A Rationally Designed Novel Bifunctional Human TNF-α- and Janus Kinase-Targeted soloMER Drug Conjugate (SDC) with a Neutrophil Elastase Cleavable Linker Delivering Inflammation Site-Specific Release of Payload.

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.