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

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Project Summary: Tumor necrosis factor α (TNFα) is often considered the “master cytokine” in rheumatoid arthritis (RA). Anti‐TNFα 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 TNFα are synovial monocytes and macrophages that, in turn, have been activated by “danger‐associated‐molecular‐patterns” (DAMPs). Transmembrane TNFα (tmTNFα) is initially produced in response to this activation and is subsequently cleaved by TNFα converting enzyme (TACE) to produce soluble TNFα. A recent report has shown that anti‐TNFα antibodies such as adalimumab bind to tmTNFα and become internalized and trafficked to lysosomes. The goal of this proposal is to take advantage of the internalization of tmTNFα in order to develop antibody drug conjugates (ADCs) that deliver anti‐inflammatory payloads directly to TNFα‐ producing cells. The monocytes/macrophages that are producing the most TNFα will internalize the most anti‐TNFα ADC, while non‐inflamed tissue will internalize little or no ADC. As the inflammatory episode subsides, TNFα 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 tmTNFα are effectively internalized and lysosomally processed and 2) To demonstrate that the activation of tmTNFα‐expressing cells can be suppressed by an anti‐TNFα ADC that delivers an immunosuppressive agent. Accomplishment of the aims proposed herein will provide in vitro validation of tmTNFα as an ADC target and will position this technology for a true therapeutic development program. Agents that specifically target TNFα expressing cells may lead to improved treatments for rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and plaque psoriasis.