Covalent biologics: a new class of drugs on the horizon

covalent biologics

The budding field of covalent biologics has made headway recently, as the only biotech pioneering the space has bagged $100 million in funding to move its pipeline to the clinic.

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

Biologic drugs like ADCs are typically designed to bind to a target that induces some effect that’s beneficial for a patient. 

“Those drugs have on and off rates, meaning they bind, they do their business, then they are reversible,” said Sergio Duron, chief executive officer (CEO) of Enlaza. “The idea of covalency – you turn that off rate to zero, meaning, when they bind, they crosslink, form a bond and become part of the chemical bond to the target that is designed to bind to it.”

How can covalency improve efficacy? 

Covalency has been a strategy used in drug discovery for more than a century now. Pain relief drugs like 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 where a chemical bond is forced between two molecules. Unlike other medicines that bind reversibly, covalent drugs create a lasting link with their target. This can enable potent and selective inhibition of target proteins.

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

“The entirety of covalency has been in the world of small molecules,” said Duron. “And so, that’s been the strategy that has been applied there, simply because the chemistry for covalency is easier to engineer.”

Although biologic drugs like antibodies are long-lived, there is a lot of scope for protein drugs, particularly small format protein drugs that are about one tenth the size of a traditional antibody, explained Duron. However, the problem is that they get cleared out through the kidneys very quickly because of their small size.

“Your body is designed to eliminate things in your bloodstream. And you typically end up with what’s called a low exposure, meaning: ‘I dose a patient with a protein drug, and it gets cleared very fast, and so I can’t get the efficacy that I need from these drugs,’” said Duron.

One of the ways to circumvent this is to incorporate covalency. This way, the protein drug can lock onto a certain target. Covalent biologics are also called warlock 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 like antibodies would typically possess, but also leverage the Achilles heel of small format biologics, which is high clearance, Duron pointed out.

So, while antibodies have had major success in treating solid tumors, they “have difficulties penetrating solid tumors due to what’s called the barrier effect,” said Duron. This means that antibodies may find it hard to infiltrate tumor sites as they tend to bind to the receptors closer to the surface.

“Our molecules, a tenth of the size of an antibody, have a superior distribution into solid tumors, and then can deliver and lock onto the target. Our goal is to have better efficacy and a better safety opportunity 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. Then, it latches onto a site on the target where crosslinking takes place. If it weren’t for this mechanism, the drug would circulate in the bloodstream only to rapidly get cleared.

“So, the way it ends up being is – you dose, it finds a target, locks onto it and you get a high clearance. You’re essentially left with a patient with the drug loaded onto the place you want it to and then your natural clearance mechanism removes the remaining drugs so that you have a patient who is not exposed long-term to the drug outside of where you want it to be,” said Duron.

“We’re not aware of any other companies in the covalent biologic strategy. That’s what’s exciting about our company.”

Sergio Duron, CEO of Enlaza Therapeutics

In preclinical studies, the biotech demonstrated that employing covalency in a small format protein drug can offer high clearance and longer residence time – the time a drug spends with a target – on the tumor as well as deliver the payload in a beneficial way. 

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

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

Enlaza’s covalent biologics set to take on solid tumors

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

As the only biotech to pursue covalent biologic drug development, the $100 million series A financing 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 it was launched back in 2022, before which, it was operating in stealth mode.

Duron said: “We’re not aware of any other companies in the covalent biologic strategy. That’s what’s exciting about our company. We’re the first company to do that; to be able to invest and build the drug discovery engine to build covalent protein drugs.”

As Duron’s team looks to “unleash the power of covalent protein drugs,” the company, which is still in early stages of drug development, will most likely face the challenges that come with creating ADCs.

This might include ensuring that the drug is able to penetrate the tumor microenvironment, overcoming low payload potency, as well as minimizing the possibility of toxic side effects, according to a report published in the National Library of Medicine.

“There’s so much potential with covalent protein drugs, we’re spearheading this. We’re paving the way for this and this is an exciting time for the company. We’re glad to close this round and start building the next generation of protein drugs that enable covalency as a strategy,” said Duron. “We think it’s going to be transformative. We think it’ll be part of the toolbox of biologics drug discovery as we go forward.”

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