Antibody-drug Conjugate Information

General Information of This Antibody-drug Conjugate (ADC)
ADC ID
DRG0FBKIO
ADC Name
ABBV-3373
Synonyms
ABBV 3373; ABBV3773; anti-TNF-GRM-antibody-drug-conjugate; glucocorticoid receptor modulator (GRM) linked to adalimumab
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Organization
AbbVie, Inc.
Drug Status
Phase 2
Indication
In total 1 Indication(s)
Rheumatoid arthritis [ICD11:FA20]
Phase 2
Drug-to-Antibody Ratio
4
Structure
Antibody Name
Anti-TNF mAb alpha-TNF
  Antibody Info 
Antigen Name
Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A)
  Antigen Info 
Payload Name
GRM cpd 17
  Payload Info 
Therapeutic Target
Glucocorticoid receptor (NR3C1)
  Target Info 
Linker Name
MP-Ala-Ala
  Linker Info 
Conjugate Type
Random conjugation through reduced inter-chain cysteines.
Puchem SID
478109840 , 472419813 , 404719682
ChEBI ID
CHEMBL4297572
General Information of The Activity Data Related to This ADC
Identified from the Human Clinical Data
Click To Hide/Show 2 Activity Data Related to This Level
Standard Type NCT Number Clinical Status Clinical Trial Description
Undisclosed  NCT03823391
Phase 2
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.

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Undisclosed  NCT03823391
Phase 2
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.

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Obtained from the Model Organism Data
Click To Hide/Show 8 Activity Data Related to This Level
Standard Type Value Units Animal Model (No. of PDX)
Paw swelling AUC 
81
%
Collagen-induced arthritis (mCIA) model
Paw swelling AUC 
98
%
Collagen-induced arthritis (mCIA) model
P1NP inhibition 
0
%
Acute contact hypersensitivity (CHS) model
P1NP inhibition 
19
%
Acute contact hypersensitivity (CHS) model
Ear swelling inhibition 
55
%
Fluorescein isothiocyanate (FITC)-induced CHS model
Ear swelling inhibition 
88
%
Fluorescein isothiocyanate (FITC)-induced CHS model
Corticosterone inhibition 
6
%
Acute contact hypersensitivity (CHS) model
Corticosterone inhibition 
15
%
Acute contact hypersensitivity (CHS) model
Revealed Based on the Cell Line Data
Click To Hide/Show 2 Activity Data Related to This Level
Standard Type Value Units Cell Line Disease Model
Half Maximal Effective Concentration (EC50) 
0.08
ug/mL
K-562 cells (TNF expression)
Chronic myelogenous leukemia
Half Maximal Effective Concentration (EC50) 
5.8
ug/mL
K-562 cells
Chronic myelogenous leukemia
Full List of Activity Data of This Antibody-drug Conjugate
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
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  Clinical 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 [2]
Related Clinical Trial
NCT Number NCT03823391  Clinical 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 [3]
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 [3]
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 [3]
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.

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In Vivo Model Acute contact hypersensitivity (CHS) model
Experiment 4 Reporting the Activity Date of This ADC [3]
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.

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In Vivo Model Acute contact hypersensitivity (CHS) model
Experiment 5 Reporting the Activity Date of This ADC [3]
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 [3]
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 [3]
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 [3]
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 [3]
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 [3]
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
References
Ref 1 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 2 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 3 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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