IE 3: Cytokines and Interferons Totonchy

What are two major properties of cytokines that make them difficult to translate into therapeutics?

• They usually act in combination with each other not alone

• They usually act locally, not systemically.

• Pleiotropic functions

Define "pleiotropic" and provide one specific example of a cytokine having a pleiotropic function.

• Stimulation by a cytokine causes a cell to release multiple other cytokines

• Example: IL2 → IFNg → TNFa/IL6/etc, etc.

What are two issues that limit the effectiveness of current cytokine therapeutics?

• Dose-limiting toxicity

• Poor pharmacokinetics

• Off target effects

  
  

Why is IL-2 being aggressively pursued as an anti-cancer therapeutic strategy?

• IL-2 potently activates T cells! Tumor-specific T cells exist and can be leveraged to effectively and specifically attack tumors.

What is one strategy being used to try to reduce the problem of pleiotropic function for IL-2 therapeutics?

• Engineered variants of IL-2 are being developed to make the activation more specific (effector T cells vs. Treg) one such selective drug bempegaldesleukin was given Breakthrough Therapy designation by the FDA in 2019

What is one strategy being developed to improve the pharmakokinetics of cytokine therapeutics?

• Protein fusions: Albumin (non-specific but cost-effective); antibodies (can help with targeting)

• PEGylation

What is one strategy being developed to improve the targeted release of cytokine therapeutics at local sites of action?

• Nanoparticles with targeting action that are stable in circulation but unstable in sites of action

• Inactive Pro-drugs that can be cleaved into active forms by enzymes present in the site of action