Linker Information

General Information of This Linker
Linker ID
LIN0MESCO
Linker Name
Sulfo-SPDB
Linker Type
Flexible dual-reactive (amino/thiol) linker; Thiol-sensitive linker
Antibody-Linker Relation
Cleavable
Structure
Formula
C13H14N2O7S3
Isosmiles
C1CC(=O)N(C1=O)OC(=O)C(CCSSC2=CC=CC=N2)S(=O)(=O)O
PubChem CID
53248044
InChI
InChI=1S/C13H14N2O7S3/c16-11-4-5-12(17)15(11)22-13(18)9(25(19,20)21)6-8-23-24-10-3-1-2-7-14-10/h1-3,7,9H,4-6,8H2,(H,19,20,21)
InChIKey
FUHCFUVCWLZEDQ-UHFFFAOYSA-N
IUPAC Name
1-(2,5-dioxopyrrolidin-1-yl)oxy-1-oxo-4-(pyridin-2-yldisulfanyl)butane-2-sulfonic acid
Pharmaceutical Properties
Molecule Weight
406.5
Polar area
190
Complexity
604
xlogp Value
0
Heavy Count
25
Rot Bonds
9
Hbond acc
10
Hbond Donor
1
Each Antibody-drug Conjugate Related to This Linker
Full Information of The Activity Data of The ADC(s) Related to This Linker
Mirvetuximab soravtansine [Approved]
 ADC Info 
Identified from the Human Clinical Data
Click To Hide/Show 3 Activity Data Related to This Level
Experiment 1 Reporting the Activity Date of This ADC [1]
Efficacy Data Objective Response Rate (ORR)
22.00%
High FOLR1 expression (FOLR1+++)
Patients Enrolled
Platinum-resistant epithelial ovarian cancer (EOC); Eligible patients with 1-3 prior lines of therapy and whose tumors were positive for FR expression.
Administration Dosage
6 mg/kg Q3W.
Related Clinical Trial
NCT Number NCT02631876  Clinical Status Phase 3
Clinical Description
FORWARD I: A randomized, open label phase 3 study to evaluate the safety and efficacy of mirvetuximab soravtansine (IMGN853) versus investigator's choice of chemotherapy in women with folate receptor alpha positive advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer.
Primary Endpoint
For the ITT population, Kaplan-Meier estimates showed no significant difference (HR, 0.98; 95% Cl, 0.73-1.31; P=0.897) in progression-free survival (PFS) between groups Median PFS was 4.10 and 4.40 months for MIRV and IC chemotherapy, respectively. In the prespecified high FR subgroup, PFS was longer in patients in the MIRV group compared with IC chemotherapy (median, 4.80 months versus 3.30 months; HR, 0.69, 95% CI, 0.48 to 1.00; P = 0.049). Based on the Hochberg procedure used in the statistical analysis plan for the study, this P value did not meet statistical significanceBoth in the ITT group and high FR subgroup, OS were not significantly different.

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Other Endpoint
Mirvetuximab soravtansine vs IC chemotherapy in the ITT group: ORR=22.00% vs 12.00%, P=0.015; cancer antigen-125 (CA-125) responses=51.00% vs 27.00%, P<0001; median PFS2 duration (time from randomization to second disease progression or death)=10.00 vs 8.40 months, HR=0.64, 95% Cl, 0.49-0.84, P<0.001); PRO in the EORTC QLQ-OV28 Abdominal/GI Symptom Subscale=32.00% vs 14.00%, P=0.016; Mirvetuximab soravtansine vs IC chemotherapy in the high FR subset, ORR=24.00% vs 10.00%, P=0.014; cancer antigen-125 (CA-125) responses=53.00% vs 25.00%, P=0.001; median PFS2 duration=10.10 vs 8.40 months, HR=0.56, 95% Cl, 0.39-0.79, P<0.001); PRO in the EORTC QLQ-OV28 Abdominal/GI Symptom Subscale=27.00% vs 13.00%, P=0.143.

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Experiment 2 Reporting the Activity Date of This ADC [2]
Efficacy Data Objective Response Rate (ORR)
31.73%
High FOLR1 expression (FOLR1+++)
Patients Enrolled
Platinum-Resistant, Advanced High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers With High Folate Receptor-Alpha Expression.
Administration Dosage
6 mg/kg Q3W.
Related Clinical Trial
NCT Number NCT04296890  Clinical Status Phase 3
Clinical Description
SORAYA: A Phase 3, single arm study of mirvetuximab soravtansine in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression.
Primary Endpoint
Confirmed Overall Response Rate=31.73% [(N=104, 95% Cl, 22.90-41.60), Complete response rate=4.80%, Partial response rate=26.90%].
Other Endpoint
Median duration of response=6.90 months (N=33, 95% Cl 5.60-9.70).
Experiment 3 Reporting the Activity Date of This ADC [3]
Efficacy Data Objective Response Rate (ORR)
39.00%
Moderate FOLR1 expression (FOLR1++)
Patients Enrolled
Platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer.
Administration Dosage
6 mg/kg (adjusted ideal body weight) once every 3 weeks.
Related Clinical Trial
NCT Number NCT02606305  Clinical Status Phase 1b/2
Clinical Description
A phase 1b/2 study to evaluate the safety, tolerability and pharmacokinetics of mirvetuximab soravtansine (IMGN853) in combination with bevacizumab, carboplatin, pegylated liposomal doxorubicin, pembrolizumab, or bevacizumab + carboplatin, in adults with folate receptor alpha positive advanced epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.

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Primary Endpoint
For AURELIA-type patients (N=16, bevacizumab-naive and 1-2 prior lines of therapy, plus medium/high FRa expression), confirmed ORR=56.00%, median duration of response (mDOR)=12.0 months, median progression-free survival (mPFS) = 9.9 months.
Discovered Using Patient-derived Xenograft Model
Click To Hide/Show 2 Activity Data Related to This Level
Experiment 1 Reporting the Activity Date of This ADC [4]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 99.40% (Day 30) Moderate ROR1 expression (ROR1++)
Method Description
In vivoexperiments comparing the antitumor activity of IMGN853 versus ADC isotype control, PBS and M9346A were conducted using both high grade endometrioid/clear cell xenografts as well as a uterine serous tumor PDX model (BIO (K)1).all treatments were given twice, one week apart by retro-orbital injection at a concentration of 5 mg/kg.
In Vivo Model Uterine serous carcinomas PDX model (PDX: BIO(K)1)
Experiment 2 Reporting the Activity Date of This ADC [4]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 100.00% (Day 25) Moderate ROR1 expression (ROR1++)
Method Description
In vivoexperiments comparing the antitumor activity of IMGN853 versus ADC isotype control, PBS and M9346A were conducted using both high grade endometrioid/clear cell xenografts as well as a uterine serous tumor PDX model (BIO (K)1).all treatments were given twice, one week apart by retro-orbital injection at a concentration of 5 mg/kg.
In Vivo Model Uterine serous carcinomas PDX model (PDX: END(K)265)
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 [5]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 33.00% (Day 5) Positive FOLR1 expression (FOLR1 +++/++)
Method Description
Conjugates of the exemplary anti-FOLR1 antibodies were tested using an established xenograft model of OV-90 cells implanted subcutaneous into SCID mice. Mice were randomized by body weight into treatment groups and treated once post cell inoculation with 25 ug/kg of one of the conjugates listed above or with PBS only.
In Vivo Model OV-90 CDX model
In Vitro Model Ovarian adenocarcinoma OV-90 cells CVCL_3768
Experiment 2 Reporting the Activity Date of This ADC [5]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 45.00% (Day 6) Positive FOLR1 expression (FOLR1 +++/++)
Method Description
Conjugates of the exemplary anti-FOLR1 antibodies were tested using an established xenograft model of IGROV-1 cells implanted subcutaneous into SCID mice. Mice were randomized by body weight into treatment groups and treated once post cell inoculation with 25 ug/kg of one of the conjugates listed above or with PBS only.
In Vivo Model IGROV-1 CDX model
In Vitro Model Ovarian endometrioid adenocarcinoma IGROV-1 cells CVCL_1304
Experiment 3 Reporting the Activity Date of This ADC [5]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 64.00% (Day 26) Positive FOLR1 expression (FOLR1 +++/++)
Method Description
Conjugates of the exemplary anti-FOLR1 antibodies were tested using an established xenograft model of OV-90 cells implanted subcutaneous into SCID mice. Mice were randomized by body weight into treatment groups and treated once post cell inoculation with 50 ug/kg of one of the conjugates listed above or with PBS only.
In Vivo Model OV-90 CDX model
In Vitro Model Ovarian adenocarcinoma OV-90 cells CVCL_3768
Experiment 4 Reporting the Activity Date of This ADC [5]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 82.00% (Day 40) Positive FOLR1 expression (FOLR1 +++/++)
Method Description
Conjugates of the exemplary anti-FOLR1 antibodies were tested using an established xenograft model of OV-90 cells implanted subcutaneous into SCID mice. Mice were randomized by body weight into treatment groups and treated once post cell inoculation with 100 ug/kg of one of the conjugates listed above or with PBS only.
In Vivo Model OV-90 CDX model
In Vitro Model Ovarian adenocarcinoma OV-90 cells CVCL_3768
Experiment 5 Reporting the Activity Date of This ADC [5]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 82.00% (Day 21) Positive FOLR1 expression (FOLR1 +++/++)
Method Description
Conjugates of the exemplary anti-FOLR1 antibodies were tested using an established xenograft model of OVCAR-3 cells implanted subcutaneous into SCID mice. Mice were randomized by body weight into treatment groups and treated once post cell inoculation with 25 ug/kg of one of the conjugates listed above or with PBS only.
In Vivo Model OVCAR-3 CDX model
In Vitro Model Ovarian serous adenocarcinoma OVCAR-3 cells CVCL_0465
Experiment 6 Reporting the Activity Date of This ADC [6]
Efficacy Data Tumor Growth Inhibition value (TGI)
93.00% (Day 32)
High FOLR1 expression (FOLR1+++; 1,300,000 FOLR1 molecules/cell)
Method Description
Animals with established tumors of about 130 mm3 were treated with intravenous single injection of the M9346A-DM conjugates at 2.5±0.2 mg/kg, equivalent to 51±3 ug conjugated maytansinoid per kg The conjugates were injected on day 7 after cell inoculation.
In Vivo Model Ovarian carcinoma Igrov-1 CDX model
In Vitro Model Ovarian endometrioid adenocarcinoma IGROV-1 cells CVCL_1304
Experiment 7 Reporting the Activity Date of This ADC [5]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 93.00% (Day 41) Positive FOLR1 expression (FOLR1 +++/++)
Method Description
Conjugates of the exemplary anti-FOLR1 antibodies were tested using an established xenograft model of IGROV-1 cells implanted subcutaneous into SCID mice. Mice were randomized by body weight into treatment groups and treated once post cell inoculation with 50 ug/kg of one of the conjugates listed above or with PBS only.
In Vivo Model IGROV-1 CDX model
In Vitro Model Ovarian endometrioid adenocarcinoma IGROV-1 cells CVCL_1304
Experiment 8 Reporting the Activity Date of This ADC [5]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 95.00% (Day 67) Positive FOLR1 expression (FOLR1 +++/++)
Method Description
Conjugates of the exemplary anti-FOLR1 antibodies were tested using an established xenograft model of IGROV-1 cells implanted subcutaneous into SCID mice. Mice were randomized by body weight into treatment groups and treated once post cell inoculation with 100 ug/kg of one of the conjugates listed above or with PBS only.
In Vivo Model IGROV-1 CDX model
In Vitro Model Ovarian endometrioid adenocarcinoma IGROV-1 cells CVCL_1304
Experiment 9 Reporting the Activity Date of This ADC [6]
Efficacy Data Tumor Growth Inhibition value (TGI)
99.07% (Day 30)
High FOLR1 expression (FOLR1+++; 4,500,000 FOLR1 molecules/cell)
Method Description
Animals with established tumors of about 130 mm3 were treated with intravenous single injection of the M9346A-DM conjugates at 2.5±0.2 mg/kg, equivalent to 51±3 ug conjugated maytansinoid per kg The conjugates were injected on day 20 after cell inoculation.
In Vivo Model FRalpha-positive KB CDX model
In Vitro Model Human papillomavirus-related endocervical adenocarcinoma KB cells CVCL_0372
Experiment 10 Reporting the Activity Date of This ADC [5]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 100.00% (Day 75) Positive FOLR1 expression (FOLR1 +++/++)
Method Description
Conjugates of the exemplary anti-FOLR1 antibodies were tested using an established xenograft model of OVCAR-3 cells implanted subcutaneous into SCID mice. Mice were randomized by body weight into treatment groups and treated once post cell inoculation with 50 ug/kg of one of the conjugates listed above or with PBS only.
In Vivo Model OVCAR-3 CDX model
In Vitro Model Ovarian serous adenocarcinoma OVCAR-3 cells CVCL_0465
Experiment 11 Reporting the Activity Date of This ADC [5]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 100.00% (Day 120) Positive FOLR1 expression (FOLR1 +++/++)
Method Description
Conjugates of the exemplary anti-FOLR1 antibodies were tested using an established xenograft model of OVCAR-3 cells implanted subcutaneous into SCID mice. Mice were randomized by body weight into treatment groups and treated once post cell inoculation with 100 ug/kg of one of the conjugates listed above or with PBS only.
In Vivo Model OVCAR-3 CDX model
In Vitro Model Ovarian serous adenocarcinoma OVCAR-3 cells CVCL_0465
Revealed Based on the Cell Line Data
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Date of This ADC [6]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
0.15±0.08 nM
Method Description
Dilutions of conjugates or unconjugated maytansinoid in the appropriate culture medium were added to wells of 96-well flat-bottomed plates containing 1 x103 cells per well The plates were incubated at 37°C, 6% CO2 for either 5 days (continuos exposure) or for 4 hours followed by 5-day incubation in conjugate-free medium (short exposure). Cell viability was determined by the WST-8 assay in accordance with the manufacturer's protocol, and IC50 were generated using a sigmoidal dose-response (variable slope) nonlinear regression curve fit.

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In Vitro Model Human papillomavirus-related endocervical adenocarcinoma KB cells CVCL_0372
Experiment 2 Reporting the Activity Date of This ADC [6]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
0.20±0.10 nM
Method Description
Dilutions of conjugates or unconjugated maytansinoid in the appropriate culture medium were added to wells of 96-well flat-bottomed plates containing 1 x103 cells per well The plates were incubated at 37°C, 6% CO2 for either 5 days (continuos exposure) or for 4 hours followed by 5-day incubation in conjugate-free medium (short exposure). Cell viability was determined by the WST-8 assay in accordance with the manufacturer's protocol, and IC50 were generated using a sigmoidal dose-response (variable slope) nonlinear regression curve fit.

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In Vitro Model Gestational choriocarcinoma JEG-3 cells CVCL_0363
Experiment 3 Reporting the Activity Date of This ADC [6]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
1.00±0.40 nM
Method Description
Dilutions of conjugates or unconjugated maytansinoid in the appropriate culture medium were added to wells of 96-well flat-bottomed plates containing 1 x103 cells per well The plates were incubated at 37°C, 6% CO2 for either 5 days (continuos exposure) or for 4 hours followed by 5-day incubation in conjugate-free medium (short exposure). Cell viability was determined by the WST-8 assay in accordance with the manufacturer's protocol, and IC50 were generated using a sigmoidal dose-response (variable slope) nonlinear regression curve fit.

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In Vitro Model Ovarian endometrioid adenocarcinoma IGROV-1 cells CVCL_1304
Experiment 4 Reporting the Activity Date of This ADC [4]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
0.20 ug/mL
Positive ROR1 expression (ROR1+++/++)
Method Description
Cell cytotoxicity was tested with IMGN853, ADC isotype control and M9346A in pure and mixed endometrial endometrioid cell lines harboring high FOLR1 expression.
In Vitro Model Endometrial undifferentiated carcinoma END-2 cells CVCL_B5KE
Experiment 5 Reporting the Activity Date of This ADC [4]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
74.60 ng/mL
Positive ROR1 expression (ROR1+++/++)
Method Description
Cell cytotoxicity was tested with IMGN853, ADC isotype control and M9346A in pure and mixed endometrial endometrioid cell lines harboring high FOLR1 expression.
In Vitro Model Endometrial undifferentiated carcinoma END-1 cells CVCL_B5JE
IMGN-779 [Clinical candidate]
 ADC Info 
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 [7]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 100.00% (Day 15) Positive CD33 expression (CD33+++/++)
Method Description
EOL-1 tumor-bearing mice received a single intravenous bolus administration of vehicle, IMGN779, or Ab-DGN462, with each conjugate molecule dosed at approximately 1.5 mg/kg ADC by antibody concentration (i.e., 10 or 30 ug/kg linked IGN).
In Vivo Model EOL-1 CDX model
In Vitro Model Chronic eosinophilic leukemia EoL-1 cells CVCL_0258
Experiment 2 Reporting the Activity Date of This ADC [7]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 100.00% (Day 30) Positive CD33 expression (CD33+++/++)
Method Description
IMGN779 (0.5 mg/kg, a single dose) induces efficient tumor cell killing in cell line-derived models of MV4-11 cells with CD33 expression with high expression.
In Vivo Model MV4-11 CDX model
In Vitro Model Childhood acute monocytic leukemia MV4-11 cells CVCL_0064
NOV0712-DM4 [Investigative]
 ADC Info 
Discovered Using Cell Line-derived Xenograft Model
Click To Hide/Show 9 Activity Data Related to This Level
Experiment 1 Reporting the Activity Date of This ADC [8]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 0.00% (Day 13) Negative CDH6 expression (CDH6-)
Method Description
The CDH6-negative human ovarian tumor cell line ES-2 was subcutaneously inoculated at a dose of 1,000,000 cells to the right flank region of each female nude mouse (Day 0). On the day 7 of grouping, the antibody-drug conjugate NOV0712-DM4 was intravenously administered at doses of 1 mg/kg to thetail of each mouse.
In Vivo Model ES-2 CDX model
In Vitro Model Ovarian clear cell adenocarcinoma ES-2 cells CVCL_3509
Experiment 2 Reporting the Activity Date of This ADC [8]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 0.00% (Day 13) Negative CDH6 expression (CDH6-)
Method Description
The CDH6-negative human ovarian tumor cell line ES-2 was subcutaneously inoculated at a dose of 1,000,000 cells to the right flank region of each female nude mouse (Day 0). On the day 7 of grouping, the antibody-drug conjugate NOV0712-DM4 was intravenously administered at doses of 3 mg/kg to thetail of each mouse.
In Vivo Model ES-2 CDX model
In Vitro Model Ovarian clear cell adenocarcinoma ES-2 cells CVCL_3509
Experiment 3 Reporting the Activity Date of This ADC [8]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 3.10% (Day 28) Positive CDH6 expression (CDH6+++/++)
Method Description
The CDH6-positive human ovarian tumor cell line OVCAR-3 was subcutane-ously inoculated at a dose of 10,000,000 cells to the right flank region of each female nude mouse (Day 0). On the day 22 of grouping, theantibody-drug conjugate NOV0712-DM4 was intravenously administered at doses of 1 mg/kg to the tail of each mouse.
In Vivo Model OVCAR-3 CDX model
In Vitro Model Ovarian serous adenocarcinoma OVCAR-3 cells CVCL_0465
Experiment 4 Reporting the Activity Date of This ADC [8]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 6.77% (Day 21) Positive CDH6 expression (CDH6+++/++)
Method Description
The CDH6-positive human ovarian tumor cell line PA-1 was subcutaneously inoculatedat a dose of 8,500,000 cells to the right flank region of eachfemale nude mouse (Day 0). On the day 11 of grouping, the antibody-drug conjugate NOV0712-DM4 was intravenously administered at doses of 3 mg/kg to the tail of each mouse.
In Vivo Model PA-1 CDX model
In Vitro Model Ovarian mixed germ cell tumor PA-1 cells CVCL_0479
Experiment 5 Reporting the Activity Date of This ADC [8]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 9.52% (Day 23) Positive CDH6 expression (CDH6+++/++)
Method Description
The CDH6-positive human renal cell tumor cell line786-0 was subcutaneously inoculated at a dose of 5,000,000 cells to the right flank regionof each male SCID mouse (Day 0). On the day 20 of grouping, the anti-body-drug conjugate NOV0712-DM4 was intravenously administered at doses of 1 mg/kg to thetail of each mouse.
In Vivo Model 786-O CDX model
In Vitro Model Renal cell carcinoma 786-O cells CVCL_1051
Experiment 6 Reporting the Activity Date of This ADC [8]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 12.03% (Day 21) Positive CDH6 expression (CDH6+++/++)
Method Description
The CDH6-positive human ovarian tumor cell line PA-1 was subcutaneously inoculatedat a dose of 8,500,000 cells to the right flank region of eachfemale nude mouse (Day 0). On the day 11 of grouping, the antibody-drug conjugate NOV0712-DM4 was intravenously administered at doses of 1 mg/kg to the tail of each mouse.
In Vivo Model PA-1 CDX model
In Vitro Model Ovarian mixed germ cell tumor PA-1 cells CVCL_0479
Experiment 7 Reporting the Activity Date of This ADC [8]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 23.91% (Day 23) Positive CDH6 expression (CDH6+++/++)
Method Description
The CDH6-positive human renal cell tumor cell line786-0 was subcutaneously inoculated at a dose of 5,000,000 cells to the right flank regionof each male SCID mouse (Day 0). On the day 20 of grouping, the anti-body-drug conjugate NOV0712-DM4 was intravenously administered at doses of 3 mg/kg to thetail of each mouse.
In Vivo Model 786-O CDX model
In Vitro Model Renal cell carcinoma 786-O cells CVCL_1051
Experiment 8 Reporting the Activity Date of This ADC [8]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 30.02% (Day 24) Positive CDH6 expression (CDH6+++/++)
Method Description
The CDH6-positive human renal cell tumor cell line 786-O was subcutaneously inoculated at a dose of 5,000,000 cells to the right flank regionof each male SCID mouse (Day 0). On the day 18 of grouping, NOV0712-DM4 was intravenously administered at a dose of 3 mg/kg to the tail of each mouse.
In Vivo Model 786-O CDX model
In Vitro Model Renal cell carcinoma 786-O cells CVCL_1051
Experiment 9 Reporting the Activity Date of This ADC [8]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 72.30% (Day 28) Positive CDH6 expression (CDH6+++/++)
Method Description
The CDH6-positive human ovarian tumor cell line OVCAR-3 was subcutane-ously inoculated at a dose of 10,000,000 cells to the right flank region of each female nude mouse (Day 0). On the day 22 of grouping, theantibody-drug conjugate NOV0712-DM4 was intravenously administered at doses of 3 mg/kg to the tail of each mouse.
In Vivo Model OVCAR-3 CDX model
In Vitro Model Ovarian serous adenocarcinoma OVCAR-3 cells CVCL_0465
Revealed Based on the Cell Line Data
Click To Hide/Show 1 Activity Data Related to This Level
Experiment 1 Reporting the Activity Date of This ADC [8]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
1.00-10.00 nM
Positive CDH6 expression (CDH6+++/++)
Method Description
CDH6-positive human ovarian tumor cell line PA-1 was seeded over a 96-well plate at 2,000 cells/100 L/well in MEM medium supplemented with 10% FBS, and the cells were then cultured overnight. On the next day, each of the 4 humanized hG019-drug conjugates or NOV0712-DM4 was added to the cells.
In Vitro Model Ovarian mixed germ cell tumor PA-1 cells CVCL_0479
huMov19-sulfo-SPDB-DM4 (DAR6.8) [Investigative]
 ADC Info 
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 [5]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 90.72% (Day 17) Positive FOLR1 expression (FOLR1 +++/++)
Method Description
Conjugates of the exemplary anti-FOLR1 antibodies were tested using an established xenograft model of KB cells implanted subcutaneous into SCID mice. Mice were randomized by body weight into treatment groups and treated once on day 6 post cell inoculation with 2.5 mg/kg of one of the conjugates listed above or with PBS only.
In Vivo Model KB CDX model
In Vitro Model Human papillomavirus-related endocervical adenocarcinoma KB cells CVCL_0372
Experiment 2 Reporting the Activity Date of This ADC [5]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 100.00% (Day 17) Positive FOLR1 expression (FOLR1 +++/++)
Method Description
Conjugates of the exemplary anti-FOLR1 antibodies were tested using an established xenograft model of KB cells implanted subcutaneous into SCID mice. Mice were randomized by body weight into treatment groups and treated once on day 6 post cell inoculation with 5 mg/kg of one of the conjugates listed above or with PBS only.
In Vivo Model KB CDX model
In Vitro Model Human papillomavirus-related endocervical adenocarcinoma KB cells CVCL_0372
huMov19-sulfo-SPDB-DM4 (DAR3.8) [Investigative]
 ADC Info 
Discovered Using Cell Line-derived Xenograft Model
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Date of This ADC [5]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 96.08% (Day 17) Positive FOLR1 expression (FOLR1 +++/++)
Method Description
Conjugates of the exemplary anti-FOLR1 antibodies were tested using an established xenograft model of KB cells implanted subcutaneous into SCID mice. Mice were randomized by body weight into treatment groups and treated once on day 6 post cell inoculation with 2.5 mg/kg of one of the conjugates listed above or with PBS only.
In Vivo Model KB CDX model
In Vitro Model Human papillomavirus-related endocervical adenocarcinoma KB cells CVCL_0372
Experiment 2 Reporting the Activity Date of This ADC [5]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 100.00% (Day 17) Positive FOLR1 expression (FOLR1 +++/++)
Method Description
Conjugates of the exemplary anti-FOLR1 antibodies were tested using an established xenograft model of KB cells implanted subcutaneous into SCID mice. Mice were randomized by body weight into treatment groups and treated once on day 6 post cell inoculation with 5 mg/kg of one of the conjugates listed above or with PBS only.
In Vivo Model KB CDX model
In Vitro Model Human papillomavirus-related endocervical adenocarcinoma KB cells CVCL_0372
Experiment 3 Reporting the Activity Date of This ADC [5]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
0.10 nM
Positive FOLR1 expression (FOLR1 +++/++)
Method Description
Conjugate in various concentrations was added to FOLR1-expressing cells in a 96 well plate at 1,000 cells per well in 100 pL in complete RPMI medium.
In Vitro Model Human papillomavirus-related endocervical adenocarcinoma KB cells CVCL_0372
Experiment 4 Reporting the Activity Date of This ADC [5]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
0.30 nM
Positive FOLR1 expression (FOLR1 +++/++)
Method Description
Conjugate in various concentrations was added to FOLR1-expressing cells in a 96 well plate at 1,000 cells per well in 100 pL in complete RPMI medium.
In Vitro Model Ovarian endometrioid adenocarcinoma IGROV-1 cells CVCL_1304
Experiment 5 Reporting the Activity Date of This ADC [5]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
3.00 nM
Moderate FOLR1 expression (FOLR1 ++)
Method Description
Conjugate in various concentrations was added to FOLR1-expressing cells in a 96 well plate at 1,000 cells per well in 100 pL in complete RPMI medium.
In Vitro Model Gestational choriocarcinoma JEG-3 cells CVCL_0363
Farletuzumab-sulfo SPDB-DM4 [Investigative]
 ADC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Date of This ADC [9]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
0.09 nM
High FOLR1 expression(FOLR1+++)
Method Description
Cells were sub-cultured and seeded at 5,000 cells/well in complete growth medium in 96-well tissue culture plates, and incubated at 37°C, 5% CO2 overnight. Test reagents were serially diluted and added to the cell plates (initial concentration of 100 nM). Plates were incubated at 37°C, 5% CO2 for an additional 3 d.
In Vitro Model Ovarian endometrioid adenocarcinoma IGROV-1 cells CVCL_1304
Experiment 2 Reporting the Activity Date of This ADC [9]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
0.49 nM
Moderate FOLR1 expression(FOLR1++)
Method Description
Cells were sub-cultured and seeded at 5,000 cells/well in complete growth medium in 96-well tissue culture plates, and incubated at 37°C, 5% CO2 overnight. Test reagents were serially diluted and added to the cell plates (initial concentration of 100 nM). Plates were incubated at 37°C, 5% CO2 for an additional 3 d.
In Vitro Model Ovarian serous adenocarcinoma OVCAR-3 cells CVCL_0465
Experiment 3 Reporting the Activity Date of This ADC [9]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
0.52 nM
Moderate FOLR1 expression(FOLR1++)
Method Description
Cells were sub-cultured and seeded at 5,000 cells/well in complete growth medium in 96-well tissue culture plates, and incubated at 37°C, 5% CO2 overnight. Test reagents were serially diluted and added to the cell plates (initial concentration of 100 nM). Plates were incubated at 37°C, 5% CO2 for an additional 3 d.
In Vitro Model Lung non-small cell carcinoma NCI-H2110 cells CVCL_1530
Experiment 4 Reporting the Activity Date of This ADC [9]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
0.85 nM
Low FOLR1 expression(FOLR1+)
Method Description
Cells were sub-cultured and seeded at 5,000 cells/well in complete growth medium in 96-well tissue culture plates, and incubated at 37°C, 5% CO2 overnight. Test reagents were serially diluted and added to the cell plates (initial concentration of 100 nM). Plates were incubated at 37°C, 5% CO2 for an additional 3 d.
In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cells CVCL_1603
Experiment 5 Reporting the Activity Date of This ADC [9]
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
4.28 nM
Negative FOLR1 expression(FOLR1-)
Method Description
Cells were sub-cultured and seeded at 5,000 cells/well in complete growth medium in 96-well tissue culture plates, and incubated at 37°C, 5% CO2 overnight. Test reagents were serially diluted and added to the cell plates (initial concentration of 100 nM). Plates were incubated at 37°C, 5% CO2 for an additional 3 d.
In Vitro Model Skin squamous cell carcinoma A431 cells CVCL_0037
HKT-288 [Terminated in phase 1]
 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 [10]
Patients Enrolled
Advanced (metastatic or locally advanced) serous epithelial ovarian, serous fallopian tubal or serous primary peritoneal cancer or advanced clear cell or papillary renal cell carcinoma (RCC), who had received or were intolerant to all therapies known to confer clinical benefit for their disease and Eastern Cooperative Oncology Group (ECOG) performance status 2.

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Administration Dosage
HKT288 was administered intravenously (IV) every 3 weeks until patients experienced unacceptable toxicity or progressive disease (PD). The starting dose of 0.30 mg/kg was determined based on the highest nonseverely toxic dose in monkeys, which was 2 mg/kg IV weekly.
Related Clinical Trial
NCT Number NCT02947152  Clinical Status Phase 1
Clinical Description
A phase 1, multicenter, open-label dose escalation and expansion study of HKT288, administered intravenously in adult patients with advanced solid tumors, including epithelial ovarian cancer and renal cell carcinoma.
Primary Endpoint
The best overall response on the 0.30 mg/kg cohort in patients with measurable disease was RECIST v1.1 stable disease in 3 patients and PD in 2 patients.
Experiment 2 Reporting the Activity Date of This ADC [11]
Patients Enrolled
Patients with advanced solid tumors, including epithelial ovarian cancer and renal cell carcinoma.
Administration Dosage
Cadherin-6-targeting ADC iv at dose of 0.30, 0.75 mg/kg.
Related Clinical Trial
NCT Number NCT02947152  Clinical Status Phase 1
Clinical Description
A phase 1, multicenter, open-label dose escalation and expansion study of HKT288, administered intravenously in adult patients with advanced solid tumors, including epithelial ovarian cancer and renal cell carcinoma.
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 [12]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 90.00% (Day 45) High CDH6 expression (CDH6+++)
Method Description
CDH6-sulfo-DM4 induces efficient tumor cell killing in cell PDX models with CDH6 expression.
In Vivo Model Ovarian cancer CDX model
In Vitro Model Ovarian serous adenocarcinoma OVCAR-3 cells CVCL_0465
Experiment 2 Reporting the Activity Date of This ADC [12]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 100.00% (Day 45) High CDH6 expression (CDH6+++)
Method Description
CDH6-sulfo-DM4 induces efficient tumor cell killing in cell PDX models with CDH6 expression.
In Vivo Model Ovarian cancer CDX model
In Vitro Model Ovarian serous adenocarcinoma OVCAR-3 cells CVCL_0465
References
Ref 1 Phase III, randomized trial of mirvetuximab soravtansine versus chemotherapy in patients with platinum-resistant ovarian cancer: primaryanalysis of FORWARD I. Ann Oncol. 2021 Jun;32(6):757-765.
Ref 2 Tisotumab Vedotin Continued Treatment in Patients With Solid Tumors.
Ref 3 Phase Ib study of mirvetuximab soravtansine, a folate receptor alpha (FR)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 2020 May;157(2):379-385.
Ref 4 In Vitro and In Vivo Activity of IMGN853, an Antibody-Drug Conjugate Targeting Folate Receptor Alpha Linked to DM4, in Biologically Aggressive Endometrial Cancers. Mol Cancer Ther. 2018 May;17(5):1003-1011. doi: 10.1158/1535-7163.MCT-17-0930.
Ref 5 Folate receptor 1 antibodies and immunoconjugates and uses thereof; 2011-09-01.
Ref 6 IMGN853, a Folate Receptor- (FR)-Targeting Antibody-Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FR-Expressing Tumors. Mol Cancer Ther. 2015 Jul;14(7):1605-13.
Ref 7 IMGN779, a Novel CD33-Targeting Antibody-Drug Conjugate with DNA-Alkylating Activity, Exhibits Potent Antitumor Activity in Models of AML. Mol Cancer Ther. 2018 Jun;17(6):1271-1279. doi: 10.1158/1535-7163.MCT-17-1077. Epub 2018 Mar 27.
Ref 8 Anti-cdh6 antibody and anti-cdh6 antibody-drug conjugate.
Ref 9 MORAb-202, an Antibody-Drug Conjugate Utilizing Humanized Anti-human FR Farletuzumab and the Microtubule-targeting Agent Eribulin, has Potent Antitumor Activity. Mol Cancer Ther. 2018 Dec;17(12):2665-2675. doi: 10.1158/1535-7163.MCT-17-1215. Epub 2018 Sep 27.
Ref 10 A Phase 1 Study of a CDH6-Targeting Antibody-Drug Conjugate in Patients with Advanced Solid Tumors with Evaluation of Inflammatory and Neurological Adverse Events. Oncol Res Treat. 2021;44(10):547-556.
Ref 11 A Phase I, Multicenter, Open-label Dose Escalation and Expansion Study of HKT288, Administered Intravenously in Adult Patients With Advanced Solid Tumors, Including Epithelial Ovarian Cancer and Renal Cell Carcinoma
Ref 12 Discovery and Optimization of HKT288, a Cadherin-6-Targeting ADC for the Treatment of Ovarian and Renal Cancers. Cancer Discov. 2017 Sep;7(9):1030-1045.

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