Polymer-conjugated inhibitors of tumor necrosis factor-α for local control of inflammation

Abstract

Burns, chronic wounds, osteoarthritis, and uveitis are examples of conditions characterized by local, intense inflammatory responses that can impede healing or even further tissue degradation. The most powerful anti-inflammatory drugs available are often administered systemically, but these carry significant side effects and are not compatible for patients that have underlying complications associated with their condition. Conjugation of monoclonal antibodies that neutralize pro-inflammatory cytokines to high molecular weight hydrophilic polymers has been shown to be an effective strategy for local control of inflammation. Lead formulations are based on antibody inhibitors of tumor necrosis factor-α conjugated to hyaluronic acid having molecular weight greater than 1 MDa. This review will discuss fundamental aspects of medical conditions that could be treated with these conjugates and design principles for preparing these cytokine-neutralizing polymer conjugates. Results demonstrating that infliximab, an approved inhibitor of tumor necrosis factor-α, can be incorporated into the conjugates using a broad range of water-soluble polymers are also presented, along with a prospectus for clinical translation.

Effects of Sulfated Fucans from Laminaria hyperborea Regarding VEGF Secretion, Cell Viability, and Oxidative Stress and Correlation with Molecular Weight

“…In addition, it has been found that polymers with conjugated inhibitors have a higher inhibitory effect on tumor necrosis factor-α (TNF-α) if the inhibitors are attached to higher-molecular-weight polymers; this is due to an increased diffusion time [39]. Since the binding of VEGF to highly sulfated fucans has been proven, a similar effect of increased diffusion time could play a role.…”

Physiochemical properties and application of hyaluronic acid: a systematic review

“…Of course, a combination of antibodies to a polymer requires painstaking research. Whether the local neutralization of the inflammatory process will be effective in the human model is at this time unknown but at the same strategy is what makes this fascinating …”

Progress in antiandrogen design targeting hormone binding pocket to circumvent mutation based resistance

“…Cross coupling and conjugation strategies are wildly applied to develop the modulator with multivalent and heterobifunctional constructs, which exhibit high affinity and specificity to the biomolecular target (Lambert, 2013 ; Washburn et al, 2013 ) (Figure 3C ). To date, there are limited examples targeting the AR with steroidal conjugates (Levine et al, 2014 ).…”