Past Success - Startup

Targeted EPO: Safely Normalizing Oxygen Delivery in a Broad Range of Disease Conditions

First-in-class safe engineered fusion protein addresses life-threatening and limiting low-oxygen conditions in a large patient population, and is commercialized by General Biologics

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Platform

Synthetic Biology

Technology Development Team

Jeffrey Way Pam Silver

Key Features

Protein therapy to treat lack of oxygen in patients with a range of diseases, including COPD, cystic fibrosis, severe COVID-19, and anemias, such as those in kidney failure
Creative use of protein engineering technology enables conversion of a potent, yet potentially harmful, into a safe, much broader applicable therapy
Targeted erythropoietin (EPO) is a first-in-class fusion protein therapeutic that simultaneously binds to two surface proteins exclusively on red blood cell precursors.

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General Biologics commercializes targeted EPO as a therapy to raise oxygen levels in patients suffering from COPD, cystic fibrosis, COVID-19, and severe anemias.

The Problem

Patients with diseases such as, for example, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), congestive heart failure, asthma, severe COVID-19, and different forms of anemia are at an increased risk for hypoxia, a condition caused by lower-than-normal blood oxygen levels. COPD alone affects 300 million people worldwide, resulting in 64 million disability-adjusted life years. In the U.S., the health care costs for COPD are projected to dramatically increase over the next 20 years, approaching $40 billion dollars per year. In patients, the long-term exposure to indoor and outdoor air pollutants results in chronic lung inflammation and, as a consequence, the permanent constriction of air-conducting bronchioles and expansion of oxygen-exchanging alveoli. Although current treatments can partially normalize some lung functions, the overall tissue damage in COPD, CF, and other oxygen-depriving conditions cannot be fully repaired. Therefore, therapies that increase oxygen transport and delivery are urgently needed and have great potential to improve and safe patients’ lives.

Targeted EPO: Safely Normalizing Oxygen Delivery in a Broad Range of Disease Conditions — 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 human GPA, 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.

Our Solution

A recombinant version of the hormone erythropoietin (EPO) increases the production of oxygen-delivering red blood cells and is used to treat anemia by supplementing natural EPO in the body. However, in addition to binding to the EPO receptor molecule on red blood cell precursors, and potently stimulating their desired proliferation, EPO, by binding to the same EPO-receptor molecule on other cell types, also causes blot clotting that results in heart attacks, stroke and deep vein thrombosis, as well as increased risk of tumor progression or recurrence. These observations prompted the FDA already in 2007 to issue a black-box warning limiting the use of EPO to only patients with severe anemia.

To make EPO therapy safe and highly specific to red blood cell precursors, Wyss researchers have devised a “whispering protein” strategy in the form of an engineered “Targeted EPO” protein that whispers its instructions only to EPO receptors on cells that are supposed to receive its message, as opposed to shouting it out loud to all EPO receptor-expressing cells in the body. They achieved this goal, first, by introducing a mutation into the protein sequence of EPO the researchers weakened EPO’s binding to the EPO receptor on all cell types. Then, by fusing the mutated EPO protein to an antibody fragment that binds to a second protein, the blood group protein glycophorin A (GPA), which is specifically expressed on the surface of red blood cell precursors (and mature red blood cells), they rescued the weakened binding potential again, but exclusively on red blood cell precursors. Due to this highly cell-specific two-step binding strategy, Targeted EPO avoids unspecific EPO binding to other cells such as blood clot-forming platelets, heart and neuronal cells. This protein engineering feat created an EPO version that is safer for patients who currently are treated with natural EPO for kidney failure and the associated severe anemia, and opens up new healthcare applications for COPD, cystic fibrosis, and COVID-19 patients on ventilators.

Product Journey

The team, led by Jeffrey Way, Lecturer in the Department of Systems Biology and in the Laboratory of Systems Pharmacology at Harvard Medical School (HMS) and former Wyss Senior Staff Scientist, and Wyss Core Faculty member Pamela Silver, developed and de-risked targeted EPO with close attention to the blood clotting side-effects caused by the unmodified recombinant EPO protein through a series of protein engineering studies. At first, not knowing for certain whether GPA was closely co-expressed with the EPO receptor on the surface of red blood cell precursors, Devin Burrill and other researchers on the team used transgenic mice, which were engineered to produce the human GPA protein, to show that Targeted EPO was indeed able to simultaneously bind to both GPA and the EPO receptor as a basis for the desired effects. In 2016, they had created the most advanced “dual specificity fusion protein” of the time and validated a new concept in therapeutic protein engineering. This breakthrough was enhanced by the fact that the team was able to turn an existing potent, yet harmful drug into a safe drug by using protein engineering technology.

On the way to their final product, the researchers had to extensively troubleshoot their original fusion protein design. The initial fusion protein was able to bind to GPA and the EPO receptor on the same cells, but also to GPA on one cell and the EPO receptor on a different cell, thus cross-linking them together. The unfortunate result was that, in mice, red blood cells stuck to blood cell types with EPO receptor, which actually enhanced blood clotting. To address this problem, the team re-designed their fusion protein by fine-tuning the geometry of the two binding domains so that it could not reach between cells anymore, but only between receptors on the same cell surface.

These studies were followed by careful demonstrations in cell-based assays in vitro and in mice by Jungmin Lee and others on the Silver-Way team, showing that an improved Targeted EPO could specifically promote red blood cell formation and protect neurons, without producing blood clot-causing platelets.

Compared to currently available EPO drugs, our molecule is engineered to prevent EPO from binding to and activating cells that promote side effects such as blood clotting or tumor growth. This cell-targeted EPO approach demonstrates a new theoretical basis for the rational design of engineered protein fusion drugs.

Jeffrey Way

Their accomplishments led the team to form the startup General Biologics with Way as CEO and President, and Silver as Founder and Scientific Adviser, and obtain an exclusive license from Harvard’s Office of Technology Development to commercialize Targeted EPO. General Biologics currently develops Targeted EPO in its lead program (GB-001) as a novel protein drug toward patients with a broad range of diseases in which hypoxia is a life-threatening or life-limiting condition. In 2023, General Biologics also became a member of the 2023 cohort of startups selected by MassBioDrive, MassBio’s Biotech Accelerator, facilitating its commercialization efforts, and partnered with Air Force Research Labs for an ongoing collaboration. More recently, the startup was joined by biotech entrepreneur Rogers Yocum as CSO, and has started operations in the Blavatnik Harvard Life Lab Longwood.