Author: Jia, Ying ; Wang, Zhi ; Mathieu, Suzanne ; Pang, Yinuo ; Wang, Ce ; Phillips, Lucy ; McPherson, Michael J. ; Hernandez, Axel ; Wang, Lu ; Tian, Yu ; Pitney, Victoria ; Brown, Nathan J. ; Kang, Bit Na ; Ruzek, Melanie ; Oh, Jason Z. ; Schmidt, Diana ; Shi, Dan ; Stoffel, Robert ; Zheng, Pingping ; Goess, Christian ; Xu, Jianwen ; Zhu, Haizhong ; McCarthy, Kimberley ; Parmentier, Julie ; Hayes, Martin E. ; Hobson, Adrian D. ; Qiu, Wei ; D’Cunha, Ronilda R. ; Bi, Yingtao ; Waegell, Wendy ; Longenecker, Kenton L. ; Bryant, Shaughn ; Marvin, Christopher C. ; Graff, Candace ; Liu, Wei

Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti–tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity. Consequently, we have generated an anti–TNF-GRM ADC with the aim of inhibiting pro-inflammatory cytokine production from stimulated human immune cells. In an acute mouse model of contact hypersensitivity, a murine surrogate anti–TNF-GRM ADC inhibited inflammatory responses with minimal effect on systemic GC biomarkers. In addition, in a mouse model of collagen-induced arthritis, single-dose administration of the ADC, delivered at disease onset, was able to completely inhibit arthritis for greater than 30 days, whereas an anti-TNF monoclonal antibody only partially inhibited disease. ADC treatment at the peak of disease was also able to attenuate the arthritic phenotype. Clinical data for a human anti–TNF-GRM ADC (ABBV-3373) from a single ascending dose phase 1 study in healthy volunteers demonstrated antibody-like pharmacokinetic profiles and a lack of impact on serum cortisol concentrations at predicted therapeutic doses. These data suggest that an anti–TNF-GRM ADC may provide improved efficacy beyond anti-TNF alone in immune mediated diseases while minimizing systemic side effects associated with standard GC treatment.

08 Dec 2022·Journal of Medicinal ChemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: Hobson, Adrian D. ; Randolph, John T. ; Yu, Yajie ; Santora, Ling C. ; Sun, Liang ; Bryant, Shaughn H. ; Mathieu, Suzanne L. ; McPherson, Michael J. ; Yang, Jindong ; Shrestha, Anurupa ; Zhou, Jian ; Fettis, Margaret M. ; Qu, Pei ; Li, Xiaofeng ; Wang, Zhi ; Wang, Zhongyuan ; Fitzgibbons, Julia ; Patel, Meena V. ; Hernandez, Axel ; Tian, Yu ; Bischoff, Agnieszka K. ; Henry, Rodger F. ; Li, Tongmei ; Li, Xiang ; Marvin, Christopher C. ; Wang, Lu ; Hayes, Martin E. ; Aguirre, Ana L. ; Yang, Shi ; Zhang, Qiang ; Graff, Candace ; Schmidt, Diana L. ; Goess, Christian

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.

15 Jun 2022·American Journal of Respiratory and Critical Care Medicine

CD4⁺T-Cell Dysfunction in Severe COVID-19 Disease Is Tumor Necrosis Factor-α/Tumor Necrosis Factor Receptor 1–Dependent

Article

Author: Snyder, Mark E. ; Iasella, Carlo J. ; Bhatt, Payal ; Popescu, Iulia ; Brown, Mark J. ; McDyer, John F. ; Koshy, Ritchie ; Chen, Kong ; Lendermon, Elizabeth A. ; Sembrat, John C. ; An, Xiaojing ; Wells, Alan H. ; Alder, Jonathan K. ; Konstantinidis, Ioannis ; Das, Antu ; Hannan, Stefanie J. ; Kass, Daniel J. ; Johnson, Bruce ; Kiss, Joseph E. ; Morris, Alison ; Chen, Bill B. ; McVerry, Bryan J. ; Burke, Robin ; Kitsios, Georgios ; Kilaru, Silpa ; Saul, Melissa ; Chen, Xiaoping ; Pilewski, Joseph M. ; Sanchez, Pablo G. ; Linstrum, Kelsey ; Lyons, Emily J. ; Deng, Evan ; Lieber, Sophia C. ; McMahon, Deborah K. ; Triulzi, Darrell J.

Rationale: Lymphopenia is common in severe coronavirus disease (COVID-19), yet the immune mechanisms are poorly understood. As inflammatory cytokines are increased in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we hypothesized a role in contributing to reduced T-cell numbers. Objectives: We sought to characterize the functional SARS-CoV-2 T-cell responses in patients with severe versus recovered, mild COVID-19 to determine whether differences were detectable. Methods: Using flow cytometry and single-cell RNA sequence analyses, we assessed SARS-CoV-2-specific responses in our cohort. Measurements and Main Results: In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4⁺ lymphopenia predominated, with lower CD4⁺/CD8⁺ ratios in severe COVID-19 compared with patients with mild disease (P < 0.0001). In severe disease, immunodominant CD4⁺ T-cell responses to Spike-1 (S1) produced increased in vitro TNF-α (tumor necrosis factor-α) but demonstrated impaired S1-specific proliferation and increased susceptibility to activation-induced cell death after antigen exposure. CD4⁺TNF-α⁺ T-cell responses inversely correlated with absolute CD4⁺ counts from patients with severe COVID-19 (n = 76; R = -0.797; P < 0.0001). In vitro TNF-α blockade, including infliximab or anti-TNF receptor 1 antibodies, strikingly rescued S1-specific CD4⁺ T-cell proliferation and abrogated S1-specific activation-induced cell death in peripheral blood mononuclear cells from patients with severe COVID-19 (P < 0.001). Single-cell RNA sequencing demonstrated marked downregulation of type-1 cytokines and NFκB signaling in S1-stimulated CD4⁺ cells with infliximab treatment. We also evaluated BAL and lung explant CD4⁺ T cells recovered from patients with severe COVID-19 and observed that lung T cells produced higher TNF-α compared with peripheral blood mononuclear cells. Conclusions: Together, our findings show CD4⁺ dysfunction in severe COVID-19 is TNF-α/TNF receptor 1-dependent through immune mechanisms that may contribute to lymphopenia. TNF-α blockade may be beneficial in severe COVID-19.

100 Deals associated with Atrosab

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Indication	Highest Phase	Country/Location	Organization	Date
Nonalcoholic Steatohepatitis	Preclinical	CH	Baliopharm AG	28 Jun 2023
Ankylosing Spondylitis	Discovery	CH	Baliopharm AG	28 Jun 2023
Arthritis, Psoriatic	Discovery	CH	Baliopharm AG	28 Jun 2023
Plaque psoriasis	Discovery	CH	Baliopharm AG	28 Jun 2023
Rheumatoid Arthritis	Discovery	CH	Baliopharm AG	28 Jun 2023

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