The Biomedical Footprint of the Iraq War, Resulting Medical Innovation

The 21st anniversary of the Iraq War this year reminds us not only of the loss of life suffered during the conflict, but the need to improve our ability to treat the injuries that are an inevitable part of modern warfare. Armed combat and medical advancement have shared a collective history for centuries. The lessons learned from treating servicemembers in war directly shape how we treat the wider population. The ability to treat injury of increasing severity, deliver faster recovery times and achieve a better quality of life in the long-term has stimulated research innovation that is opening up new avenues for treatment well away from the front line.

In Iraq, asymmetrical warfare tactics used by insurgent groups relied heavily on unconventional weaponry such as improvised explosive devices to inflict harm on personnel and cause equipment damage. As a result, a significant proportion of US personnel suffered massive trauma and injury to their extremities, requiring military physicians to improvise new medical techniques in order to increase rates of survival.

Advancements such as improvements in tourniquets and the use of new hemostatic agents enabled physicians to control blood loss after traumatic injuries and resulted in increased survival rates for US personnel. These new approaches have multiple applications for managing trauma outside of warfare as well, such as for stabilizing a patient in the immediate aftermath of a traffic or industrial accident.

However, the changing nature of warfare also reinforced some of the limitations in current medical technology, both on and off the battlefield. In the aftermath of the conflicts in Iraq and Afghanistan, we saw an increase in delayed amputations. This occurs when a limb is saved due to initial medical intervention, but there is subsequent failure of the bone and tissue to heal sufficiently to allow that limb to function; this can lead to amputation weeks or months down the line. This problem has led to significant investment in regenerative medicine research from the US Department of Defense and other government bodies to improve outcomes for injured service personnel.

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Applying Scientific Progress to Address Unmet Needs Beyond the Battlefield

A major focus of this research has been around the role of native proteins in stimulating bone and tissue repair. Improving our ability to harness and direct therapeutic proteins has the potential to transform outcomes across a multitude of conditions beyond trauma, such as spinal degeneration, correction of congenital deformity, bone repair, and maxillofacial surgery.

The use of therapeutic proteins in regenerative medicine is currently limited because we lack the ability to reliably target the activity of a protein to a specific location in the body with anatomical precision for an extended period of time. With current technology, the proteins used to regenerate bone disperse away from the site where they are needed, leading to off-target effects such as bone growth and inflammation elsewhere in the body.

Theradaptive’s mission is to solve this problem and unlock the therapeutic potential of proteins across multiple areas of medicine. At the core of our approach is making proteins ‘sticky’ so we can direct their placement and action more effectively in the body.

New Directions in Protein Engineering

We developed a unique protein engineering platform that enables us to create variants of bioactive proteins that have the ability to bind to implants or devices. Our computationally-informed process mines vast protein sequence libraries to identify variants that display promising binding potential. We then put those proteins through a process of computationally informed accelerated evolution; repeatedly modifying and optimizing these to refine the characteristics we want while preserving their therapeutic activity.

The result is a protein that can be applied to an implant or device like a coat of paint, enabling the precise delivery of the protein through placement of the implant and ensuring it stays in place to optimize efficacy and reduce the risk of off-target effects.

Transforming Spinal Fusion Outcomes

Our lead molecule—called AMP2—is a ‘sticky’ variant of recombinant human bone morphogenetic protein 2 (BMP2), a naturally occurring protein that has been used for decades to stimulate bone formation. However, its use is limited because it easily diffuses away from the site it is placed in, causing inflammation and bone growth in other areas of the body.

AMP2 retains the naturally-occurring osteoinductive properties of BMP2, but delivers bone growth in a targeted, anatomically precise manner. Our lead product (OsteoAdapt SP) is a resorbable spinal fusion implant with a bioactive surface coating of AMP2. This enables the precise placement of this powerful bone formation protein in the exact location where it is needed to maximize therapeutic effect while eliminating off-target effects associated with BMP2.

Our lead product has received 3 breakthrough device designations from the FDA, allowing prioritized FDA review times and a federal recognition of the importance of the technology. The product has also received FDA approval for investigational use and has now entered human clinical trials to assess its safety and efficacy in transforaminal lumbar interbody fusion, a procedure used for a range of conditions including degenerative disc disease, lumbar spondylolisthesis, and spinal stenosis.

Beyond Orthopedics to Precision Oncology

The ability to reengineer proteins for precise delivery and local effect has significant implications across other areas of medicine, such as oncology, where targeting the action of a protein at the location of a tumor can increase therapeutic efficacy and reduce the systemic side effects associated with many cancer therapeutics.

We are developing a variant of interleukin 2 (IL-2), a powerful molecule that is used as an immunotherapy for patients with certain types of metastatic melanoma and kidney cancer. IL-2 activates a powerful immune response that targets and destroys metastatic cancer cells, but it is associated with severe side effects.

Our engineered variant—called IL2X—is designed to be retained within a tumor and its draining lymph nodes. This eliminates systemic exposure and side effects. In preclinical studies, IL2X not only triggers the desired immune response locally but initiates immune-mediated identification and destruction of distant metastases, without the severity of side effects associated with native IL-2.

As we continue to evaluate the efficacy of IL2X in diverse cancer types, we plan to leverage emerging findings in tumor immunogenicity and the directed modulation of T-cell status in the tumor microenvironment.

What started as a novel solution to address urgent needs for service personnel and veterans has grown into a platform for targeted therapeutic delivery. This has stimulated new directions and holds promise in improving treatment outcomes and quality of life for millions of patients in the future.

About the Author

Luis Alvarez, CEO and founder of Theradaptive, shares his insight into how the changing nature of warfare has catalyzed scientific innovation and advances that are now extending into some unexpected areas of medicine.