"Molecular whack-a-mole”: Targeting Transmembrane-TNFα for the Delivery of Anti-Inflammatory Drugs

State University Of Ny,Binghamton, Binghamton NY

Investigators

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Abstract

Project Summary: Tumor necrosis factor ? (TNF?) is often considered the ?master cytokine? in rheumatoid arthritis (RA). Anti?TNF? therapy has revolutionized the treatment of RA and related inflammatory disorders by depleting the plasma levels of this pro?inflammatory cytokine. The primary source of circulating TNF? are synovial monocytes and macrophages that, in turn, have been activated by ?danger?associated?molecular?patterns? (DAMPs). Transmembrane TNF? (tmTNF?) is initially produced in response to this activation and is subsequently cleaved by TNF? converting enzyme (TACE) to produce soluble TNF?. A recent report has shown that anti?TNF? antibodies such as adalimumab bind to tmTNF? and become internalized and trafficked to lysosomes. The goal of this proposal is to take advantage of the internalization of tmTNF? in order to develop antibody drug conjugates (ADCs) that deliver anti?inflammatory payloads directly to TNF?? producing cells. The monocytes/macrophages that are producing the most TNF? will internalize the most anti?TNF? ADC, while non?inflamed tissue will internalize little or no ADC. As the inflammatory episode subsides, TNF? expression will decrease and the rate of drug?delivery will slow, thus limiting side?effects and immunosuppression of the ADC. Like a player of the classic ?whack?a?mole? game, the ADC then harmlessly circulates through the body vigilantly awaiting the next inflammatory event. The two primary aims of this project are: 1) To establish that ADCs targeting tmTNF? are effectively internalized and lysosomally processed and 2) To demonstrate that the activation of tmTNF??expressing cells can be suppressed by an anti?TNF? ADC that delivers an immunosuppressive agent. Accomplishment of the aims proposed herein will provide in vitro validation of tmTNF? as an ADC target and will position this technology for a true therapeutic development program. Agents that specifically target TNF? expressing cells may lead to improved treatments for rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and plaque psoriasis.