Linker Information

General Information of This Linker (ID: LIN0IHRSU)
Name
L2-MC
Linker Type
Flexible reactive (amine/acid) linker
Antibody-Linker Relation
Uncleavable
Structure
Formula
C13H22N2O4S
Isosmiles
NCCCSC1CC(=O)N(CCCCCC(=O)O)C1=O
InChI
InChI=1S/C13H22N2O4S/c14-6-4-8-20-10-9-11(16)15(13(10)19)7-3-1-2-5-12(17)18/h10H,1-9,14H2,(H,17,18)
InChIKey
IDHWJWPSAOOUIU-UHFFFAOYSA-N
Pharmaceutical Properties
Molecule Weight
302.396
Polar area
100.7
Complexity
20
xlogp Value
0.8409
Heavy Count
20
Rot Bonds
10
Hbond acc
5
Hbond Donor
2
Each Antibody-drug Conjugate Related to This Linker
Full Information of The Activity Data of The ADC(s) Related to This Linker
SHR-A1403 [Phase 1 (discontinued)]
 ADC Info 
Identified from the Human Clinical Data
Click To Hide/Show 2 Activity Data Related to This Level
Experiment 1 Reporting the Activity Date of This ADC [1]
Patients Enrolled
Eligible patients have ECOG 0-1, life expectancy ≥12 weeks, measurable advanced/metastatic solid tumors, and adequate organ function. Exclusions include prior ADC/hypersensitivity, unresolved toxicities (>G1), active CNS metastases, NYHA II-IV cardiac disease, HBV/HCV/HIV positivity, or conditions hindering compliance. Contraception is mandatory for 6 months post-treatment.

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Administration Dosage
SHR-A1403 is a humanized anti C-Met immunoglobulin G2 (IgG2) monoclonal antibody conjugated with microtubule inhibitor. SHR-A1403 is provided as the lyophilized powder,40 mg/vial.SHR-A1403 was given intravenously per 3 weeks at the day 1.Intravenous infusion over 30 min
Related Clinical Trial
NCT Number NCT03856541  Clinical Status PHASE1
Clinical Description
A Phase I, Open Label, Dose Escalation Study to Evaluate the Safety, Tolerability and Pharmacokinetics of SHR-A1403 With Intravenous Infusion in Patients With Advanced Solid Tumors
Primary Endpoint
The study assesses treatment-related AEs of SHR-A1403 in advanced solid tumor patients over 24 months, evaluating incidence, severity (NCI CTCAE), and DLTs during cycle 1, with MTD determined as the highest dose below/close to 30% toxicity probability.
Other Endpoint
Pharmacokinetic analysis includes Tmax, Cmax, T1/2, CL/F, Vd/F, AUC, Rac, and ADA assessment over 24 months. Efficacy is measured via RECIST v1.1, with C-Met expression explored in blood/tissue. RP2D will be determined based on safety using CTCAE v4.03 criteria.
Experiment 2 Reporting the Activity Date of This ADC [2]
Related Clinical Trial
NCT Number NCT03856541  Clinical Status Phase 1
Clinical Description
A phase 1, open label, dose escalation study to evaluate the safety, tolerability and pharmacokinetics of SHR-a1403 with intravenous infusion in patients with advanced solid tumors.
Discovered Using Patient-derived Xenograft Model
Click To Hide/Show 3 Activity Data Related to This Level
Experiment 1 Reporting the Activity Date of This ADC [3]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 95.50% High MET expression (MET+++)
Method Description
HCC tumor cells derived from patients (passage 5) were implanted subcutaneously in BALB/c nude mice at an initial tumor size of approximately 30 mm3. In this model,tumor-bearing mice were given vehicle,SHR-A1403 (1 mg/kg),or SHR-A1403 mAb (10 mg/kg) via twice-weekly intravenous injection for two consecutive weeks.
In Vivo Model Hepatic cancer PDX model (PDX: HCC)
Experiment 2 Reporting the Activity Date of This ADC [3]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 98.30% High MET expression (MET+++)
Method Description
HCC tumor cells derived from patients (passage 5) were implanted subcutaneously in BALB/c nude mice at an initial tumor size of approximately 30 mm3. In this model,tumor-bearing mice were given vehicle,SHR-A1403 (3 mg/kg),or SHR-A1403 mAb (10 mg/kg) via twice-weekly intravenous injection for two consecutive weeks.
In Vivo Model Hepatic cancer PDX model (PDX: HCC)
Experiment 3 Reporting the Activity Date of This ADC [3]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 98.50% High MET expression (MET+++)
Method Description
HCC tumor cells derived from patients (passage 5) were implanted subcutaneously in BALB/c nude mice at an initial tumor size of approximately 30 mm3. In this model,tumor-bearing mice were given vehicle,SHR-A1403 (10 mg/kg),or SHR-A1403 mAb (10 mg/kg) via twice-weekly intravenous injection for two consecutive weeks.
In Vivo Model Hepatic cancer PDX model (PDX: HCC)
Discovered Using Cell Line-derived Xenograft Model
Click To Hide/Show 11 Activity Data Related to This Level
Experiment 1 Reporting the Activity Date of This ADC [4]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 0% Negative MET expression (MET-)
Method Description
Effects of SHR-A1403 were further determined in vivo by assessing the growth of HCC827 and HA1 xenograft tumors. Tumor-bearing mice,established by s.c. inoculation of HCC827 and HA1 cells,were randomized into vehicle,AZD9291 (3 mg/kg single dose,i.g.) and SHR-A1403 (10 mg/kg single dose,i.v.) treatment groups when average tumor volumes reached approximately 100-200 mm3.

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In Vivo Model Non-small cell lung cancer HCC827 CDX model (CDX: HA1; Afatinib resistant)
In Vitro Model Lung adenocarcinoma HCC827 cells (Afatinib resistant; HA1) CVCL_2063
Experiment 2 Reporting the Activity Date of This ADC [3]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 34.50% High MET expression (MET+++)
Method Description
SHR-A1403 was evaluated in xenograft mice bearing cancer cells with high c-Met expression,including hepatic cancer HCCLM3,lung cancer NCI-H1993,and gastric cancer MKN-45 cells,and the effects were compared with the effects of SHR-A1403 mAb,the free toxin,or their combination. In the HCCLM3 xenograft model,SHR-A1403 was administered at a single dose of 1 mg/kg.

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In Vivo Model Hepatic cancer CDX model
In Vitro Model Adult hepatocellular carcinoma HCCLM3 cells CVCL_6832
Experiment 3 Reporting the Activity Date of This ADC [3]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 41.80% High MET expression (MET+++)
Method Description
SHR-A1403 was evaluated in xenograft mice bearing cancer cells with high c-Met expression,including hepatic cancer HCCLM3,lung cancer NCI-H1993,and gastric cancer MKN-45 cells,and the effects were compared with the effects of SHR-A1403 mAb,the free toxin,or their combination. In the NCI-H1993 xenograft model,SHR-A1403 was administered at a single dose of 1 mg/kg.

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In Vivo Model Lung cancer CDX model
In Vitro Model Lung cancer Lung cancer cells Homo sapiens
Experiment 4 Reporting the Activity Date of This ADC [3]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 42.80% High MET expression (MET+++)
Method Description
SHR-A1403 was evaluated in xenograft mice bearing cancer cells with high c-Met expression,including hepatic cancer HCCLM3,lung cancer NCI-H1993,and gastric cancer MKN-45 cells,and the effects were compared with the effects of SHR-A1403 mAb,the free toxin,or their combination. In the MKN-45 xenograft model,SHR-A1403 was administered at a single dose of 1 mg/kg.

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In Vivo Model Gastric cancer CDX model
In Vitro Model Gastric cancer Gastric cancer cells Homo sapiens
Experiment 5 Reporting the Activity Date of This ADC [3]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 59.30% High MET expression (MET+++)
Method Description
SHR-A1403 was evaluated in xenograft mice bearing cancer cells with high c-Met expression,including hepatic cancer HCCLM3,lung cancer NCI-H1993,and gastric cancer MKN-45 cells,and the effects were compared with the effects of SHR-A1403 mAb,the free toxin,or their combination. In the NCI-H1993 xenograft model,SHR-A1403 was administered at a single dose of 3 mg/kg.

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In Vivo Model Lung cancer CDX model
In Vitro Model Lung cancer Lung cancer cells Homo sapiens
Experiment 6 Reporting the Activity Date of This ADC [3]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 83.30% High MET expression (MET+++)
Method Description
SHR-A1403 was evaluated in xenograft mice bearing cancer cells with high c-Met expression,including hepatic cancer HCCLM3,lung cancer NCI-H1993,and gastric cancer MKN-45 cells,and the effects were compared with the effects of SHR-A1403 mAb,the free toxin,or their combination. In the HCCLM3 xenograft model,SHR-A1403 was administered at a single dose of 3 mg/kg.

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In Vivo Model Hepatic cancer CDX model
In Vitro Model Adult hepatocellular carcinoma HCCLM3 cells CVCL_6832
Experiment 7 Reporting the Activity Date of This ADC [3]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 84.60% High MET expression (MET+++)
Method Description
SHR-A1403 was evaluated in xenograft mice bearing cancer cells with high c-Met expression,including hepatic cancer HCCLM3,lung cancer NCI-H1993,and gastric cancer MKN-45 cells,and the effects were compared with the effects of SHR-A1403 mAb,the free toxin,or their combination. In the MKN-45 xenograft model,SHR-A1403 was administered at a single dose of 3 mg/kg.

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In Vivo Model Gastric cancer CDX model
In Vitro Model Gastric adenocarcinoma MKN45 cells CVCL_0434
Experiment 8 Reporting the Activity Date of This ADC [3]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 89.90% High MET expression (MET+++)
Method Description
SHR-A1403 was evaluated in xenograft mice bearing cancer cells with high c-Met expression,including hepatic cancer HCCLM3,lung cancer NCI-H1993,and gastric cancer MKN-45 cells,and the effects were compared with the effects of SHR-A1403 mAb,the free toxin,or their combination. In the MKN-45 xenograft model,SHR-A1403 was administered at a single dose of 10 mg/kg.

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In Vivo Model Gastric cancer CDX model
In Vitro Model Gastric adenocarcinoma MKN45 cells CVCL_0434
Experiment 9 Reporting the Activity Date of This ADC [3]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 91.60% High MET expression (MET+++)
Method Description
SHR-A1403 was evaluated in xenograft mice bearing cancer cells with high c-Met expression,including hepatic cancer HCCLM3,lung cancer NCI-H1993,and gastric cancer MKN-45 cells,and the effects were compared with the effects of SHR-A1403 mAb,the free toxin,or their combination. In the NCI-H1993 xenograft model,SHR-A1403 was administered at a single dose of 10 mg/kg.

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In Vivo Model Lung cancer CDX model
In Vitro Model Lung adenocarcinoma NCI-H1993 cells CVCL_1512
Experiment 10 Reporting the Activity Date of This ADC [4]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 92.80% High MET expression (MET+++)
Method Description
Effects of SHR-A1403 were further determined in vivo by assessing the growth of HCC827 and HA1 xenograft tumors. Tumor-bearing mice,established by s.c. inoculation of HCC827 and HA1 cells,were randomized into vehicle,AZD9291 (3 mg/kg single dose,i.g.) and SHR-A1403 (10 mg/kg single dose,i.v.) treatment groups when average tumor volumes reached approximately 100-200 mm3.

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In Vivo Model Non-small cell lung cancer CDX model
In Vitro Model Lung adenocarcinoma HCC827 cells CVCL_2063
Experiment 11 Reporting the Activity Date of This ADC [3]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 98.80% High MET expression (MET+++)
Method Description
SHR-A1403 was evaluated in xenograft mice bearing cancer cells with high c-Met expression,including hepatic cancer HCCLM3,lung cancer NCI-H1993,and gastric cancer MKN-45 cells,and the effects were compared with the effects of SHR-A1403 mAb,the free toxin,or their combination. In the HCCLM3 xenograft model,SHR-A1403 was administered at a single dose of 10 mg/kg.

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In Vivo Model Hepatic cancer CDX model
In Vitro Model Adult hepatocellular carcinoma HCCLM3 cells CVCL_6832
Revealed Based on the Cell Line Data
Click To Hide/Show 16 Activity Data Related to This Level
Experiment 1 Reporting the Activity Date of This ADC [3]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
3.2 ng/mL
High MET expression (MET+++; IHC 3+)
Method Description
The effects of SHR-A1403 on the proliferation of various types of human cancer cells were evaluated and compared with the effects of SHR-A1403 mAb and the free toxin SHR152852.
In Vitro Model Adult hepatocellular carcinoma HCCLM3 cells CVCL_6832
Experiment 2 Reporting the Activity Date of This ADC [3]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
7.8 ng/mL
Negative MET expression (MET-)
Method Description
The effects of SHR-A1403 on the proliferation of various types of human cancer cells were evaluated and compared with the effects of SHR-A1403 mAb and the free toxin SHR152852.
In Vitro Model Gastric adenocarcinoma MKN45 cells CVCL_0434
Experiment 3 Reporting the Activity Date of This ADC [4]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
11.8 ng/mL
Moderate MET expression (MET++)
Method Description
To establish the EGFR inhibitor-resistant NSCLC cells,HCC827 cells were grown initially in medium containing 10 nmol/L gefitinib or afatinib. To exam the ability of the ADC,SHR-A1403,to overcome AZD9291 resistance. Human tumor xenografts were established by s.c. inoculation of nude mice with HCC827,HA1 or HG3 cells. Tumor-bearing mice were randomized into groups and treated with vehicle,AZD9291 intragastric administration (i.g.) or SHR-A1403 intravenous injection (i.v.) when average tumor volume reached approximately 100-200 mm3. Resistance ratio = IC50 (resistant cells)/IC50 (HCC827).

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In Vitro Model Lung adenocarcinoma HCC827 cells (Afatinib resistant; HA1) CVCL_2063
Experiment 4 Reporting the Activity Date of This ADC [3]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
16.3 ng/mL
High MET expression (MET+++)
Method Description
The effects of SHR-A1403 on the proliferation of various types of human cancer cells were evaluated and compared with the effects of SHR-A1403 mAb and the free toxin SHR152852.
In Vitro Model Lung adenocarcinoma NCI-H1993 cells CVCL_1512
Experiment 5 Reporting the Activity Date of This ADC [4]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
17.8 ng/mL
High MET expression (MET+++)
Method Description
To establish the EGFR inhibitor-resistant NSCLC cells,HCC827 cells were grown initially in medium containing 10 nmol/L gefitinib or afatinib. To exam the ability of the ADC,SHR-A1403,to overcome AZD9291 resistance. Human tumor xenografts were established by s.c. inoculation of nude mice with HCC827,HA1 or HG3 cells. Tumor-bearing mice were randomized into groups and treated with vehicle,AZD9291 intragastric administration (i.g.) or SHR-A1403 intravenous injection (i.v.) when average tumor volume reached approximately 100-200 mm3. Resistance ratio = IC50 (resistant cells)/IC50 (HCC827).

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In Vitro Model Lung adenocarcinoma HCC827 cells (Gefitinib resistant) CVCL_2063
Experiment 6 Reporting the Activity Date of This ADC [4]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
26.6 ng/mL
Negative MET expression (MET-)
Method Description
To establish the EGFR inhibitor-resistant NSCLC cells,HCC827 cells were grown initially in medium containing 10 nmol/L gefitinib or afatinib. To exam the ability of the ADC,SHR-A1403,to overcome AZD9291 resistance. Human tumor xenografts were established by s.c. inoculation of nude mice with HCC827,HA1 or HG3 cells. Tumor-bearing mice were randomized into groups and treated with vehicle,AZD9291 intragastric administration (i.g.) or SHR-A1403 intravenous injection (i.v.) when average tumor volume reached approximately 100-200 mm3. Resistance ratio = IC50 (resistant cells)/IC50 (HCC827).

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In Vitro Model Lung adenocarcinoma HCC827 cells (Gefitinib resistant) CVCL_2063
Experiment 7 Reporting the Activity Date of This ADC [3]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
46.7 ng/mL
Moderate MET expression (MET++)
Method Description
The effects of SHR-A1403 on the proliferation of various types of human cancer cells were evaluated and compared with the effects of SHR-A1403 mAb and the free toxin SHR152852.
In Vitro Model Lung papillary adenocarcinoma NCI-H441 cells CVCL_1561
Experiment 8 Reporting the Activity Date of This ADC [3]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
53.9 ng/mL
High MET expression (MET+++; IHC 3+)
Method Description
The effects of SHR-A1403 on the proliferation of various types of human cancer cells were evaluated and compared with the effects of SHR-A1403 mAb and the free toxin SHR152852.
In Vitro Model Invasive breast carcinoma Hs 578T cells CVCL_0332
Experiment 9 Reporting the Activity Date of This ADC [3]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
78.2 ng/mL
High MET expression (MET+++)
Method Description
The effects of SHR-A1403 on the proliferation of various types of human cancer cells were evaluated and compared with the effects of SHR-A1403 mAb and the free toxin SHR152852.
In Vitro Model Prostate carcinoma PC-3 cells CVCL_0035
Experiment 10 Reporting the Activity Date of This ADC [4]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
99.4 ng/mL
Moderate MET expression (MET++)
Method Description
To establish the EGFR inhibitor-resistant NSCLC cells,HCC827 cells were grown initially in medium containing 10 nmol/L gefitinib or afatinib. To exam the ability of the ADC,SHR-A1403,to overcome AZD9291 resistance. Human tumor xenografts were established by s.c. inoculation of nude mice with HCC827,HA1 or HG3 cells. Tumor-bearing mice were randomized into groups and treated with vehicle,AZD9291 intragastric administration (i.g.) or SHR-A1403 intravenous injection (i.v.) when average tumor volume reached approximately 100-200 mm3. Resistance ratio = IC50 (resistant cells)/IC50 (HCC827).

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In Vitro Model Lung adenocarcinoma HCC827 cells (Gefitinib resistant) CVCL_2063
Experiment 11 Reporting the Activity Date of This ADC [4]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
130.8 ng/mL
High MET expression (MET+++)
Method Description
To establish the EGFR inhibitor-resistant NSCLC cells,HCC827 cells were grown initially in medium containing 10 nmol/L gefitinib or afatinib. To exam the ability of the ADC,SHR-A1403,to overcome AZD9291 resistance. Human tumor xenografts were established by s.c. inoculation of nude mice with HCC827,HA1 or HG3 cells. Tumor-bearing mice were randomized into groups and treated with vehicle,AZD9291 intragastric administration (i.g.) or SHR-A1403 intravenous injection (i.v.) when average tumor volume reached approximately 100-200 mm3. Resistance ratio = IC50 (resistant cells)/IC50 (HCC827).

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In Vitro Model Lung adenocarcinoma HCC827 cells (Gefitinib resistant) CVCL_2063
Experiment 12 Reporting the Activity Date of This ADC [3]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
214.8 ng/mL
Moderate MET expression (MET++)
Method Description
The effects of SHR-A1403 on the proliferation of various types of human cancer cells were evaluated and compared with the effects of SHR-A1403 mAb and the free toxin SHR152852.
In Vitro Model Clear cell renal cell carcinoma Caki-1 cells CVCL_0234
Experiment 13 Reporting the Activity Date of This ADC [4]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
918.9 ng/mL
Moderate MET expression (MET++)
Method Description
To establish the EGFR inhibitor-resistant NSCLC cells,HCC827 cells were grown initially in medium containing 10 nmol/L gefitinib or afatinib. To exam the ability of the ADC,SHR-A1403,to overcome AZD9291 resistance. Human tumor xenografts were established by s.c. inoculation of nude mice with HCC827,HA1 or HG3 cells. Tumor-bearing mice were randomized into groups and treated with vehicle,AZD9291 intragastric administration (i.g.) or SHR-A1403 intravenous injection (i.v.) when average tumor volume reached approximately 100-200 mm3. Resistance ratio = IC50 (resistant cells)/IC50 (HCC827).

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In Vitro Model Lung adenocarcinoma HCC827 cells CVCL_2063
Experiment 14 Reporting the Activity Date of This ADC [3]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
1987.5 ng/mL
High MET expression (MET+++; IHC 3+)
Method Description
The effects of SHR-A1403 on the proliferation of various types of human cancer cells were evaluated and compared with the effects of SHR-A1403 mAb and the free toxin SHR152852.
In Vitro Model Lung adenocarcinoma A-549 cells CVCL_0023
Experiment 15 Reporting the Activity Date of This ADC [3]
Efficacy Data Half Maximal Inhibitory Concentration (IC50) > 10 ug/mL High MET expression (MET+++)
Method Description
The effects of SHR-A1403 on the proliferation of various types of human cancer cells were evaluated and compared with the effects of SHR-A1403 mAb and the free toxin SHR152852.
In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cells CVCL_1603
Experiment 16 Reporting the Activity Date of This ADC [4]
Efficacy Data Half Maximal Inhibitory Concentration (IC50) > 30 ug/mL Negative MET expression (MET-)
Method Description
To establish the EGFR inhibitor-resistant NSCLC cells,HCC827 cells were grown initially in medium containing 10 nmol/L gefitinib or afatinib. To exam the ability of the ADC,SHR-A1403,to overcome AZD9291 resistance. Human tumor xenografts were established by s.c. inoculation of nude mice with HCC827,HA1 or HG3 cells. Tumor-bearing mice were randomized into groups and treated with vehicle,AZD9291 intragastric administration (i.g.) or SHR-A1403 intravenous injection (i.v.) when average tumor volume reached approximately 100-200 mm3. Resistance ratio = IC50 (resistant cells)/IC50 (HCC827).

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In Vitro Model Lung adenocarcinoma HCC827 cells (Afatinib resistant; HA2) CVCL_2063
References
Ref 1 A Study of SHR-A1403 in Patients With Advanced Solid Tumor
Ref 2 A Phase I, Open Label, Dose Escalation Study to Evaluate the Safety, Tolerability and Pharmacokinetics of SHR-A1403 With Intravenous Infusion in Patients With Advanced Solid Tumors
Ref 3 SHR-A1403, a novel c-Met antibody-drug conjugate, exerts encouraging anti-tumor activity in c-Met-overexpressing models. Acta Pharmacol Sin. 2019 Jul;40(7):971-979.
Ref 4 SHR-A1403, a novel c-mesenchymal-epithelial transition factor (c-Met) antibody-drug conjugate, overcomes AZD9291 resistance in non-small cell lung cancer cells overexpressing c-Met. Cancer Sci. 2019 Nov;110(11):3584-3594.