Cytokines and Interferons (Totonchy)

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

1. They usually act in combination with each other not alone

2. They usually act locally, not systemically.

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? (totonchy put three tho…?)

1. Dose-limiting toxicity

2. Poor pharmacokinetics

3. 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? (totonchy put two tho…?)

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

2. PEGylation

What is one strategy being developed to improve the targeted release of cytokine therapeutics at local sites of action? (totonchy put two tho…?)

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

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

What is the brand name for Interferon alpha 2b?

Intron A, PegIntron, Sylatron, Besremi

What diseases does Interferon alpha 2b treat?

Hepatitis B&C, Melanoma, Kaposi Sarcoma, Various lymphoma/leukemia, Polycythemia vera

What is the brand name for Interferon alpha 2a?

Roferon-A

What diseases does Interferon alpha 2a treat?

Hepatitis C, Hairy cell leukemia

What is the brand name for synthetic Interferon alpha?

Infergen

What disease does synthetic Interferon alpha treat?

Hepatitis C

What is the brand name for Interferon beta 1a?

Rebif, Avonex, Plegridy

What disease does Interferon beta 1a treat?

Multiple Sclerosis

What is the brand name for Interferon beta 1b?

Betaseron, Extavia

What disease does Interferon beta 1b treat?

Multiple Sclerosis

What is the brand name for Interferon Gamma?

Actimmune

What diseases does Interferon Gamma treat?

Chronic Granulomatous Disease, Osteoporosis