Targeting the Hemoglobin Scavenger receptor CD163 in Macrophages Highly Increases the Anti-inflammatory Potency of Dexamethasone

Abstract

Synthetic glucocorticoids are potent anti-inflammatory drugs but serious side effects such as bone mobilization, muscle mass loss, immunosuppression, and metabolic alterations make glucocorticoid therapy a difficult balance. The therapeutic anti-inflammatory effect of glucocorticoids relies largely on the suppressed release of tumor-necrosis factor-α and other cytokines by macrophages at the sites of inflammation. We have now developed a new biodegradable anti-CD163 antibody-drug conjugate that specifically targets the glucocorticoid, dexamethasone to the hemoglobin scavenger receptor CD163 in macrophages. The conjugate, that in average contains four dexamethasone molecules per antibody, exhibits retained high functional affinity for CD163. In vitro studies in rat macrophages and in vivo studies of Lewis rats showed a strong anti-inflammatory effect of the conjugate measured as reduced lipopolysaccharide-induced secretion of tumor-necrosis factor-α. The in vivo potency of conjugated dexamethasone was about 50-fold that of nonconjugated dexamethasone. In contrast to a strong systemic effect of nonconjugated dexamethasone, the equipotent dose of the conjugate had no such effect, measured as thymus lymphocytes apoptosis, body weight loss, and suppression of endogenous cortisol levels. In conclusion, the study shows antibody-drug conjugates as a future approach in anti-inflammatory macrophage-directed therapy. Furthermore, the data demonstrate CD163 as an excellent macrophage target for anti-inflammatory drug delivery.

Immunogenicity of Antibody Drug Conjugates: Bioanalytical Methods and Monitoring Strategy for a Novel Therapeutic Modality

“…However, it may prove that ADCs are a promising and safe platform for other indications such as inflammatory diseases (59) and antibacterial therapy (60). The unique facets of immunogenicity support for ADCs will remain in non-oncology indications, but the risk assessment will have to be modified to reflect the population-specific likelihood (including immune status) and consequences of immunogenicity.…”

Antibody Drug Conjugates: Preclinical Considerations

“…Moreover, about 30 new antibody drug conjugates are currently undergoing clinical evaluation (2). Equally important, while ADCs have historically been developed as agents for the treatment of cancer, the potential to employ this class of therapeutics to treat disease indications outside of oncology is also gaining momentum (3,4).…”

Alcoholic hepatitis: The pivotal role of Kupffer cells

“…However blocking TNF-α had led to unacceptable complications. More targeted inhibition using dexamethasone conjugates targeting the CD163 receptor on macrophages have shown some success in rats [85,86] . Yet another unique way of managing inflammation in AH patients is apheresis.…”