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3d rendering red blood cells in vein

Fusion Proteins for Reduced Drug Toxicity

A strategy for increasing target cell specificity of protein drugs to enhance safety and efficacy

Therapeutic variants of the natural hormone erythropoietin (EPO) which is produced in the kidney to boost the production of red blood cells are commonly used to treat anemias stemming from kidney disease, chemotherapy and other complications. However, many drugs that are based on therapeutic proteins, including EPO, often cause unwanted side effects because they not only bind the cells they are supposed to target, but also other cells that then evoke unwanted responses. EPO, in addition to binding the desired red blood cell-producing precursor cells, also has an affinity to other cells within the hemato-vascular system resulting in deleterious blood clots and abnormal sprouting of blood vessels which poses risks for heart attacks, strokes and tumor growth.

Fusion Proteins for Reduced Drug Toxicity
The targeted EPO therapeutic is a fusion protein containing a binding domain and an activation domain. The binding domain is an antibody fragment (light blue) against huGYPA, a surface protein expressed exclusively on red blood precursor cells (purple). The activation domain is a mutated EPO protein (red) with reduced ability to bind the Epo receptor but retained ability to activate it (pink). This molecular design ensures that only red blood cell-producing precursor cells and no other Epo receptor expressing cells are targeted.

Researchers at the Wyss Institute and Harvard Medical School (HMS) have devised a protein fusion strategy that limits EPO binding exclusively to red blood cell precursors. They engineered a genetically mutated version of EPO with a weakened ability to bind to its natural receptor and, using a flexible linker sequence, fused it to an antibody fragment that strongly recognizes a surface protein called glycophorin A, only present on red blood cell precursors (and mature red blood cells). As a result, EPO binding to red blood cell precursors now depends first on a high-affinity capturing event mediated by the antibody fragment and a subsequent lower affinity EPO receptor binding event. The approach strongly reduces binding of the EPO component to unwanted cell types and thereby reduces side effects.  In proof-of-concept studies in mice, the EPO fusion strategy was able to increase the number of red blood cells with only minimal effects on other cell types.

Our concept is completely general. We can reduce the toxicity of approved protein drugs, and may also be able to rehabilitate protein fusion drugs that have so far failed in clinical trials due to unacceptable side effects

Pamela Silver

The team currently uses the same ‘bottom-up’ engineering approach to design new fusion protein drugs that can overcome risk scenarios in other therapies. A first follow-up candidate under intense investigation is a “targeted interferon alfa” version as an anti-cancer therapy.

The technology is currently available for licensing.

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