Saturday, December 3, 2022

Why Protein Engineering Is Opening Up New Horizons for Medical Devices By Dr Luis Alvarez

Dr Luis Alvarez, CEO and Founder of Theradaptive, sets out how current limitations in medical device biologic delivery may soon be a thing of the past

US army veterans know better than perhaps any other group the marvels, but also the limitations of medical devices and trauma treatment. When a veteran suffers trauma from an IED, often their limbs can initially be saved by the wonders of modern medicine. However, they will then find themselves forced to undergo delayed amputations weeks or months down the line.

It would seem logical that once the most difficult surgical operations have been successfully carried out in the minutes and hours after a traumatic event, a soldier should be out of danger. However, tissue damage often lingers and cannot be repaired and if the bone doesn’t heal, amputation becomes the only option. In a review of 348 US combat casualties who underwent amputation, it was reported that 15.2% were performed as a late procedure (defined as being more than 12 weeks after injury). Complex reconstructive attempts are doing the initial work to save limbs, but too many amputations are having to take place after the fact, forcing these soldiers to make the difficult choice of staying bedridden, or losing their limbs.

“This is a dramatic and considerable example of a wider problem. Tissue regeneration has not so far kept up to speed with improvements in limb salvage techniques. This has wider implications for medical devices designed to be implanted in areas with bone or tissue damage.”

Currently, devices do not retain therapeutic proteins at implant sites, meaning that they are unable to regenerate tissue around the site. Current devices are ill-suited to deliver any biologics capable of healing the affected area, and biologics are ill-suited for targeted delivery.

Often it is necessary to use a biologic in tandem with a medical device, but because the two don’t bind together well or at all, large doses are required when delivering systemically, causing adverse events. But while systemic delivery of regenerative therapeutics can be unsafe and has narrow indications, the need for precise delivery is urgent.

When proteins cannot be precisely targeted, they will have little clinical effect in the damaged tissues where they are needed most, and they may cause complications elsewhere. For example, in the case of spinal disc degeneration, around 40% of adults over the age of 40 and 80% of adults over the age of 80 have at least one degenerated vertebral disc. Approximately 900,000 spinal fusions occur per year to treat this painful and debilitating condition. With 1 in 6 people reaching the age of 60 by 2030, spinal degeneration will become even more of an issue as time goes on. But the most effective biologic currently used in spinal fusion, Bone Morphogenetic Protein 2 (BMP2), also has adverse safety outcomes associated with it. BMP2 is a naturally occurring, vital component of the body’s bone-healing response. However, when it is used in routine bone grafts or on medical devices today, it is not well-targeted, as it easily diffuses away from the implant site. This increases the risk of off-target effects, such as unwanted bone formation outside the spine. Currently, many surgeons are ambivalent about whether safety concerns outweigh the benefits of using BMP2. They recognize that it is a powerful agent, but they would be more comfortable if the biologic were only active where it was delivered on a medical device.

Fortunately, advances in protein engineering promise to improve physicians’ ability to deliver biologics directly and precisely to the site of a medical device like a spinal fusion implant. Although naturally occurring proteins don’t bind well to medical devices, via a combination of in vitro and computational methods, it is possible to identify and engineer novel material-binding variants of biologically potent proteins that have valuable material-binding properties.

For example, advances in protein engineering have made it possible to create new protein variants like AMP2 (targetable BMP2) which binds much more tightly to devices, while retaining all of the functionality of BMP2, allowing for bone regeneration in a fully targeted manner. This novel technology is starting to permit new ways to bind bioactive molecules to implantable substrates, and in the case of spine and trauma, localizing bone or tissue growth only where it is needed over the long term. Overall, the result is greater efficacy and a much better safety profile. Positive benefits also include reduced costs for physicians and their patients because far less biologic is required for the same result. These proteins can be precisely coated onto medical devices and delivered exactly where they need to go. Biologically active adhesive binding variant proteins can be engineered to coat a range of medical device materials including meshes, stents, wafers, and injectable carriers. They can also be engineered to survive terminal sterilization.

Ground-breaking advances in molecular biology are opening up new horizons for medical devices. In orthopaedics, the novel AMP2 protein binds to implant materials and enables the creation of implants that are highly osteoinductive to drive bone formation and regenerate tissue, thus enabling truly regenerative medical devices for the first time.

However, this approach can be applied to areas beyond orthopaedics, including wound repair, vascular repair, targeted liver therapeutics, and targeted cancer therapeutics, just to start. For example, protein engineering has also been used to develop targeted IL2 variants that permit high tumoral dosing while avoiding systemic exposure.

When you have control over the localization and bioactivity of an engineered protein, not only are biologics then more precisely targeted, but it also becomes possible to tune their therapeutic effect with much greater precision.

Soon biologic-carrying medical devices will help deliver powerful treatments and beat the standard of care in a broad range of indications. They will help to stop delayed amputations in veterans. They will also have life-changing implications for patients who currently have few options, be it due to spinal injuries, orthopaedic injuries, or cancer.

Of course, these novel protein therapeutics are new on the scene and will require FDA approval. However, because molecules like BMP2 and IL2 are already known to work and familiar to clinicians, the arrival and adoption of these new binding-variant protein molecules will usher in a new era in targeted therapeutics.

Editor’s Note: ‘A graduate of West Point, Dr Luis Alvarez served in the US Army for 20 years. Following a combat tour and seeing fellow service members forced to undergo delayed amputations due to tissue damage, Luis was motivated to pursue a PhD in biological engineering at MIT where he was a Hertz Foundation Fellow. Luis founded Theradaptive following his time in the Army, using what he learned from his research to create a platform that can now deliver biologics in a highly targeted way. Previously he was the founding Deputy Director of the Department of Defense’s Regenerative Medicine Program Office as well as Director of the DoD’s $720M nerve agent pharmaceutical countermeasures program. As CEO and Co-Founder, Luis has seen the Theradaptive team grow from 4 to 20 people, with the FDA granting the company three breakthrough designations for various spine indications, accelerating the process of reaching phase 2 clinical trials.’

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