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A Rationally Designed Novel Bifunctional Human TNF-α- and Janus Kinase-Targeted soloMER Drug Conjugate (SDC) with a
Euan Murray1, Stella Priyanka1, Julia Martinez-Fraile1
1Elasmogen Ltd., Liberty Building Foresterhill Road, Aberdeen AB25 2ZP, U.K.
Abstract:
Antibody-drug conjugates have been used predominantly in oncology, but their potential in inflammatory disease remains largely unexplored. Here, we describe ELN28-135-01, a soluble TNF-α-targeted soloMER drug conjugate that extends this concept to immune-mediated inflammatory disease. ELN28-135-01 binds soluble TNF-α enriched at inflamed sites and delivers the Janus kinase inhibitor tofacitinib through a neutrophil elastase-cleavable linker, thereby coupling cytokine targeting with inflammation-triggered payload release. We report its rational design and synthesis, demonstrate selective linker cleavage in vitro and in vivo, and show that the conjugate retains potent TNF-α neutralization while enabling protease-dependent JAK inhibition. In human PBMC assays and preclinical models of acute and chronic inflammation, ELN28-135-01 achieved superior pharmacodynamic control compared with nonconjugated anti-TNF-α comparators while minimizing exposure to free tofacitinib. These findings support soluble cytokine-directed soloMERⓇ drug conjugates as a strategy for site-restricted dual-node inflammatory pathway modulation with the potential to improve efficacy and reduce JAK inhibitor toxicities.
Insights
This study introduces a novel drug conjugate targeting tumor necrosis factor-alpha (TNF-α) for inflammatory diseases. The conjugate delivers a Janus kinase (JAK) inhibitor specifically to inflamed sites, improving efficacy and reducing toxicity.
Area of Science:
- Immunology
- Pharmacology
- Drug Development
Background:
- Antibody-drug conjugates (ADCs) are primarily used in oncology.
- Their application in immune-mediated inflammatory diseases is underdeveloped.
- Targeting soluble cytokines like TNF-α offers a therapeutic avenue.
Purpose of the Study:
- To develop and evaluate a novel soloMER drug conjugate (ELN28-135-01) for immune-mediated inflammatory diseases.
- To investigate the targeted delivery of a Janus kinase (JAK) inhibitor (tofacitinib) via a cleavable linker.
- To assess the efficacy and safety profile compared to existing treatments.
Main Methods:
- Rational design and synthesis of ELN28-135-01, a TNF-α-targeted soloMER drug conjugate.
- In vitro and in vivo assessment of linker cleavage by neutrophil elastase.
- Evaluation of TNF-α neutralization and JAK inhibition in human peripheral blood mononuclear cell (PBMC) assays.
- Preclinical testing in acute and chronic inflammation models.
Main Results:
- ELN28-135-01 demonstrated selective linker cleavage in response to inflammation.
- The conjugate maintained potent TNF-α neutralization and enabled protease-dependent JAK inhibition.
- Superior pharmacodynamic control was observed in inflammation models compared to nonconjugated anti-TNF-α agents.
- Minimized exposure to free tofacitinib was achieved, reducing potential toxicities.
Conclusions:
- Soluble cytokine-directed soloMER drug conjugates represent a promising strategy for treating inflammatory diseases.
- Site-restricted dual-node inflammatory pathway modulation can enhance efficacy.
- This approach has the potential to reduce the toxicities associated with JAK inhibitors.
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