanism of action of DS-8201 DS-8201 Global Approval Timeline and Indications On December 20, 2019, the FDA approved DS-8201 (Enhertu, fam-trastuzumab deruxtecan-nxki) for the treatment of adult patients with HER2-positive unresectable or metastatic breast cancer who have received two or more anti-HER2 therapies in the presence of metastases. On January 15, 2021, the FDA approved DS-8201 for the treatment of patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received prior trastuzumab therapy, the first ADC drug approved for HER2-positive gastric cancer. On May 4, 2022, the FDA approved DS-8201 for the second-line treatment of adult patients with unresectable or metastatic HER-2-positive breast cancer who have received at least one or more prior anti-HER-2 therapy.
  • 4. Huateng Pharma https://us.huatengsci.com On August 5, 2022, the FDA approved DS-8201 by intravenous infusion for the treatment of patients with unresectable or metastatic HER2 low-expressing breast cancer. This is the first therapy approved for patients with a subtype of HER2 low-expressing breast cancer, a newly defined subtype of HER2-negative breast cancer. On August 11, 2022, the FDA granted accelerated approval for DS8201 for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) who were detected by an FDA-approved test to harbor a HER2 mutation and who had received prior systemic therapy. Notably, this approval marks another "first" as it is the first FDA-approved drug for patients with HER2 mutation-positive non-small cell lung cancer. On February 24, 2023, the National Medical Products Administration (NMPA) announced that DS-8201 (Enhertu) (fam-Trastuzumab deruxtecan-nxki) for injection has been officially approved in China. According to public information, Enhertu has been granted marketing authorization for patients with unresectable or metastatic HER2-positive adult breast cancer who have been treated with one or more anti-HER2 drugs in the past. This is the first time that Enhertu has been approved in China. The Bystander Effect of DS-8201 In the current DS-8201 data, we can often see a word called "bystander effect", Daiichi Sankyo attributed a major reason for the success of DS-8201 to small molecular toxins have a bystander effect. So what exactly is the bystander effect? To put it simply, the expression marker in tumor tissues is generally uneven. For example, for some tumor cells with low expression or no expression at all, the end of ADC cannot play a targeting effect, so it cannot enter the cell to release payload to perform the killing function. These cells wait for an opportunity to move, and malignantly proliferate again, and the tumor will continue to grow. At this time, if the payload has a bystander effect, that is, after the cell is killed by lysis and release in the positive target cell, it can also enter the tumor cells next to the low expression or no expression, and kill this part of the cells, the killing of the tumor tissue will be relatively clean and thorough.
  • 5. Huateng Pharma https://us.huatengsci.com Figure 4 DS-8201 directly kills tumor cells and neighboring tumor cells through the "bystander effect." (Source: Gastric Cancer. May 2021.) There are different opinions about the bystander effect of ADC, but the data show that DS-8201 can kill HER2-negative cells near HER2-positive tumors, and the specific mechanism is speculated to be due to the excellent drug properties of Dxd.In vitro experiments, only DS-8201 can kill HER2-negative tumor cells, and the other two ADCs can only kill HER2-positive tumor cells. Figure 5 DS-8201 bystander effect (Source: References[8])
  • 6. Huateng Pharma https://us.huatengsci.com In mice inoculated with a mixture of HER2-positive and negative cells, only DS-8201 reduced the fluorescence of HER2-negative cells and inhibited tumor growth. This inhibitory effect on negative cells had no effect on HER2-negative tumors inoculated remotely. Clinical Data of DS-8201 DS-8201 has been approved for marketing in different regions of the world for 7 indications: HER2 mutant non-small cell lung cancer, HER2 low expression breast cancer, gastroesophageal junction adenocarcinoma, HER2 positive gastric cancer, gastric cancer, breast cancer, HER2 positive breast cancer. In addition to breast cancer, gastric cancer, and lung cancer indications, DS-8201 is also exploring the possibility of treating colorectal cancer, pancreatic cancer, and biliary tract cancer. Below is a brief overview of the clinical data of DS-8201 in HER2-positive breast cancer, HER2-low expression breast cancer, stomach cancer, lung cancer, and colorectal cancer. HER2-positive breast cancer: According to data from a Phase 3 clinical trial of DS-8201 in December 2022 (DESTINY-Breast03), in patients with HER2-positive unresectable and/or metastatic breast cancer treated with trastuzumab and paclitaxanes in the past compared to T-DM1, DS-8201 showed a statistically significant and clinically significant improvement in overall survival (OS). DS-8201 reduced the risk of death by 36% compared to T-DM1. Compared with T-DM1, DS-8201 significantly prolongs the median progression-free survival time of patients by 22 months, and has statistically significant and clinically meaningful benefits in terms of progression-free survival (PFS). The confirmed objective response rate (ORR) in the DS-8201 arm was 78.5%, with 21.1% of patients in complete response (CR). The median duration of response (DoR) for DS-8201 was 36.6 months. HER2-low expression breast cancer: In patients with positive HR and low expression of HER2, DS-8201 reduced the risk of disease progression or death by 49% compared with chemotherapy, with a median progression-free survival (PFS) of 10.1 months in the DS-8201 group and 5.4 months in the chemotherapy group. Patients had a 49% lower risk of disease progression or death, with a median progression-free survival (PFS) of 10.1 months in the DS-8201 group and 5.4 months in the chemotherapy group. Lung cancer: ORR of all patients was 57.7%, 1.9% of patients (1 case) achieved complete remission, 55.8% of patients (29 cases) achieved partial
  • 7. Huateng Pharma https://us.huatengsci.com remission; median duration of response (DOR) was 8.7 months. The data show that DS-8201 has a stable effect on lung cancer. Gastric cancer: The overall survival (OS) of the DS-8201 experimental group was 12.5 months, the objective response rate (ORR) was 40.5%, the median PFS of DS-8201 was 5.6 months, the median DOR was 11.3 months, and the mortality rate was reduced up 41%. Colorectal cancer: Median treatment response was 3.5 months; 38.5% of patients continued DS-8201 treatment. Confirmed ORR in cohort A (HER2 positive) was 45.3%, including 1 complete response and 23 partial responses. The objective response rate of patients who had previously received anti-HER2 therapy was 43.8%. The disease control rate was 83.0%; the median PFS was 6.9 months; the median OS was not reached. No responses were observed in cohorts B or C. Conclusion Three HER2 ADCs have been approved for sale worldwide, including Kadcyla, Enhertu and Aidixi, of which Aidixi is the only domestic HER2 ADC product. Enhertu is the star product of HER2 ADC products, which is very powerful. It can almost double the PFS of patients with metastatic breast cancer with low expression of HER2, subvert the treatment of breast cancer patients, change the competitive landscape of HER2 ADC, and improve the approval standard of HER2 ADC drugs. It forced Ambrx to suspend internal development of the HER2 ADC drug ARX788. However, Enhertu is expensive and has security issues, and it remains to be seen whether the HER2 ADC developed later will be able to match or solve security issues. Huateng Pharma is a leading CDMO for PEG derivatives and pharmaceutical intermediates which can meet customers’ needs from lab research to pilot plant to large sacle commercial production. We are dedicated to being your most reliable partner to provide chemical synthesis and high-quality PEG linkers for ADC drugs. References: [1]. do Pazo, C., K. Nawaz, and R.M. Webster, The oncology market for antibody-drug conjugates. Nat Rev Drug Discov, 2021. 20(8): p. 583-584. [2]. Walsh, S.J., et al., General dual functionalisation of biomacromolecules via a cysteine bridging strategy. Org Biomol Chem, 2020. 18(22): p. 4224-4230. [3].. Clynes, R.A., et al.,Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med, 2000. 6(4): p. 443-6.
  • 8. Huateng Pharma https://us.huatengsci.com [4].. Yakes, F.M., et al., Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res, 2002. 62(14): p. 4132-41. [5].. Xiao, Z., et al., Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents. J Biol Chem, 2003. 278(24): p. 21767-73. [6].. Furuta, T., et al., Phosphorylation of histone H2AX and activation of Mre11, Rad50, and Nbs1 in response to replication-dependent DNA double-strand breaks induced by mammalian DNA topoisomerase I cleavage complexes. J Biol Chem, 2003. 278(22): p. 20303-12. [7]. Kaufmann, S.H., et al., Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis. Cancer Res, 1993. 53(17): p. 3976-85. [8]. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody–drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity Related articles: [1].Bystander Effects of Antibody-Drug Conjugates [2].Trodelvy: Any Chance Against Dato-DXd and Enhertu? [3].ADC Linker - Development and Challenges