Biologics for Targeting Inflammatory Cytokines, Clinical Uses, and Limitations

Abstract

Proinflammatory cytokines are potent mediators of numerous biological processes and are tightly regulated in the body. Chronic uncontrolled levels of such cytokines can initiate and derive many pathologies, including incidences of autoimmunity and cancer. Therefore, therapies that regulate the activity of inflammatory cytokines, either by supplementation of anti-inflammatory recombinant cytokines or by neutralizing them by using blocking antibodies, have been extensively used over the past decades. Over the past few years, new innovative biological agents for blocking and regulating cytokine activities have emerged. Here, we review some of the most recent approaches of cytokine targeting, focusing on anti-TNF antibodies or recombinant TNF decoy receptor, recombinant IL-1 receptor antagonist (IL-1Ra) and anti-IL-1 antibodies, anti-IL-6 receptor antibodies, and TH17 targeting antibodies. We discuss their effects as biologic drugs, as evaluated in numerous clinical trials, and highlight their therapeutic potential as well as emphasize their inherent limitations and clinical risks. We suggest that while systemic blocking of proinflammatory cytokines using biological agents can ameliorate disease pathogenesis and progression, it may also abrogate the hosts defense against infections. Moreover, we outline the rational need to develop new therapies, which block inflammatory cytokines only at sites of inflammation, while enabling their function systemically.

Figure 1

Biological drugs strategies for targeting inflammatory cytokines. The biologics can be composed of anticytokine or antireceptor neutralizing antibodies (1) or a soluble receptor that binds the cytokine (2). An inflammatory cytokine, like IL-1β, binds the IL-1R1 and the coreceptor IL-1R accessory protein (3) and transmits cell signaling, while an antagonist, like IL-1Ra, binds the receptor without recruiting the coreceptor (4), thus inhibiting signaling from the receptor and reducing the inflammation. Inflammation-dependent anticytokine strategy: enzymes such as neutrophil serine proteases or macrophage caspase-1 are released into the environment and cleave the two parts of the chimeric-IL-1Ra inactive precursor into an active antagonist (5), which blocks the receptors of tissue cells and the inflammatory cells.