What science can do

Extending the half-life of antibodies

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Overview

When it comes to breakthroughs in biotechnology research, MedImmune is a visionary company helping to shape the industry. In all areas of innovation, gaining an edge is about spotting opportunities and taking risks. With world-renowned capabilities in antibody discovery and protein engineering, a small team at MedImmune was faced with seemingly basic science – extend the half-life of an antibody. For patients, an extended half-life requires less doses of medication.
 
While most of the industry was focused solely on the antigen-binding fragment (Fab) of an antibody, the team at MedImmune made the decision to look at the crystalisable (Fc) fragment.

 

Image:
Herren Wu
Chief Technology Officer and Global Head of Antibody Discovery and Protein Engineering (ADPE), MedImmune

 

Vaheh screening protein crystals
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A leap in technology

In 2000, researchers at MedImmune were pursuing a unique way to extend the half-life of an antibody.

"I felt if we didn’t do it, someone else would," says Herren Wu, Chief Technology Officer and Global Head of Antibody Discovery and Protein Engineering (ADPE) MedImmune, about the company’s commitment to pursue a unique way to extend the half-life of an antibody. In all areas of innovation, gaining an edge is about spotting opportunities and taking risks. And in 2000, long before the value of the idea gained universal recognition, researchers at MedImmune chose to focus on improving this aspect of monoclonal antibodies that most other companies were ignoring. The research has led to the discovery of a novel and robust platform that has extended the serum persistence of some antibodies.


Today, there are over 300 therapeutic antibodies entering clinical practice, making them the fastest growing type of drug treatment. But back in the 1990s, there were less than 10 approved by the FDA. The growth stems from profound successes in the engineering of antibodies that provide effective treatments for patients who once had no alternative but to live – or not live – with their disease. The ability to engineer a part of the human immune system to combat disease unleashed a plethora of activity. But as with the introduction of any new technology, the learning curve was a steep one.

Hand-written note showing positions of the YTE mutations
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A life-extending concept

The idea was significantly basic science, elucidating a novel pathway to extend the half-life of the antibody in the bloodstream.

In 1998, MedImmune was breaking new ground by introducing the first antibody therapy to target an infectious disease. Paediatric respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections in children, and is linked to an estimated 160,000 deaths per year. Child mortality associated with RSV was the motivation behind the discovery and development of an effective treatment. When the FDA approved palivizumab (brand name SynagisTM) for the treatment of RSV, the drug was one of just nine antibody therapies approved to date.

At the time, MedImmune was a young, fledgling biotech company with limited resources to support its antibody discovery and development platform. But, amidst the pressure to focus on the company's pipeline, industry veterans William Dall'Acqua, Senior Director, R&D, Antibody Discovery and Protein Engineering at MedImmune, and Herren Wu, Chief Technology Officer, felt it was vital to make the case to support innovation for the future.

"The idea was significantly basic science, atypical of the industry," explains Dr Dall'Acqua. Discovering a way to extend the half-life of antibodies in the circulation is the fundamental idea to which Dr Dall'Acqua is referring. "Developing YTE would elucidate a novel pathway; change some lives." YTE refers to the mutations engineered into the antibody structure that would make the idea a reality.

"If the antibody lasts longer in the bloodstream you can dose much less," explains Dr Dall'Acqua. “It was one of the first projects I worked on when I joined the company. It was a very general idea, a longer half-life. My role was to put it into practice. How could we engineer this pathway and reach the desired result? Very early on we were on an island. We needed to engage different stakeholders within the business to convince them of the potential because the idea was novel."

An antibody
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A new perspective on antibody structure

While most of the industry was focused solely on the Fab binding fragment, the MedImmune team made the decision to pursue its idea by looking at the Fc fragment.

The branches of the y-shaped antibody structure each serve one of two functions. The top branches comprise the antigen-binding (Fab) fragment. The Fab identifies the antigen. The base of the Y is the crystallisable (Fc) fragment which interacts with the immune system. Most of the industry was focused solely on the Fab binding fragment when the team at MedImmune made the decision to pursue its idea to extend the half-life of an antibody by looking at the base of the molecule.

Dr Wu was also contemplating engineering antibodies to extend their half-life while working for Tanox, which was, at the time, another early-stage biotech company. "William had started some Fc engineering when I joined MedImmune in 2002. I knew it could have a big impact on therapeutics,” says Dr Wu. "I continued to work with William. We identified YTE as one of the combinations of Fc mutations that could intensify binding to the neonatal Fc receptor (FcRn). YTE was optimal at increasing binding at acidic pH and allowing release at neutral pH," Dr Wu explains. “This meant the antibody could efficiently be recycled and then linger on to act on another diseased cell.” 

Vaheh purifying proteins in the lab
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Overcoming the hurdles

While testing how the molecule behaved in living systems, the team saw the opposite result in their first pre-clinical model. The solution was a change to the pH-dependent binding.

Testing and characterising how the molecule behaves in living systems is also part of the pre-clinical testing. "While William did the hands-on work, I worked downstream," explains Melissa Damschroder, Associate Director R&D MedImmune. "My interaction was with characterizing YTE-modified molecules. How stable are they? Will YTE work on different isotypes and does it change interactions with the Fc gamma receptors?" Gamma receptors are how antibodies engage the immune system.  

Dr Dall'Acqua describes encountering the first hurdle after the initial discovery of the YTE mutations: "In the first pre-clinical model, we saw the opposite result to what we were expecting. No increase in half-life was seen. It was not what our theory had predicted would happen."

Damschroder elaborates: "We couldn’t understand where the antibodies went when they were tested or why they disappeared so rapidly. An important aspect of the mechanism is that it binds to the receptor at one pH and releases at another. This was not the case in the model we were using. The pH binding dependency was lost."

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We couldn’t understand where the antibodies went when they were tested or why they disappeared so rapidly.

Melissa Damschroder Associate Director R&D

"We spent a lot of effort to find out what was wrong," says Dr Wu.

"We eventually understood the pH of the model was the problem," Damschroder continues. Using an increasingly complex model that more closely emulated the pH situation found in the human body finally gave them the results their theory predicted.

Dr Dall’Acqua says: "This was the breakthrough. The result was beautiful. People were really happy and we published our findings." 


Meet the team

Vaheh looking at molecules 3-dimensional structure
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Reaching the clinic

Once in the clinic, YTE became the most advanced antibody half-life extension technology. The only one validated in the clinic.

But the team’s challenges weren’t over yet. "Even then, we had to alleviate fears of immunogenicity," says Dr Dall'Acqua. The team kept pushing forward amidst financial pressures. “It is difficult to fully validate a technology platform," Dr Dall'Acqua explains. "It is expensive.”

Despite internal resistance at MedImmune, YTE was used to extend the half-life of MEDI-557, a second generation anti-RSV monoclonal antibody. "I personally participated in engineering this anti-RSV molecule. We had one shot to determine if this technology would work and this molecule could be a drug," Dr Wu emphasises.

MEDI-557 entered Phase 1 development and the results were positive. The trial demonstrated that introducing the YTE mutations into an antibody was well tolerated. Results also confirmed the half-life of this second generation molecule reached up to 100 days in humans, which is about two to four-fold longer than non-YTE molecules. "This made YTE the most advanced antibody half-life extension technology and the only one validated in the clinic at the time," explains Dr Wu. 

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A persistent influence

YTE technology continues to impact the molecules in the pipeline at MedImmune.

"For technology to be successful and science to be exciting you need to know how to utilise it broadly. There will always be resistance. Experts will point to the risks; the champion needs to be able to overcome those hurdles," says Dr Wu.

Damschroder agrees. "Without this technology, we would not have the next generation YTE molecules. For instance, MEDI-8897 is another anti-RSV therapy that contains YTE and recently entered clinical trials. It’s received Fast Track designation from the US FDA and, if approved, dosing would take place just once a season due to the extension in the half-life that YTE has brought. It would provide a passive vaccine-like strategy for all infants, including healthy-term infants who are entering their first RSV season, the time when they are most at risk.” Phase 1a trials in healthy adult volunteers are near completion and a Phase 1b trial in infants has commenced.

The long-acting effects of the YTE mutation are also being used to prevent pneumonia. Also granted FDA Fast Track designation, MEDI-4893 is undergoing Phase 2 clinical trials to assess safety and efficacy in preventing pneumonia caused by Staphylococcus aureus pneumonia. MEDI-4893 takes aim at α-toxin. During the Phase 1 trial, MEDI-4893 demonstrated a half-life of 86 days, which is about four times longer than other antibody therapies. Other YTE-enhanced pre-clinical candidates are also in the development pipeline.

And there isn’t any doubt in Dr Dall'Acqua’s mind that the research has been a success. "The YTE platform is still significant and we have been approached by several companies to in-license the platform. Currently there are similar technologies out there. For example, Xencor uses a different set of mutations. But MedImmune were the pioneers who first brought this idea to life."