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‘Super-antibodies’ could curb COVID-19 and help avert future pandemics Companies are designing next-generation antibodies modeled on those taken from unique individuals whose immune systems can neutralize any COVID-19 variant—and related coronaviruses, too.

he US Food and Drug Administration (FDA) granted Emergency Use TAuthorization (EUA) in late May to sotrovimab, providing a new therapeutic weapon in the fight against SARS-CoV-2— and future coronaviruses with pandemic potential. According to analysts and researchers alike, so-called super-antibodies such as sotrovimab should have an edge over first-generation monoclonal antibody (mAb) therapies for COVID-19 because of their broad neutralization capacity in the face of emerging virus variants. “Physicians aren’t going to sequence what version of the virus people have, so they’ll go for the antibodies that have the higher barrier to resistance or the ones that work on [known] variants,” says Phil Nadeau, an analyst at Cowen. The antibody therapy from Vir Biotechnology and GlaxoSmithKline, a recombinant human immunoglobulin G1 mAb, is now the third mAb-based treatment marketed for individuals with mild-to-moderate COVID-19 who are at high risk for progression to severe disease. (Eli Lilly and Regeneron each Antibodies attacking a coronavirus (artist’s impression). Super-antibodies that can neutralize even the have a two-mAb cocktail with EUAs for most worrying versions of SARS-CoV-2 could be used both to prevent and to treat infections. Credit: the same indication.) And although sales Kiyoshi Takahase Segundo / Alamy Stock Photo opportunities should diminish for all these products as vaccination rates increase worldwide, Nadeau anticipates there will be a sustained market for COVID-19 mAbs as investment money flows in to rush some Sotrovimab traces its roots back to to help treat individuals who, for medical of the leading candidates through late-stage blood drawn in 2013 from an individual reasons, can’t mount an appropriate immune clinical development. In April, for example, who had recovered from the 2003 outbreak response to vaccination or, for whatever Adagio Therapeutics raised $336 million (on of severe acute respiratory syndrome reason, elect not to get the shot. top of the $130 million war chest it amassed (SARS); ADG20 has a similar origin According to his models, sotrovimab last year) to bankroll large-scale trials of story, while most other clinical-stage should capture around 10% of the $3 billion ADG20, an mAb now being evaluated for use mAbs were inspired by antibodies found global COVID-19 mAb market this year, as a therapy and for prevention. Startups such in more recent COVID-19 survivors. rising to 30% of the $1.67 billion market as Centivax, Corat Therapeutics, IDBiologics, Many companies then optimized their in 2022. Leyden Labs, Memo Therapeutics and mAbs by extending half-lives, enhancing Other broadly cross-reactive mAbs could SpikImm are working on next-generation neutralizing activity, manipulating constant soon be jockeying for market share as well, mAbs for COVID-19 as well. region (Fc)-mediated effector functions,

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or applying some combination of these help destroy infected cells—and those Novavax’s fridge-friendly engineering strategies. Fc-mediated activities, Virgin says, “are vaccine impresses To stay relevant, all mAb developers fundamentally important for treatment of Novavax has unveiled results from need to account for the wildcard that is SARS and COVID-19.” a large clinical trial showing that viral evolution, says Jane Osbourn, CSO Mouse studies published in Cell, in the its vaccine is 90.4% effective in of Alchemab and former head of the UK Journal of Experimental Medicine and as a preventing symptomatic COVID-19 BioIndustry Association’s antibody taskforce preprint in recent months now support this and 100% protective against moderate on COVID-19. “A number of the clinical idea. But last year, as the COVID-19 mAb and severe disease. Results from candidates out there are falling over against race was just heating up, many companies— the phase 3 PREVENT-19 trial with the [emerging] variants,” she says. “So, as a including AstraZeneca, Eli Lilly, Abpro and 30,000 participants across the United community, we should really be taking the others—chose instead to dial down effector States and Mexico had been eagerly time to think through how you stay ahead of functions in their mAbs. They wanted to awaited for the vaccine’s presumed the game in terms of that mutational drift.” minimize the risk of antibody-dependent advantages over existing jabs. Unlike the In lab studies, sotrovimab seems to enhancement of viral infection, a approved Pfizer, Moderna and Oxford/ maintain its neutralization capacity against phenomenon in which virus-specific AstraZeneca vaccines, NVX-CoV2373 is all circulating variants of concern, including antibodies can promote, rather than a protein-based vaccine that relies on a some of the most worrying versions of the inhibit, disease. well-established, traditional approach and virus, first identified in South Africa, Brazil This can be a real problem with certain is expected to have a benign safety profile. and India. Several of the leading phase pathogens, including the respiratory It can also be stored in refrigerators, a 3 mAb candidates—including Adagio’s syncytial virus and the dengue virus, but practical advantage that could boost ADG20, AstraZeneca’s AZD7442 and Brii Virgin and his colleagues realized early distribution to low- and middle-income Biosciences’ BRII-196 and BRII-198—do on that it did not seem to be an issue with countries. The Novavax vaccine also as well. But Eli Lilly’s two-mAb cocktail is SARS-CoV-2. So Vir doubled down on the appears to protect against escape by hobbled by escape mutations found in these need for strong Fc receptor binding. Not only variants. The trial data were collected variants, as is one of the agents, casirivimab, did the company leave the effector functions between January and April 2021, when in Regeneron’s mAb combination. The intact for sotrovimab, but it also engineered the Alpha (B.1.1.7) variant, first identified other Regeneron agent, imdevimab, retains its successor, the follow-on mAb VIR-7832, in the United Kingdom, became the main its activity, in large part because the mAb to have even greater Fc binding activity. strain circulating in the United States. targets an epitope that does not overlap with “The concept is to make the antibody The vaccine proved to be 93% effective in that of its cocktail companion. vaccinal,” explains Virgin. “We’re trying to preventing symptomatic disease caused That non-redundancy offers some degree make the antibody so it not only protects the by variants of concern circulating during of protection against variant-mediated individual, but it also generates an immune that period. Against symptomatic disease resistance, says Aeron Hurt, principal global response that outlasts it” through the caused by the Beta mutation, an earlier medical science director for influenza generation of pathogen-specific CD4+ and study conducted in South Africa revealed and COVID-19 therapeutics at Roche, CD8+ T cells responses. The Vir team joined a lower 51% efficacy among HIV-negative which partnered with Regeneron to handle forces last year with Jeffrey Ravetch’s lab at participants. It is unknown whether it manufacturing and distribution outside of Rockefeller University in New York City to can protect against the Delta variant, first the United States. “Single antibodies are demonstrate the Fc engineering concept identified in India, as that was unlikely vulnerable to single mutations,” Hurt says— with an anti-influenza mAb tested in mice. to be circulating during the study period. whereas a cocktail of antibodies that bind NVX-CoV2373 is a MatrixM-adjuvanted at discrete sites provides “an extra “The concept is to make the recombinant nanoparticle vaccine insurance policy.” antibody vaccinal.” engineered from the spike protein genetic But an even better variant evasion sequence of the original SARS-CoV-2 tactic, asserts Adagio CSO Laura Walker, “These are predicted benefits. They strain. Phase 3 results were announced is what her company and Vir have done: haven’t been observed in people,” Virgin in a company press release and have both organizations independently screened acknowledges, “but that’s why we’re taking yet to be published in a peer-reviewed for ultra-rare broadly neutralizing mAbs the antibody forward.” VIR-7832 and journal. At the same time, another highly that recognize highly conserved epitopes sotrovimab—both of which possess an Fc anticipated COVID-19 shot, CureVac’s found across the entire family of SARS-like mutation that confers extended half-life and mRNA vaccine CVnCov, failed to meet coronaviruses. enhances drug distribution to the lungs—are preset success criteria, delivering only The scarcity of these antibodies limits the now part of a master protocol study taking 47% efficacy against symptomatic evolutionary selection pressure for escape place in the United Kingdom. disease in a phase 2/3 trial, according mutations in nature, Walker points out. And Adagio, for its part, has focused its to an interim analysis released by the because conserved residues typically serve engineering efforts largely on affinity company. CureVac says there were at essential protein functions, “the virus often optimization rather than Fc modifications. least 13 variants circulating in the study can’t mutate those residues without suffering Although ADG20, like many other population during the analysis, which a fitness cost,” she says, “which means the next-generation mAbs, does contain Fc may have reduced the vaccine’s efficacy. barrier to escape is typically higher for these changes that improve its circulation half-life, The German biotech still plans to file for broadly neutralizing antibodies.” its most distinguishing selling point is the European approval. “But antibodies are not merely things combination of potency and breadth that that bind to and neutralize a viral protein,” it offers. Published online: 13 July 2021 notes Vir CSO Skip Virgin. Through “We took something from nature that https://doi.org/10.1038/s41587-021-00991-8 their Fc domain, mAbs also induce innate was broad, but not very potent, and then and adaptive immune responses that improved the potency while maintaining the

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breadth to essentially make a molecule that with €40 million ($49 million) to support a would never arise in nature,” explains Walker. portfolio of intranasal products that protect First Parkinson’s patients Walker and her colleagues started with against respiratory viruses such as influenza dosed with dopaminergic a natural mAb made in response to a 2003 and SARS-CoV-2. SARS infection. They then used yeast display According to Dinko Valerio, co-founder neurons technologies to introduce diversity into the and executive chairman of Leyden Labs, the A clinical study launched in June will parent clone, ultimately finding an offshoot company’s nasal spray is designed to thwart be the first to test whether transplanted with a handful of genetic changes that gave viral replication at the site of infection. And dopamine-producing neurons can it 500-fold greater binding affinity to the because of its localized delivery, patients can restore brain regions and motor function SARS-CoV-2 spike protein and a 70-fold get away with much lower doses than they lost to Parkinson’s disease. BlueRock improvement in neutralization capacity— would otherwise need for any systemically Therapeutics, a company wholly owned with no compromise in its breadth of activity administered agent. “If you put it in the by Bayer AG, initiated the phase 1 across other SARS-related coronaviruses. nose,” Valerio says, “you just need a tiny bit” study to test DA01 cells, dopaminergic In phase 1 testing, clinicians found that of the product. neurons derived from human embryonic a single dose of ADG20 yielded a similar Whatever the mechanism of mAb stem cells, by surgically transplanting level of virus-neutralizing activity in the delivery, the fact that so much development them into the putamen, the brain area blood as that seen among people vaccinated and therapeutic experimentation is affected by Parkinson’s disease. The aim against COVID-19 with one of the marketed happening today in response to COVID-19 is for the DA01 cells to replace the lost mRNA-based products. Pharmacokinetic should improve preparedness for the dopaminergic neurons, stopping and profiling also indicated that the protection future. Not only are there now products reversing the degenerative process. The might last for up to a year. Two large global like sotrovimab on the market that offer trial will assess safety and tolerability of trials are ongoing. broad protection against a viral clade that the stem-cell-derived therapy after one ADG20, like some other late-stage could easily seed the next outbreak, but the year, as well as the transplant’s survival and candidates such as AZD7442, also engineering approaches being tried now to any benefits to motor control. Eventually, offers the convenience of intramuscular combat coronaviruses should help inform BlueRock’s commercial product will injections—a formulation advantage that best practices for creating mAbs designed to likely be derived from human induced Janice Reichert, executive director of the thwart other viral families. pluripotent stem cells because such cells non-profit Antibody Society, argues can “It’s good for public health that all are easier to standardize. be just as important as innovative mAb these strategies are being tested,” remarks Neuroscientist Lorenz Studer and designs in the throes of a pandemic or other James Crowe, director of the Vanderbilt colleagues at Memorial Sloan Kettering public health crisis. “Having both would Vaccine Center in Nashville, Tennessee. Cancer Center developed the protocol be best, of course,” she adds. All the mAbs (A co-founder of IDBiologics, Crowe helped for differentiating pluripotent cells into that already have EUAs must be given discover the mAbs that form the basis of two dopaminergic neuron-like cells. Studer intravenously, although versions formulated cocktail therapies now in clinical testing, is a co-founder of the New York–based for intramuscular or subcutaneous AZD7442 from AstraZeneca and another one BlueRock, which launched in 2016 and administration are now in clinical testing. from Resilience with support from the US was acquired three years later by Bayer Some companies are beginning to Department of Defense.) “It’s very exciting for $1 billion in up-front and milestone explore inhaled delivery as well. Boehringer scientifically that COVID has allowed this payments. In parallel, and as part of its Ingelheim, for example, is evaluating many manufacturers to participate,” he ‘cell + gene’ strategy, Bayer is taking both infused and inhaled versions of says. “Every target is different, but you can a gene therapy program for treating its phase 2 mAb before deciding which typically learn some general principles.” ❐ Parkinson’s disease into the clinic through administration route to advance into pivotal its wholly owned subsidiary Asklepios testing. On 3 June, scientists from IGM Elie Dolgin BioPharmaceutical (AskBio). AskBio was Biosciences described promising mouse Somerville, MA, USA founded in 2001 by Jude Samulsky and data on their nasally spritzed product, the Sheila Mikhail. The phase 1 trial is testing immunoglobulin M mAb IGM-6286. And Published online: 22 June 2021 an adeno-associated virus serotype-2 earlier this year, Leyden Labs launched https://doi.org/10.1038/s41587-021-00980-x (AAV-2) to deliver human glial cell line-derived neurotrophic factor (GDNF) genes to neurons in the putamen to promote regeneration of midbrain neurons. BlueRock is also working to develop futuristic gene-circuit-engineered cell therapies with Senti Biosciences. On 26 May, the companies announced a collaboration to design gene circuits with Senti’s Smart Sensors and Regulator Dials to detect and distinguish between a diseased and a healthy cellular environment and respond by fine tuning the therapeutic activity from a cell or gene therapy product, even inside the patient.

Published online: 13 July 2021 https://doi.org/10.1038/s41587-021-00992-7

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