“Designer cytokines” targeting the tumor vasculature—think global and act local

Abstract

Tumor necrosis factor (TNF) was discovered in 1975 as a lipopolysaccharide‐induced serum factor that causes necrosis of tumors (Carswell et al, 1975). It was later found that TNF and cachectin, a factor causing wasting disease, were one and the same molecule (Beutler et al, 1985). Studies on the inflammatory activity of TNF have been translated into clinical success, namely blocking antibodies used to suppress autoimmune diseases. Research on TNF anti‐tumor activity, in contrast, has not yet resulted in a therapeutic breakthrough. This may change, based on a study by Huyghe et al (2020) describing novel “designer cytokines” (TNF and interferon‐γ) that increase local activity by targeting the CD13‐positive tumor vasculature, while simultaneously lowering the binding affinity to the respective cytokine receptor, thereby reducing off‐target effects on normal cells.

Systemically Administered, Target-Specific, Multi-Functional Therapeutic Recombinant Proteins in Regenerative Medicine

“…Theoretically, similar approaches inducing "immunological reaction towards connective tissue" could be applied to situations where scarring or fibrosis has ensued, and the breakage of the fibrosis is desirable without side effects in the rest of the body. Most recently, the technology to target powerful cytokines was further refined by generating novel "designer cytokines" that have reduced systemic toxicity to one afforded by the selective delivery to target organ [85,86]. Namely, these "designer cytokines", TNFα and interferon-γ (IFNγ) are delivered to the angiogenic vasculature by a separate vascular targeting domain [85].…”

“…In addition to that, they have a mutated receptor binding site in the therapeutic molecule, i.e. TNFα and IFNγ, to reduce their biological activity [85,86]. The reduced biological activity, in turn, reduces the systemic toxicity of the molecules and makes them viable, tolerated and safe drug option for systemic administration.…”