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‘Clicked’ drugs: researchers prove the remarkable chemistry in humans

July 6, 2023
in Science
‘Clicked’ drugs: researchers prove the remarkable chemistry in humans
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Bioorthogonal click chemistry is being used in patients to help target cancer medicines and diagnostic imaging agents

Click chemistry therapeutics are increasingly drawing attention from investors and big pharma. Shasqi announced in June that it is collaborating with Johnson & Johnson Enterprise Innovation to develop cancer therapies that use click chemistry to target tumors. The deal follows a recent success for Shasqi’s click-activated drug delivery system, which has passed the first human safety trials and is now in a phase 2 clinical trial. Other groups are also preparing to test click chemistry in the clinic, raising hopes that the technique could overcome some of the limitations of existing targeting approaches such as antibody–drug conjugates.

Tagworks’ MMAE delivery in mice. Adapted from Rossin, R. et al. Nat. Commun. 9, 1484 (2018).

Click chemistry has become an indispensable tool in biological research and drug discovery, and its pioneers won last year’s Nobel Prize in Chemistry for their work. “Those chemistries are all over the place in the biopharma industry,” says Carolyn Bertozzi of Stanford University, one of the prize winners, who is also a scientific advisor to Shasqi. “What Shasqi has done here is broken through the glass ceiling of actually doing the chemistry in the human patient.”

The approach involves reactions that quickly snap two complementary molecules together. Because the components only react with each other and ignore other molecules, some of these reactions can operate inside biological environments without disrupting the biochemistry around them — what is known as ‘bioorthogonal’ chemistry.

To translate the click concept into therapeutic or diagnostic agents, researchers can tag patients’ cells or tissues with a click-chemistry molecule and then inject a drug or imaging agent linked to its complementary click partner. When the two click molecules bind together, it ensures that the payload reaches only the desired target.

Shasqi’s phase 1 trial of its click-activated tumor therapy, which began in 2020, was the first to deploy click chemistry in humans. But other groups are now making progress, too. Researchers at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York recently opened a phase 1 trial of a targeted positron emission tomography (PET) imaging agent that relies on click chemistry. And Tagworks Pharmaceuticals in Nijmegen, the Netherlands, tells Nature Biotechnology that it has just raised $64.1 million in series A funding, which the company will use to support a phase 1 trial of its own click chemistry-based cancer therapy.

Researchers are optimistic that, if these trials go well, it could pave the wave for a range of other clinical applications for click chemistry. “I don’t think we’ve even scratched the surface on this,” says Jason Lewis at MSKCC, one of the leaders of the PET trial.

The concept of click chemistry was first outlined about 20 years ago Barry Sharpless at Scripps Research, La Jolla, California, and it wasn’t long before he and Morten Meldal of the University of Copenhagen independently developed the first click reaction. It was fast, reliable and produced no by-products — but it also relied on a copper catalyst that is toxic to cells. At Stanford, Bertozzi developed a copper-free click reaction that could work inside living organisms without disrupting cell chemistry. All three scientists shared the 2022 chemistry Nobel.

Yet even faster click reactions were needed for targeted drug delivery in humans. This is because the active agents are enormously diluted in the body, and at these low concentrations most click reactions are too slow to deliver a payload in a therapeutically useful timescale. A breakthrough arrived in 2008, when two groups, at the University of Delaware and Massachusetts General Hospital/Harvard Medical School, independently invented the tetrazine ligation — a fast reaction that snaps together a nitrogen-rich tetrazine with a partner containing a strained carbon–carbon double bond. Shasqi, Tagworks and the MSKCC team are all using versions of this reaction that employ tetrazine and trans-cyclooctene (TCO) as the click partners.

Once a drug has found its target, it must be freed from its click partner so that it can get to work. To achieve that, Tagworks developed a variant of the tetrazine ligation that it calls ‘click to release’. In this system, the click partners are designed so that when tetrazine and TCO click together, it triggers a follow-on reaction called a carbamate decomposition that releases the drug.

For clinical applications, the tetrazine ligation can be deployed in a variety of different ways. Shasqi’s trial uses a sodium hyaluronate biopolymer, which is peppered with tetrazine groups, and a prodrug containing the anticancer agent doxorubicin linked to TCO. Clinicians inject the tetrazine-bearing polymer into a patient’s tumor site and then follow up with five daily intravenous infusions of the prodrug. When the two meet and click together, it releases doxorubicin via the carbamate decomposition reaction, delivering the cancer drug to the tumor.

Shasqi’s prodrug overcomes doxorubicin’s main drawback: toxicity. Doxorubicin has been used for over 40 years to treat solid tumors, but its toxicity limits the amount that can be given per dose, as well as the overall lifetime dose. In contrast, the prodrug is about 80 times less toxic than doxorubicin itself, which avoids systemic side effects. Click-activation of the prodrug also generates high concentrations of doxorubicin at the tumor site that would be impossible using a conventional treatment. In a mouse model of colorectal cancer, the therapy increased survival by 63% compared with doxorubicin alone).

The phase 1 trial involved 40 patients with advanced or metastatic solid tumors. Results from the first 22 patients showed that each cycle of prodrug injections could deliver 12 times the conventional tolerable dose of doxorubicin into patients’ tumors, with manageable toxicities and side effects. Data presented in April at the American Association for Cancer Research meeting in Orlando, Florida, identified increases in cytotoxic T cell activity in patients, suggesting that the doxorubicin was working as expected. Shasqi has already dosed almost a dozen patients in a phase 2 follow-on trial and expects to complete the first past of this trial by the end of 2024.

Biopharma companies can already deliver tumor-targeting toxic agents using antibody–drug conjugates (ADCs). These combine a monoclonal antibody — which offers exquisite specificity in targeting receptors on cancer cells — linked to a cytotoxic agent that provides killing prowess. But these ADCs have some limitations: they typically rely on biological agents inside tumor cells, such as proteases, to break apart the conjugate and release the drug payload, and the approach is constrained by the type of receptors that can be targeted. “All these other approaches are based on biology, on what the tumor offers you,” says José Mejía Oneto, founder and CEO of Shasqi. “We’re trying to make it based on chemistry.” Click reactions not only offer alternative drug release profiles, he says, but should also mean that results are more consistent when translated from animal models to humans.

Bertozzi says she’s excited about Shasqi’s trial because “there’s a potentially enormous benefit for our patient population. But if the details get worked out and optimized in that setting, there’s lots of other cancer applications as well.’

One example is MSKCC’s phase 1 trial, which plans to use click chemistry to improve PET imaging of tumors using a radioisotope. (As Nature Biotechnology went to press, the trial was open but had not yet recruited its first patient.)

Radiolabeled antibodies are already widely used for diagnostic imaging. They have some drawbacks, however. It can take several days for enough antibody to accumulate on the target, and even longer for unbound conjugate to clear from the body — both essential to produce a decent image. That rules out using many short-lived isotopes that could otherwise be used in PET, which may have half-lives of mere minutes or hours. “We’re trying to take advantage of the incredible specificity of antibodies for their target, but overcoming their limitations with click chemistry,” says Lewis, who developed the approach with Brian Zeglis at Hunter College of the City University of New York.

Their strategy is to put the targeting antibody in place first, before introducing the PET radioisotope. During the trial, clinicians will inject patients with a monoclonal antibody called hu5B1 that has been modified with a click-chemistry TCO group. This antibody latches on to the CA 19-9 antigen found on pancreatic cancer cells. When a tetrazine-based molecule that carries copper-64 is injected into the bloodstream, it clicks with the TCO on the tumor cells within minutes. With the isotope locked in place, a PET scan reveals the cells’ locations in the body. In principle, “a patient could get the antibody injected during a regular doctor’s visit, then come back the following week to get injected with the radioactive part and generate an image within an hour,” says Lewis.

This approach could also be used to blast a tumor with radiotherapy after it had been imaged. Preclinical studies in mice showed that after using copper-64 for PET imaging, sufficient antibody–TCO remains on the tumor cells to then inject a tetrazine that carries copper-67, which emits beta particles to kill the targeted cells. “It’s chemically identical — we just change from a diagnostic isotope to a therapeutic isotope,” says Lewis.

The phase 1 MSKCC trial aims to determine the safety of the system, the best ratio of components, and the ideal time for imaging. If successful, Lewis hopes to incorporate the second therapeutic isotope stage into a follow-on phase 2 trial. The hu5B1 antibody used in the trial is licensed to BioNTech of Mainz, Germany, but Lewis points out that the system could easily use other antibodies for different targets or bind other imaging or therapeutic radioisotopes.

Tagworks is also developing click-assisted radioimaging agents, but its main focus is on targeted therapeutics. Its leading candidate contains an antibody fragment that targets tumor-associated glycoprotein 72, which is expressed on many adenocarcinomas. The antibody fragment is linked to monomethyl auristatin E (MMAE), a drug with much greater anticancer activity than doxorubicin that is also highly toxic. MMAE is used in ADCs such as Takeda’s Adcetris (brentuximab vedotin) to treat certain lymphomas.

In Tagworks’ system, the chemotherapeutic agent MMAE is connected to the antibody via a TCO-based linker. After first administering this ADC to a patient and allowing it to bind to tumor cells, doctors would inject a tetrazine to trigger a click-to-release reaction that frees MMAE. The approach has already shown success in mouse models of colorectal and ovarian cancer. Tagworks spent several years honing the chemistry of its click molecules to make sure that they offer the right balance of stability and reactivity. “We have a very high-performing system now that we believe will be the platform for most future applications,” says Marc Robillard, CEO of Tagworks.

Robillard hopes that using click chemistry in this way will allow them to go after a much broader range of cancer targets because they no longer have to rely on the foibles of cancer biology to release the drug. And in contrast to Shasqi’s current trial, which uses a physical injection to target a particular tumor site, Robillard says that using antibodies to put a click molecule in place means they can attack cancer cells anywhere in the body that bear a suitable target receptor.

Having raised sufficient funding from a syndicate of five US and European venture capital partners, Tagworks is now conducting animal studies that will pave the way for a phase 1 trial.

Shasqi is also working with a clickable MMAE prodrug, albeit in a different configuration than Tagworks, and has recently published promising results from a mouse model of gastric cancer. The company plans further animal studies and hopes to take a clickable MMAE prodrug into a phase 1 trial in the future. “We’ve already done one, and I’m pretty sure we can do it again,” says Mejía Oneto.

Aside from delivering targeted therapeutics and imaging agents, some researchers think that click chemistry might enable other strategies, such as assembling large drug molecules inside patients. “That was always my biggest fascination with the concept — the idea that you could make a drug [inside humans] on demand,” says Neal Devaraj at the University of California, San Diego, one of the researchers who developed the tetrazine ligation and who now consults for Shasqi.

This approach could be particularly useful for delivering bulky drugs into otherwise inaccessible tissues. “If you want to have a big bookcase in a room and you can’t get it through the door, you go to Ikea and buy it in parts and assemble where you want it,” says Joseph Fox at the University of Delaware, who also developed the tetrazine ligation.

Devaraj cautions, however, that expanding click chemistry agents into the clinic still faces serious hurdles. “I think the biggest challenge is that you need two things rather than one,” he says. “It’s already hard enough to develop one component into a drug — now imagine you have to do two of these things. Obviously, it becomes trickier.”

Still, last year’s Nobel Prize has helped to raise the profile of the technique and stimulated interest from pharmaceutical companies, says Fox. “Bringing that awareness to the broader biomedical community has been one of the many great things that’s come out of the Nobel Prize.”

“It’s great, because now I don’t have to tell people what the chemistry is,” adds Mejía Oneto. “People recognize we’re working on a Nobel Prize-winning technology.”

>>> Read full article>>>
Copyright for syndicated content belongs to the linked Source : Nature.com – https://www.nature.com/articles/s41587-023-01860-2

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