Antibody-drug Conjugate Information

General Information of This Antibody-drug Conjugate (ADC)
ADC ID
DRG0DMWXZ
ADC Name
ADC MMAE/F 4+2
Synonyms
ADC-+D1294+D1291:D1291:K1291
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Drug Status
Investigative
Indication
In total 2 Indication(s)
Breast cancer [ICD11:2C60-2C65]
Investigative
Hepatocellular carcinoma [ICD11:2C12]
Investigative
Drug-to-Antibody Ratio
4+2
Antibody Name
Trastuzumab N297A
  Antibody Info 
Antigen Name
Receptor tyrosine-protein kinase erbB-2 (ERBB2)
  Antigen Info 
Payload Name
Monomethyl auristatin E+Monomethyl auristatin F
  Payload Info 
Therapeutic Target
Microtubule (MT)
  Target Info 
Linker Name
DBCO-PEG3-Glu-Val-Cit-PABC; TCO-PEG3-Glu-Val-Cit-PABC
  Linker Info 
Conjugate Type
Linker&Payload is conjugated via amide on the Q295 side chain on Trastuzumab N297A. MMAE and MMAF are conjugated to linker via azide-DBCO and me-tetrazine-TCO-mediated click reactions, respectively.
Combination Type
DBCO-PEG3-Glu-Val-Cit-PABC-MMAE, TCO-PEG3-Glu-Val-Cit-PABC-MMAF
General Information of The Activity Data Related to This ADC
Discovered Using Cell Line-derived Xenograft Model
Click To Hide/Show 2 Activity Data Related to This Level
Standard Type Value Units Cell Line Disease Model
Tumor Growth Inhibition value (TGI) 
≈ 77.5
%
Breast cancer cells
Breast cancer
Tumor Growth Inhibition value (TGI) 
≈ 94.1
%
JIMT-1 cells/MDA-MB-231 cells
Breast ductal carcinoma
Revealed Based on the Cell Line Data
Click To Hide/Show 3 Activity Data Related to This Level
Standard Type Value Units Cell Line Disease Model
Half Maximal Effective Concentration (EC50) 
0.02
nM
KPL-4 cells
Breast inflammatory carcinoma
Half Maximal Effective Concentration (EC50) 
0.02
nM
JIMT-1 cells
Breast ductal carcinoma
Half Maximal Effective Concentration (EC50) 
0.18
nM
SK-BR-3 cells
Breast adenocarcinoma
Full List of Activity Data of This Antibody-drug Conjugate
Discovered Using Cell Line-derived Xenograft Model
Click To Hide/Show 2 Activity Data Related to This Level
Experiment 1 Reporting the Activity Date of This ADC [1]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 77.50% (Day 24) Low HER2 expression (HER2+)
Method Description
HCC1954-TDR breast tumor model shows very low HER2 expression with intratumor heterogeneity,representing refractory breast tumors. The HCC1954-TDR cell line was established by continuous treatment with T-DM1 for 8 months. Once tumors reached an average volume of 125mm3,mice were administered with a single dose of the MMAE/F 4+2 ADC (1 mg/kg).

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In Vivo Model Breast cancer CDX model
In Vitro Model Breast cancer Breast cancer cells Homo sapiens
Experiment 2 Reporting the Activity Date of This ADC [1]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 94.10% (Day 24) Positive HER2 expression (HER2+++/++)
Method Description
The in vivo validated model was a xenograft model of human breast tumor consisting of HER2-positive JIMT-1 cells and HER2-negative MDA-MB-231 cells (4:1 ratio) transferred into immunodeficient mice. This admixed tumor grew aggressively and reached a palpable size (100-150 mm 3 ) in most mice 7 days after orthotopic transplantation. Tumor-bearing mice were treated with each ADC at 3 mg/kg.

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In Vivo Model Breast cancer CDX model
In Vitro Model Breast ductal carcinoma JIMT-1 cells/MDA-MB-231 cells CVCL_2077/CVCL_0062
Revealed Based on the Cell Line Data
Click To Hide/Show 3 Activity Data Related to This Level
Experiment 1 Reporting the Activity Date of This ADC [1]
Efficacy Data Half Maximal Effective Concentration (EC50) 0.02 nM Moderate HER2 expression (HER2++)
Method Description
ADCs were evaluated in vitro cytotoxicity in HER2-positive (KPL-4,JIMT-1,and SKBR-3) and -negative (MDA-MB-231) breast cancer cell lines,human embryonic kidney 293 (HEK293) cells,and human hepatocyte carcinoma (HepG2) cells. All cells were cultured at 37°C under 5% CO2 and passaged before becoming fully confluent up to 20 passages.
In Vitro Model Breast inflammatory carcinoma KPL-4 cells CVCL_5310
Experiment 2 Reporting the Activity Date of This ADC [1]
Efficacy Data Half Maximal Effective Concentration (EC50) 0.02 nM Low HER2 expression (HER2+)
Method Description
ADCs were evaluated in vitro cytotoxicity in HER2-positive (KPL-4,JIMT-1,and SKBR-3) and -negative (MDA-MB-231) breast cancer cell lines,human embryonic kidney 293 (HEK293) cells,and human hepatocyte carcinoma (HepG2) cells. All cells were cultured at 37°C under 5% CO2 and passaged before becoming fully confluent up to 20 passages.
In Vitro Model Breast ductal carcinoma JIMT-1 cells CVCL_2077
Experiment 3 Reporting the Activity Date of This ADC [1]
Efficacy Data Half Maximal Effective Concentration (EC50) 0.18 nM Moderate HER2 expression (HER2++)
Method Description
ADCs were evaluated in vitro cytotoxicity in HER2-positive (KPL-4,JIMT-1,and SKBR-3) and -negative (MDA-MB-231) breast cancer cell lines,human embryonic kidney 293 (HEK293) cells,and human hepatocyte carcinoma (HepG2) cells. All cells were cultured at 37°C under 5% CO2 and passaged before becoming fully confluent up to 20 passages.
In Vitro Model Breast adenocarcinoma SK-BR-3 cells CVCL_0033
References
Ref 1 Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance. Nat Commun. 2021 Jun 10;12(1):3528.

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