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Mon. Jul 22nd, 2024

a new class of drugs on the horizon

By Vaseline May30,2024
a new class of drugs on the horizon

The burgeoning field of covalent biologics has been making strides lately, as the only biotech pioneering this field has secured $100 million in funding to move its pipeline to the clinic.

US company Enlaza Therapeutics’ undisclosed preclinical pipeline is primarily focused on antibody drug conjugates (ADCs). These drugs consist of an antibody that attaches to cancer cell targets, a chemotherapy drug designed to kill cancer cells, and a linker molecule that links the antibody and drug together and delivers the chemotherapy drug into the cancer cells.

Biological drugs such as ADCs are typically designed to bind to a target that produces some effect that is beneficial to a patient.

“These drugs have an on-off switch, which means they bind, do their job and then are reversible,” says Sergio Duron, CEO of Enlaza. “The idea of ​​covalence – you set that turn-off rate to zero, which means that when they bind, they cross-link, form a bond and become part of the chemical bond with the target that is designed to bind to it.”

How can covalence improve efficacy?

Covalence has been a strategy used in drug discovery for more than a century. Pain-relieving drugs such as aspirin and penicillin, one of the world’s first antibiotics, are popular examples of covalent drugs.

A covalent bond is a permanent bond between two atoms. When chemists make drugs, Duron explained that they design covalent drugs that force a chemical bond between two molecules. Unlike other drugs that bind reversibly, covalent drugs create a lasting bond with their target. This may enable potent and selective inhibition of target proteins.

Although covalent small molecules have been around for a long time, covalent biologics are a fairly new concept.

“The whole of covalence is in the world of small molecules,” says Duron. “And so that is the strategy that has been applied there, simply because the chemistry for covalence is easier to develop.”

While biologics such as antibodies have long lives, there is a lot of room for protein drugs, especially small protein drugs that are about one-tenth the size of a traditional antibody, Duron explains. The problem, however, is that due to their small size, they are removed very quickly through the kidneys.

“Your body is designed to eliminate things in your bloodstream. And you usually get what’s called low exposure, which means, ‘I give a patient a protein drug, and it goes away very quickly, and so I can’t get the efficacy that I need from these drugs,'” he said. Duron.

One of the ways to get around this is to incorporate covalence. In this way, the protein drug can target a specific target. Covalent biologics are also called wizard drugs for this reason, as they act as “warheads” that lock onto a target.

Covalent biologics are designed to not only take advantage of the selectivity and specificity that drugs such as antibodies would typically possess, but also to take advantage of the Achilles heel of small size biologics, which have high clearance, Duron pointed out.

So while antibodies have had great success in treating solid tumors, they “have difficulty penetrating solid tumors because of the so-called barrier effect,” Duron said. This means that antibodies may find it difficult to infiltrate tumor sites because they tend to bind to the receptors closer to the surface.

“Our molecules, one-tenth the size of an antibody, have superior distribution in solid tumors and can then deliver and capture the target. Our goal is to provide better efficacy and better safety with our strategy,” said Duron.

Enlaza builds covalent ADC pipeline

Enlaza’s biologics contain non-natural amino acids at the contact points – called complementarity-determining regions – of the antibodies. The amino acid is non-reactive until the drug binds to the target. It is then attached to a location on the target where cross-linking occurs. Without this mechanism, the drug would only circulate in the bloodstream to be cleared quickly.

“So the way it ends up being: you dose, it finds a target, locks it in and you get a high approval. You’re essentially left with a patient with the drug loaded where you want it to be, and then your natural clearance mechanism removes the remaining drug, so you have a patient who isn’t exposed to the drug for long periods of time outside of where you want it to be . it will be so,” Duron said.

“We are not aware of any other companies pursuing a covalent biological strategy. That’s the nice thing about our company.”

Sergio Duron, CEO of Enlaza Therapeutics

In preclinical studies, biotechnology has shown that using covalence in a small size protein drug can provide high clearance and longer residence time (the time a drug spends with a target) on the tumor and deliver the payload in a beneficial manner.

“We are not in a position where we can clearly identify the potential side effects,” Duron said. “But our strategy has delivered a significant improvement over the side effects of traditional antibodies such as antibody drug conjugates.”

The American biotech’s covalent biological platform is intended for multiple therapeutic areas. “We are not specific to therapeutic areas, we are agnostic to therapeutic areas,” Duron said.

Enlaza’s covalent biologics will target solid tumors

Nevertheless, Enlaza’s primary focus is on cancer treatment, for which it is creating a pipeline of ADCs, a therapeutic space that has been inflated in recent times with multiple investment deals. These covalent ADCs are intended to be loaded onto the tumor, where they release the payload and kill cancer cells while sparing healthy cells. Enlaza also wants to conquer autoimmunity, although the entire pipeline has yet to be revealed.

As the only biotech pursuing the development of covalent biologics, the $100 million Series A funding is a significant deal for the field as the technology will soon move to the clinic. It brings Enlaza’s total funding to $161 million since its launch in 2022, when it operated in stealth mode.

Duron said: “We are not aware of any other companies pursuing a covalent biological strategy. That’s the nice thing about our company. We are the first company to do that; to be able to invest and build the drug discovery engine to build covalent protein medicines.”

While Duron’s team aims to “unleash the power of covalent protein medicines,” the company, which is still in the early stages of drug development, will most likely face the challenges associated with creating ADCs.

This could include the drug’s ability to penetrate the tumor microenvironment, overcome low loading capacity and minimize the potential for toxic side effects, according to a report published in the National Library of Medicine.

“There is so much potential with covalent protein medicines, we are at the forefront of this. We are paving the way for this and this is an exciting time for the company. We are excited to close this round and begin building the next generation of protein therapeutics that enable covalence as a strategy,” said Duron. “We think it will be transformative. We think it will be part of the toolbox for biologic drug discovery in the future.”

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