Payload Information | ADCdb

General Information of This Payload

Payload ID	PAY0ELHVP
Name	GRM cpd 17
Synonyms	GRM cpd 17 Click to Show/Hide
Target(s)	Glucocorticoid receptor (NR3C1)					Target Info
Structure
Structure	3D MOL			2D MOL
Formula	C34H37NO6
Isosmiles	CC12C=CC(=O)C=C1CCC1C3CC4OC(c5ccc(Cc6cccc(N)c6)cc5)OC4(C(=O)CO)C3CC(O)C12
InChI	InChI=1S/C34H37NO6/c1-33-12-11-24(37)15-22(33)9-10-25-26-16-30-34(29(39)18-36,27(26)17-28(38)31(25)33)41-32(40-30)21-7-5-19(6-8-21)13-20-3-2-4-23(35)14-20/h2-8,11-12,14-15,25-28,30-32,36,38H,9-10,13,16-18,35H2,1H3
InChIKey	KGDLJHKCSJFVMZ-UHFFFAOYSA-N
Pharmaceutical Properties	Molecule Weight		555.671	Polar area		119.08
	Complexity		41	xlogp Value		4.0723
	Heavy Count		41	Rot Bonds		5
	Hbond acc		7	Hbond Donor		3

The activity data of This Payload

Standard Type	Value	Units	Cell line	Disease Model	Cell line ID	Reference
Glucocorticoid response element reporter EC50	0.0026±0.0032	uM	Undisclosed	Undisclosed	Undisclosed	[1]
Glucocorticoid Receptor binding IC50	0.003±0.001	uM	Undisclosed	Undisclosed	Undisclosed	[1]

Each Antibody-drug Conjugate Related to This Payload

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

ABBV-3373 [Phase 2]

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					[2]
Patients Enrolled	RA (based on the 1987 American College of Rheumatology [ACR] classification criteria or 2010 ACR/EULAR criteria [16, 17]), with disease duration >3 months, and active disease defined as a Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) (18) of 3.2 and 4 of 28 swollen joints and 4 of 28 tender joints.
Administration Dosage	Intravenously (IV) ABBV-3373 100 mg every other week for 12 weeks, followed by placebo for 12 weeks, or subcutaneous adalimumab 80 mg every other week for 24 weeks.
*Related Clinical Trial*
NCT Number	NCT03823391	Phase Status	Phase 2
Clinical Description	A randomized, double-blind, double-dummy, active controlled study to evaluate the safety, tolerability, pharmacokinetics, and efficacy of ABBV-3373 in subjects with moderate to severe rheumatoid arthritis.
Primary Endpoint	48 patients were randomized to ABBV-3373 (n=31) or adalimumab (n=17). At week 12, ABBV-3373 reduced DAS28 (CRP) versus historical adalimumab (2.65 versus 2.13; P=0.022) and combined in-trial/historical adalimumab (2.65 versus 2.29; probability=89.9%), with numerically greater improvement than in-trial adalimumab (2.51).
Other Endpoint	For secondary endpoints, greater efficacy was observed with ABBV-3373 versus historical adalimumab; ABBV-3373 was predicted with 79.30-99.50% probability to be better than adalimumab based on combined in-trial/historical adalimumab data.
Experiment 2 Reporting the Activity Date of This ADC					[3]
*Related Clinical Trial*
NCT Number	NCT03823391	Phase Status	Phase 2
Clinical Description	A randomized, double-blind, double-dummy, active controlled study to evaluate the safety, tolerability, pharmacokinetics, and efficacy of ABBV-3373 in subjects with moderate to severe rheumatoid arthritis.

Obtained from the Model Organism Data

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

Experiment 1 Reporting the Activity Date of This ADC					[4]
Efficacy Data	Paw swelling AUC	81.00%	Positive TNF expression (TNF+++/++)
Method Description	To evaluate the impact of the anti-mTNF GRM ADCs on inflammation in a chronic inflammatory setting,we progressed several ADCs into a mouse collagen-induced arthritis (mCIA) model. A single 3 mg/kg dose of the ADC was given at the first clinical signs of disease,a time point of intervention where anti-TNF treatment has a moderate impact.
In Vivo Model	Collagen-induced arthritis (mCIA) model
Experiment 2 Reporting the Activity Date of This ADC					[4]
Efficacy Data	Paw swelling AUC	98.00%	Positive TNF expression (TNF+++/++)
Method Description	To evaluate the impact of the anti-mTNF GRM ADCs on inflammation in a chronic inflammatory setting,we progressed several ADCs into a mouse collagen-induced arthritis (mCIA) model. A single 10 mg/kg dose of the ADC was given at the first clinical signs of disease,a time point of intervention where anti-TNF treatment has a moderate impact.
In Vivo Model	Collagen-induced arthritis (mCIA) model
Experiment 3 Reporting the Activity Date of This ADC					[4]
Efficacy Data	P1NP inhibition	0.00%	Positive TNF expression (TNF+++/++)
Method Description	In an acute in vivo model of contact hypersensitivity (CHS) mice were sensitized with fluorescein isothiocyanate (FITC) on the abdomen and challenged 6 days later with FITC on the ear,which resulted in an increase in ear swelling that was measured 24 h postchallenge. Anti-mTNF GRM ADCs were dosed at either 3 mg/kg once prior to FITC sensitization. Mice were challenged with adrenocorticotropic hormone (ACTH) 72 h following ADC dosing and plasma was collected 30 min later to assess P1NP level. Click to Show/Hide
In Vivo Model	Acute contact hypersensitivity (CHS) model
Experiment 4 Reporting the Activity Date of This ADC					[4]
Efficacy Data	P1NP inhibition	19.00%	Positive TNF expression (TNF+++/++)
Method Description	In an acute in vivo model of contact hypersensitivity (CHS) mice were sensitized with fluorescein isothiocyanate (FITC) on the abdomen and challenged 6 days later with FITC on the ear,which resulted in an increase in ear swelling that was measured 24 h postchallenge. Anti-mTNF GRM ADCs were dosed at either 10 mg/kg once prior to FITC sensitization. Mice were challenged with adrenocorticotropic hormone (ACTH) 72 h following ADC dosing and plasma was collected 30 min later to assess P1NP level. Click to Show/Hide
In Vivo Model	Acute contact hypersensitivity (CHS) model
Experiment 5 Reporting the Activity Date of This ADC					[4]
Efficacy Data	Ear swelling inhibition	55.00%	Positive TNF expression (TNF+++/++)
Method Description	In an acute in vivo model of contact hypersensitivity (CHS) mice were sensitized with fluorescein isothiocyanate (FITC) on the abdomen and challenged 6 days later with FITC on the ear,which resulted in an increase in ear swelling that was measured 24 h postchallenge. Anti-mTNF GRM ADCs were dosed at either 3 mg/kg once prior to FITC sensitization.
In Vivo Model	Fluorescein isothiocyanate (FITC)-induced CHS model
Experiment 6 Reporting the Activity Date of This ADC					[4]
Efficacy Data	Ear swelling inhibition	88.00%	Positive TNF expression (TNF+++/++)
Method Description	In an acute in vivo model of contact hypersensitivity (CHS) mice were sensitized with fluorescein isothiocyanate (FITC) on the abdomen and challenged 6 days later with FITC on the ear,which resulted in an increase in ear swelling that was measured 24 h postchallenge. Anti-mTNF GRM ADCs were dosed at either 10 mg/kg once prior to FITC sensitization.
In Vivo Model	Fluorescein isothiocyanate (FITC)-induced CHS model
Experiment 7 Reporting the Activity Date of This ADC					[4]
Efficacy Data	Corticosterone inhibition	6.00%	Positive TNF expression (TNF+++/++)
Method Description	In an acute in vivo model of contact hypersensitivity (CHS) mice were sensitized with fluorescein isothiocyanate (FITC) on the abdomen and challenged 6 days later with FITC on the ear,which resulted in an increase in ear swelling that was measured 24 h postchallenge. Anti-mTNF GRM ADCs were dosed at either 3 mg/kg once prior to FITC sensitization. Mice were challenged with adrenocorticotropic hormone (ACTH) 72 h following ADC dosing and plasma was collected 30 min later to assess corticosterone level. Click to Show/Hide
In Vivo Model	Acute contact hypersensitivity (CHS) model
Experiment 8 Reporting the Activity Date of This ADC					[4]
Efficacy Data	Corticosterone inhibition	15.00%	Positive TNF expression (TNF+++/++)
Method Description	In an acute in vivo model of contact hypersensitivity (CHS) mice were sensitized with fluorescein isothiocyanate (FITC) on the abdomen and challenged 6 days later with FITC on the ear,which resulted in an increase in ear swelling that was measured 24 h postchallenge. Anti-mTNF GRM ADCs were dosed at either 10 mg/kg once prior to FITC sensitization. Mice were challenged with adrenocorticotropic hormone (ACTH) 72 h following ADC dosing and plasma was collected 30 min later to assess corticosterone level. Click to Show/Hide
In Vivo Model	Acute contact hypersensitivity (CHS) model

Revealed Based on the Cell Line Data

Click To Hide/Show 2 Activity Data Related to This Level

Experiment 1 Reporting the Activity Date of This ADC					[4]
Efficacy Data	Half Maximal Effective Concentration (EC50)	0.08 ug/mL	Positive TNF expression (TNF+++/++)
Method Description	All the DAR purified ADCs were screened in both the TNF-expressing and wild-type K562 GRE reporter cell assay to confirm that their activity was consistent with ADCs having heterogeneous average DAR.
In Vitro Model	Chronic myelogenous leukemia	K-562 cells (TNF expression)		CVCL_0004
Experiment 2 Reporting the Activity Date of This ADC					[4]
Efficacy Data	Half Maximal Effective Concentration (EC50)	5.80 ug/mL	Negative TNF expression (TNF-)
Method Description	All the DAR purified ADCs were screened in both the TNF-expressing and wild-type K562 GRE reporter cell assay to confirm that their activity was consistent with ADCs having heterogeneous average DAR.
In Vitro Model	Chronic myelogenous leukemia	K-562 cells		CVCL_0004

Anti-TNF ADC 121 [Investigative]

ADC Info

Obtained from the Model Organism Data

Click To Hide/Show 2 Activity Data Related to This Level

Experiment 1 Reporting the Activity Date of This ADC					[4]
Efficacy Data	Paw swelling AUC	74.00%	Positive TNF expression (TNF+++/++)
Method Description	To evaluate the impact of the anti-mTNF GRM ADCs on inflammation in a chronic inflammatory setting,we progressed several ADCs into a mouse collagen-induced arthritis (mCIA) model. A single 3 mg/kg dose of the ADC was given at the first clinical signs of disease,a time point of intervention where anti-TNF treatment has a moderate impact.
In Vivo Model	Collagen-induced arthritis (mCIA) model
Experiment 2 Reporting the Activity Date of This ADC					[4]
Efficacy Data	Paw swelling AUC	96.00%	Positive TNF expression (TNF+++/++)
Method Description	To evaluate the impact of the anti-mTNF GRM ADCs on inflammation in a chronic inflammatory setting,we progressed several ADCs into a mouse collagen-induced arthritis (mCIA) model. A single 10 mg/kg dose of the ADC was given at the first clinical signs of disease,a time point of intervention where anti-TNF treatment has a moderate impact.
In Vivo Model	Collagen-induced arthritis (mCIA) model

Revealed Based on the Cell Line Data

Click To Hide/Show 2 Activity Data Related to This Level

Experiment 1 Reporting the Activity Date of This ADC					[4]
Efficacy Data	Half Maximal Effective Concentration (EC50)	0.09 ug/mL	Positive TNF expression (TNF+++/++)
Method Description	All the DAR purified ADCs were screened in both the TNF-expressing and wild-type K562 GRE reporter cell assay to confirm that their activity was consistent with ADCs having heterogeneous average DAR.
In Vitro Model	Chronic myelogenous leukemia	K-562 cells (TNF expression)		CVCL_0004
Experiment 2 Reporting the Activity Date of This ADC					[4]
Efficacy Data	Half Maximal Effective Concentration (EC50)	43.70 ug/mL	Negative TNF expression (TNF-)
Method Description	All the DAR purified ADCs were screened in both the TNF-expressing and wild-type K562 GRE reporter cell assay to confirm that their activity was consistent with ADCs having heterogeneous average DAR.
In Vitro Model	Chronic myelogenous leukemia	K-562 cells		CVCL_0004

Anti-TNF ADC 106 [Investigative]

ADC Info

Revealed Based on the Cell Line Data

Click To Hide/Show 2 Activity Data Related to This Level

Experiment 1 Reporting the Activity Date of This ADC					[4]
Efficacy Data	Half Maximal Effective Concentration (EC50)	0.45 ug/mL	Positive TNF expression (TNF+++/++)
Method Description	All the DAR purified ADCs were screened in both the TNF-expressing and wild-type K562 GRE reporter cell assay to confirm that their activity was consistent with ADCs having heterogeneous average DAR.
In Vitro Model	Chronic myelogenous leukemia	K-562 cells (TNF expression)		CVCL_0004
Experiment 2 Reporting the Activity Date of This ADC					[4]
Efficacy Data	Half Maximal Effective Concentration (EC50)	3.40 ug/mL	Negative TNF expression (TNF-)
Method Description	All the DAR purified ADCs were screened in both the TNF-expressing and wild-type K562 GRE reporter cell assay to confirm that their activity was consistent with ADCs having heterogeneous average DAR.
In Vitro Model	Chronic myelogenous leukemia	K-562 cells		CVCL_0004

References

Ref 1	Discovery of ABBV-3373, an Anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody Drug Conjugate. J Med Chem. 2022 Dec 8;65(23):15893-15934.
Ref 2	Efficacy and Safety of ABBV-3373, a Novel Anti-Tumor Necrosis Factor Glucocorticoid Receptor Modulator Antibody-Drug Conjugate, in Adults with Moderate-to-Severe Rheumatoid Arthritis Despite Methotrexate Therapy: A Randomized, Double-Blind, Active-Controlled Proof-of-Concept Phase IIa Trial. Arthritis Rheumatol. 2023 Jun;75(6):879-889.
Ref 3	A Randomized, Double-Blind, Double-Dummy, Active Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of ABBV-3373 in Subjects With Moderate to Severe Rheumatoid Arthritis, NCT03823391
Ref 4	Discovery of ABBV-3373, an Anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody Drug Conjugate. J Med Chem. 2022 Dec 8;65(23):15893-15934.

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