Discovery of ABBV-3373, an Anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody Drug Conjugate

Abstract

Using a convergent synthetic route to enable multiple points of diversity, a series of glucocorticoid receptor modulators (GRM) were profiled for potency, selectivity, and drug-like properties in vitro. Despite covering a large range of diversity, profiling the nonconjugated small molecule was suboptimal and they were conjugated to a mouse antitumor necrosis factor (TNF) antibody using the MP-Ala-Ala linker. Screening of the resulting antibody drug conjugates (ADCs) provided a better assessment of efficacy and physical properties, reinforcing the need to conduct structure–activity relationship studies on the complete ADC. DAR4 ADCs were screened in an acute mouse contact hypersensitivity model measuring biomarkers to ensure a sufficient therapeutic window. In a chronic mouse arthritis model, mouse anti-TNF GRM ADCs were efficacious after a single dose of 10 mg/kg i.p. for over 30 days. Data on the unconjugated payloads and mouse surrogate anti-TNF ADCs identified payload 17 which was conjugated to a human anti-TNF antibody and advanced to the clinic as ABBV-3373.

Optimization of Drug-Linker to Enable Long-term Storage of Antibody–Drug Conjugate for Subcutaneous Dosing

“…In the oncology field this approach has been validated with the success of oncology antibody–drug conjugates (oADCs) to treat cancers . Encouraged by this success, there has been an expansion of ADCs outside of oncology, with ABBV-3373, an α-TNF glucocorticoid receptor modulator immunology antibody–drug conjugate (iADC), demonstrating clinical efficacy in a phase 2a proof-of-concept study and its potential to provide improved outcomes for arthritis compared to adalimumab while having a similar safety profile . To date, all oADCs have been dosed by intravenous (IV) injection after reconstitution of the lyophilized dry powder. , However, subcutaneous (SC) delivery of biotherapeutics has become the preferred dosing method for immunology drugs like the highly successfully α-TNF monoclonal antibodies such as adalimumab with the development of autoinjection delivery systems to facilitate self-administration by the patient .…”

“…1 In the oncology field this approach has been validated with the success of oncology antibody−drug conjugates (oADCs) to treat cancers. 2 Encouraged by this success, there has been an expansion of ADCs outside of oncology, 3 with ABBV-3373, 4 an α-TNF glucocorticoid receptor modulator immunology antibody−drug conjugate (iADC), demonstrating clinical efficacy in a phase 2a proof-of-concept study and its potential to provide improved outcomes for arthritis compared to adalimumab while having a similar safety profile. 5 To date, all oADCs have been dosed by intravenous (IV) injection after reconstitution of the lyophilized dry powder.…”

Discovery of ABBV-154, an anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody-Drug Conjugate (iADC)

“…3 Buoyed by this success, other disease areas are investigating the use of ADCs. 4,5 An immunology ADC ABBV-3373, 6 an anti-TNF glucocorticoid receptor modulator immunology antibody-drug conjugate (iADC), demonstrated clinical efficacy in a phase 2a proof of concept study for its potential to provide improved outcomes for arthritis compared to adalimumab while having a similar safety profile. 7,8 While many of the lessons learned from the approved oADCs provide great insight into nononcology ADC design and development, many will need tailoring to the particular needs of that therapeutic area.…”

“…Oncology antibody-drug conjugates (oADC) have been successfully validated with more than a dozen oADCs approved to treat various cancers . Buoyed by this success, other disease areas are investigating the use of ADCs. , An immunology ADC ABBV-3373, an anti-TNF glucocorticoid receptor modulator immunology antibody-drug conjugate (iADC), demonstrated clinical efficacy in a phase 2a proof of concept study for its potential to provide improved outcomes for arthritis compared to adalimumab while having a similar safety profile. , While many of the lessons learned from the approved oADCs provide great insight into nononcology ADC design and development, many will need tailoring to the particular needs of that therapeutic area. For example, all approved oADCs are dosed by intravenous (IV) injection after reconstitution of the lyophilized ADC by a qualified professional. , However, for many therapeutic areas, subcutaneous delivery of the biotherapeutic has become the preferred dosing method.…”

Self-Immolative Carbamate Linkers for CD19-Budesonide Antibody–Drug Conjugates

“…We have been interested in the discovery and development of ADCs for autoimmune disease. , Glucocorticoids are potent small molecules that are well-established in the clinic for the treatment of conditions such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, polymyalgia rheumatica, lupus, and others. While effective, glucocorticoid use is limited by undesired side effects that are driven by on-target activity in nondiseased tissues.…”