Linker Information

Linker Information

Prof. Feng ZHU (zhufeng@zju.edu.cn)

Prof. Xiaowu DONG (dongxw@zju.edu.cn)

Prof. Luo FANG (fangluo@zjcc.org.cn)

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General Information of This Linker

Each Antibody-drug Conjugate Related to This Linker

Full Information of The Activity Data of The ADC(s) Related to This Linker

Upifitamab rilsodotin [Phase 3]

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)	34.00% (all) 35.00% (SLC34A2 high) 29.00% (SLC34A2 low)	High SLC34A2 expression (SLC34A2+++; 66,000 SLC34A2 antigens/cell)
Patients Enrolled	Ovarian cancer patients with 1-3 prior lines in platinum-resistant; 4 prior lines patients regardless of platinum status.
Administration Dosage	36 or 43 mg/m 2 IV once every 4 weeks.
*Related Clinical Trial*
NCT Number	NCT03319628	Clinical Status	Phase 1/2
Clinical Description	Open-label, dose escalation to reach mtd. the mtd will be confirmed in parallel cohorts: patients with platinum-resistant ovarian cancer; patients with non-squamous nsclc, adenocarcinoma subtype.
Experiment 2 Reporting the Activity Date of This ADC				[2]
*Related Clinical Trial*
NCT Number	NCT05329545	Clinical Status	Phase 3
Clinical Description	A phase 3, randomized, double-blind, placebo-controlled, multicenter study of upifitamab rilsodotin (XMT-1536) as post-platinum maintenance therapy for participants with recurrent, platinum-sensitive, ovarian cancer (up-next).
Experiment 3 Reporting the Activity Date of This ADC				[3]
Patients Enrolled	Patients with a histological diagnosis of metastatic or recurrent high-grade serous ovarian cancer, including fallopian tube, or primary peritoneal cancer and have received 1-3 prior lines of therapy.
*Related Clinical Trial*
NCT Number	NCT04907968	Clinical Status	Phase 1
Clinical Description	Upifitamab rilsodotin (XMT-1536) an open-label, multicenter, dose escalation and expansion study of upifitamab rilsodotin in combination with carboplatin in participants with high grade serous ovarian cancer (UP GRADE-A).

Discovered Using Patient-derived Xenograft Model

Click To Hide/Show 6 Activity Data Related to This Level

Experiment 1 Reporting the Activity Date of This ADC				[4]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 58.60% (Day 35)	Moderate SLC34A2 expression (SLC34A2++)
Method Description	Animals were randomized into treatment groups (n = 10) when the tumor target volume reached 100-150 mm³. Test articles were administered intravenously via tail vein injection. Mice received a single dose of either saline vehicle; XMT-1535 at 3 mg/kg; XMT-1536 (DAR 12.4) at 3 mg/kg; IgG1-Dolaflexin (DAR 18.1) at 3 mg/kg,or lifastuzumab vedotin (DAR 4.1) at 3 mg/kg. Tumors were measured twice per week. XMT-1536 and lifastuzumab vedotin were administered at a single dose of 3 mg/kg qwk x 3. Click to Show/Hide
In Vivo Model	Lung cancer PDX model (PDX: CTG-0178)
Experiment 2 Reporting the Activity Date of This ADC				[4]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 60.60% (Day 28)	Moderate SLC34A2 expression (SLC34A2++)
Method Description	Animals were randomized into treatment groups (n = 10) when the tumor target volume reached 100-150 mm³. Test articles were administered intravenously via tail vein injection. Mice received a single dose of either saline vehicle; XMT-1535 at 3 mg/kg; XMT-1536 (DAR 12.4) at 3 mg/kg; IgG1-Dolaflexin (DAR 18.1) at 3 mg/kg,or lifastuzumab vedotin (DAR 4.1) at 3 mg/kg. Tumors were measured twice per week. XMT-1536 and lifastuzumab vedotin were administered at a single dose of 3 mg/kg qwk x 3. Click to Show/Hide
In Vivo Model	Lung cancer PDX model (PDX: CTG-0178)
Experiment 3 Reporting the Activity Date of This ADC				[4]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 87.40% (Day 17)	Moderate SLC34A2 expression (SLC34A2++)
Method Description	Animals were randomized into treatment groups (n = 10) when the tumor target volume reached 100-150 mm³. Test articles were administered intravenously via tail vein injection. Mice received a single dose of either saline vehicle; XMT-1535 at 3 mg/kg; XMT-1536 (DAR 12.4) at 3 mg/kg; IgG1-Dolaflexin (DAR 18.1) at 3 mg/kg,or lifastuzumab vedotin (DAR 4.1) at 3 mg/kg. Tumors were measured twice per week. XMT-1536 and lifastuzumab vedotin were administered at a single dose of 3 mg/kg qwk x 3. Click to Show/Hide
In Vivo Model	Non-small cell lung cancer PDX model (PDX: CTG-0860)
Experiment 4 Reporting the Activity Date of This ADC				[4]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 94.10% (Day 28)	High SLC34A2 expression (SLC34A2+++)
Method Description	Animals were randomized into treatment groups (n = 10) when the tumor target volume reached 100-150 mm³. Test articles were administered intravenously via tail vein injection. Mice received a single dose of either saline vehicle; XMT-1535 at 3 mg/kg; XMT-1536 (DAR 12.4) at 3 mg/kg; IgG1-Dolaflexin (DAR 18.1) at 3 mg/kg,or lifastuzumab vedotin (DAR 4.1) at 3 mg/kg. Tumors were measured twice per week. XMT-1536 and lifastuzumab vedotin were administered at a single dose of 3 mg/kg qwk x 3. Click to Show/Hide
In Vivo Model	Lung cancer PDX model (PDX: CTG-0852)
Experiment 5 Reporting the Activity Date of This ADC				[4]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 95.40% (Day 35)	High SLC34A2 expression (SLC34A2+++)
Method Description	Animals were randomized into treatment groups (n = 10) when the tumor target volume reached 100-150 mm³. Test articles were administered intravenously via tail vein injection. Mice received a single dose of either saline vehicle; XMT-1535 at 3 mg/kg; XMT-1536 (DAR 12.4) at 3 mg/kg; IgG1-Dolaflexin (DAR 18.1) at 3 mg/kg,or lifastuzumab vedotin (DAR 4.1) at 3 mg/kg. Tumors were measured twice per week. XMT-1536 and lifastuzumab vedotin were administered at a single dose of 3 mg/kg qwk x 3. Click to Show/Hide
In Vivo Model	Lung cancer PDX model (PDX: CTG-0852)
Experiment 6 Reporting the Activity Date of This ADC				[4]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 96.70% (Day 62)	High SLC34A2 expression (SLC34A2+++)
Method Description	Animals were randomized into treatment groups (n = 10) when the tumor target volume reached 100-150 mm³. Test articles were administered intravenously via tail vein injection. Mice received a single dose of either saline vehicle; XMT-1535 at 3 mg/kg; XMT-1536 (DAR 12.4) at 3 mg/kg; IgG1-Dolaflexin (DAR 18.1) at 3 mg/kg,or lifastuzumab vedotin (DAR 4.1) at 3 mg/kg. Tumors were measured twice per week. XMT-1536 and lifastuzumab vedotin were administered at a single dose of 3 mg/kg qwk x 3. Click to Show/Hide
In Vivo Model	Lung cancer PDX model (PDX: CTG-0852)

Discovered Using Cell Line-derived Xenograft Model

Click To Hide/Show 1 Activity Data Related to This Level

Experiment 1 Reporting the Activity Date of This ADC					[4]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 94.00% (Day 28)	High SLC34A2 expression (SLC34A2+++)
Method Description	Animals were randomized into treatment groups (n = 10) when the tumor target volume reached 100-150 mm³. Test articles were administered intravenously via tail vein injection. Mice received a single dose of either saline vehicle; XMT-1535 at 3 mg/kg; XMT-1536 (DAR 12.4) at 3 mg/kg; IgG1-Dolaflexin (DAR 18.1) at 3 mg/kg,or lifastuzumab vedotin (DAR 4.1) at 3 mg/kg. Tumors were measured twice per week. XMT-1536 and lifastuzumab vedotin were administered at a single dose of 3 mg/kg. Click to Show/Hide
In Vivo Model	Ovarian adenocarcinoma 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				[4]
Efficacy Data	Half Maximal Effective Concentration (EC50)	0.52 nM
Method Description	OVCAR3 cells were grown in RPMI1640 media supplemented with 20% FBS and 1% penicillin/streptomycin,seeded at a density of 5, 000 cells per well in 100 L of growth media in a 96-well,white flat-bottom plate. Following overnight incubation,the media was replaced with 100 L of fresh media containing the test compounds at a 3-fold titration up to 33 nmol/L. The treated cells were incubated for 96 hours at 37°C in the presence of 5% CO₂. In the OVCAR3 cell line,XMT-1536 was cytotoxic in a 96-hour cellular cytotoxicity assay. Click to Show/Hide
In Vitro Model	Ovarian serous adenocarcinoma	OVCAR-3 cells	CVCL_0465

CLL1-6 ADC [Investigative]

ADC Info

Discovered Using Cell Line-derived Xenograft Model

Click To Hide/Show 3 Activity Data Related to This Level

Experiment 1 Reporting the Activity Date of This ADC					[5]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 3.10% (Day 11)	High CCL1 expression (CCL1 +++)
Method Description	Single intravenous (IV) administration of the CLL1-5 ADC to mice bearing HL-60 AML xenografts, each conjugate (in 5 mg/kg) that were administered once IV at the day 0 time point.
In Vivo Model	HL-60 CDX model
In Vitro Model	Adult acute myeloid leukemia	HL-60 cells		CVCL_0002
Experiment 2 Reporting the Activity Date of This ADC					[5]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 17.24% (Day 11)	High CCL1 expression (CCL1 +++)
Method Description	Single intravenous (IV) administration of the CLL1-5 ADC to mice bearing HL-60 AML xenografts, each conjugate (in 10 mg/kg) that were administered once IV at the day 0 time point.
In Vivo Model	HL-60 CDX model
In Vitro Model	Adult acute myeloid leukemia	HL-60 cells		CVCL_0002
Experiment 3 Reporting the Activity Date of This ADC					[5]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 34.80% (Day 6)	High CCL1 expression (CCL1 +++)
Method Description	Single intravenous (IV) administration of the CLL1-5 ADC to mice bearing EOL-1 AML xenografts, each conjugate (in 10 mg/kg) that were administered once IV at the day 0 time point.
In Vivo Model	EOL-1 CDX model
In Vitro Model	Chronic eosinophilic leukemia	EoL-1 cells		CVCL_0258

CLL1-5 ADC [Investigative]

ADC Info

Discovered Using Cell Line-derived Xenograft Model

Click To Hide/Show 8 Activity Data Related to This Level

Experiment 1 Reporting the Activity Date of This ADC					[5]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 27.70% (Day 6)	High CCL1 expression (CCL1 +++)
Method Description	Single intravenous (IV) administration of the CLL1-5 ADC to mice bearing EOL-1 AML xenografts, each conjugate (in 0.5 mg/kg) that were administered once IV at the day 0 time point.
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					[5]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 48.81% (Day 10)	High CCL1 expression (CCL1 +++)
Method Description	Single intravenous (IV) administration of the CLL1-5 ADC to mice bearing HL-60 AML xenografts, each conjugate (in 0.5 mg/kg) that were administered once IV at the day 0 time point.
In Vivo Model	HL-60 CDX model
In Vitro Model	Adult acute myeloid leukemia	HL-60 cells		CVCL_0002
Experiment 3 Reporting the Activity Date of This ADC					[5]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 61.20% (Day 6)	High CCL1 expression (CCL1 +++)
Method Description	Single intravenous (IV) administration of the CLL1-5 ADC to mice bearing EOL-1 AML xenografts, each conjugate (in 1.5 mg/kg) that were administered once IV at the day 0 time point.
In Vivo Model	EOL-1 CDX model
In Vitro Model	Chronic eosinophilic leukemia	EoL-1 cells		CVCL_0258
Experiment 4 Reporting the Activity Date of This ADC					[5]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 71.08% (Day 10)	High CCL1 expression (CCL1 +++)
Method Description	Single intravenous (IV) administration of the CLL1-5 ADC to mice bearing HL-60 AML xenografts, each conjugate (in 1.5 mg/kg) that were administered once IV at the day 0 time point.
In Vivo Model	HL-60 CDX model
In Vitro Model	Adult acute myeloid leukemia	HL-60 cells		CVCL_0002
Experiment 5 Reporting the Activity Date of This ADC					[5]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 79.20% (Day 6)	High CCL1 expression (CCL1 +++)
Method Description	Single intravenous (IV) administration of the CLL1-5 ADC to mice bearing EOL-1 AML xenografts, each conjugate (in 5 mg/kg) that were administered once IV at the day 0 time point.
In Vivo Model	EOL-1 CDX model
In Vitro Model	Chronic eosinophilic leukemia	EoL-1 cells		CVCL_0258
Experiment 6 Reporting the Activity Date of This ADC					[5]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 89.20% (Day 6)	High CCL1 expression (CCL1 +++)
Method Description	Single intravenous (IV) administration of the CLL1-5 ADC to mice bearing EOL-1 AML xenografts, each conjugate (in 10 mg/kg) that were administered once IV at the day 0 time point.
In Vivo Model	EOL-1 CDX model
In Vitro Model	Chronic eosinophilic leukemia	EoL-1 cells		CVCL_0258
Experiment 7 Reporting the Activity Date of This ADC					[5]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 93.89% (Day 10)	High CCL1 expression (CCL1 +++)
Method Description	Single intravenous (IV) administration of the CLL1-5 ADC to mice bearing HL-60 AML xenografts, each conjugate (in 5 mg/kg) that were administered once IV at the day 0 time point.
In Vivo Model	HL-60 CDX model
In Vitro Model	Adult acute myeloid leukemia	HL-60 cells		CVCL_0002
Experiment 8 Reporting the Activity Date of This ADC					[5]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 100.00% (Day 10)	High CCL1 expression (CCL1 +++)
Method Description	Single intravenous (IV) administration of the CLL1-5 ADC to mice bearing HL-60 AML xenografts, each conjugate (in 10 mg/kg) that were administered once IV at the day 0 time point.
In Vivo Model	HL-60 CDX model
In Vitro Model	Adult acute myeloid leukemia	HL-60 cells		CVCL_0002

References

Ref 1	Safety and efficacy of XMT-1536 in ovarian cancer: A subgroup analysis from the phase I expansion study of XMT-1536, a NaPi2b antibody-drug conjugate. Ann. Oncol. 2020 Sept; 31(4):Supplement S627-S628.
Ref 2	A Phase 3, Randomized, Double-blind, Placebo-controlled, Multicenter Study of Upifitamab Rilsodotin (XMT-1536) as Post-Platinum Maintenance Therapy for Participants With Recurrent, Platinum-Sensitive, Ovarian Cancer (UP-NEXT), NCT05329545
Ref 3	Upifitamab Rilsodotin (Xmt-1536) An Open-Label, Multicenter, Dose Escalation And Expansion Study Of Upifitamab Rilsodotin In Combination With Carboplatin In Participants With High Grade Serous Ovarian Cancer (Upgrade-A), NCT04907968
Ref 4	The Dolaflexin-based Antibody-Drug Conjugate XMT-1536 Targets the Solid Tumor Lineage Antigen SLC34A2/NaPi2b. Mol Cancer Ther. 2021 May;20(5):896-905.
Ref 5	Antibody Conjugation of a Chimeric BET Degrader Enables in?vivo Activity. ChemMedChem. 2020 Jan 7;15(1):17-25. doi: 10.1002/cmdc.201900497. Epub 2019 Nov 14.

Linker Name

Dolaflexin polymer

Linker Type

Polymer linker

Antibody-Linker Relation