Tillman Gerngross, PhD, Adagio Therapeutics co-founder and CEO

Six months after launching, then raising $130 million in two financing rounds, Adagio Therapeutics is heading into the clinic with an antibody that has shown promise against not only COVID-19 but also other coronaviruses, including SARS-CoV-1 (SARS-CoV) and MERS.

Adagio, a spinout of Adimab launched in July, filed November 30 for an IND with the FDA for ADG20. The antibody was engineered to confer a longer duration of protection than its precursor ADG2 by extending the antibody’s serum half-life.

“We expect to be in the clinic before the end of the year,” co-founder and CEO Tillman Gerngross, PhD, told GEN—a little sooner than the early 2021 timeframe announced by the company just last month.

The IND filing came some two weeks after Adagio researchers posted a bioRxiv preprint, “An Engineered Antibody with Broad Protective Efficacy in Murine Models of SARS and COVID-19,” reporting that a precursor to ADG20 successfully offers complete protection against severe SARS-CoV-2 and SARS-CoV in mouse models.

ADG2 showed broad and potent neutralization against a range of viruses posing a threat to humans—SARS-CoV-2, SARS-CoV, and two SARS-related coronaviruses known to circulate in bat populations, WIV-1 and SHC014. ADG2 performed best of three Adagio antibodies evaluated in the pre-publication.

And in a series of in vitro assays, ADG2 also demonstrated favorable biophysical properties predictive of downstream behaviors such as serum half-life, ease of manufacturing, ability to formulate to high concentrations, and long-term stability.

“ADG2 represents a promising candidate for the prevention and treatment of not only COVID-19 but also future respiratory diseases caused by pre-emergent SARS-related CoVs,” the researchers concluded.

According to Adagio, the epitope targeted by ADG2 is highly conserved across clade 1 sarbecoviruses—the viral subgenus that contains SARS-CoV-2 and SARS-CoV. ADG2 binds tightly to a large panel of clade 1 sarbecovirus receptor binding domains (RBDs). ADG2 was also shown to bind with high affinity to the 30 most frequently observed SARS-CoV-2 RBD variants reported in the GISAID database, including variants resistant to other monoclonal antibodies in development.

“Our view was, it’s great to have a treatment for this particular outbreak, but why not aim a little bit higher and figure out a way of finding antibodies that neutralize the entire clade of coronaviruses that target human ACE2?” Gerngross said, referring to angiotensin-converting enzyme 2.

“Unlike an antibody that only treats SARS-CoV-2, we were aiming for something that covered SARS-CoV-2, covers SARS, and then goes into the animal reservoir and looks for viruses that are present in animals that are pre-pandemic or pre-emergent, and make sure that we neutralize those as well. That was the difference. We set the bar higher. That took longer to engineer.”

“Protection for over a year”

According to the study, in the more than 152,000 full length viral genomic sequences of SARS-CoV-2 included in the GISAID database as of October 19, no mutations had been reported at key ADG20 contact residues—a finding that according to Adagio suggests a low risk of pre-existing resistance to ADG20 in the clinic.

“In our antibodies, with the half-life extension and potency, we think we have protection for over a year,” Gerngross said. “That’s very compelling vis-a-vis vaccines, because at this point, we don’t know how long [the protection of] vaccines will last.”

Both of the leading COVID-19 vaccine candidates—BNT162b2 (Pfizer and BioNTech) and mRNA-1273 (Moderna)—have generated rates of 95% efficacy and 94.5% efficacy, respectively. “These 90-plus percent numbers are really very encouraging,” Gerngross observed, “but what we’re seeing is the titers are coming down. So now we don’t know: Is the protection gone in three months, four, five, six months, a year? We don’t know.”

The bioRxiv preprint also reported that in two neutralization assays, the precursor antibody ADG2 showed similar or higher potency against SARS-CoV2 compared to three monoclonal antibodies being developed against COVID-19: Etesevimab (also known as LY-CoV016 or JS016), licensed by Eli Lilly from Junshi Biosciences; REGEN-COV2 (casirivimab and imdevimab), Regeneron Pharmaceuticals’ two-antibody “cocktail” authorized for emergency use on November 21 by the FDA; and S309, a precursor to two antibody candidates being developed by Vir Biotechnology and GlaxoSmithKline (GSK; VIR-7831/GSK4182136 and VIR-7832).

Among the two Adagio antibodies studied with ADG2, ADG3 was similar to S309 in cross-neutralizing all four sarbecoviruses studied, but with lower potency than ADG2. ADG1 potently neutralized SARS-CoV-2, SARS-CoV, and WIV1, but lacked activity against SHC014.

Etesevimab is Lilly’s second antibody in development against COVID-19. The first is bamlanivimab (LY-CoV555), which Lilly developed through a partnership with AbCellera that has since expanded to a potential nine Lilly-selected therapeutic targets. As with Regeneron’s cocktail, bamlanivimab also received FDA emergency use authorization (EUA) last month.

Gerngross said ‘016 was studied because at the time the study was being conducted, its sequence was available for comparison, and bamlanivimab’s was not. Adagio has since gathered data on bamlanivimab.

Beyond SARS-CoV-2

Gerngross is also the co-founder and CEO of Adimab, a Lebanon, NH-based technology provider focused on discovery and optimization of fully human monoclonal and bispecific antibodies. Since it was founded in 2007 by Gerngross and another pioneer in yeast biotechnology, K. Dane Wittrup, PhD, of MIT, Adimab has worked on more than 350 drug discovery campaigns, of which 41 have advanced into the clinic.

Soon after COVID-19 emerged, Adimab’s director of antibody sciences, Laura Walker, PhD, suggested to Gerngross a more expansive approach to fighting the virus. Walker leads a group at Adimab that has focused on the discovery and optimization of antibodies using yeast library technology and single B cell cloning.

Walker is the corresponding author of the bioRxiv preprint—as well as an earlier study published in August in Science. The earlier study used a blood sample from a person infected with SARS in 2003 to identify eight antibodies targeting the domain that binds to ACE2—all of which neutralized SARS-like WIV-1 coronavirus without leaving any viral fraction.

“It was her idea to say, ‘Let’s not just also develop another neutralizing anybody against SARS-CoV-2,’ but to ask, ‘What’s the real problem here?’ The real problem was a much more systemic problem of beta coronavirus family members being able to target ACE2 to get into humans,” Gerngross recalled. “It was really her insight that then led to the development of the molecules. And once we have the molecules, we’re just not a development organization. We are a drug discovery company. So, that’s when we decided, let’s spin out the asset. Let’s hire some really competent drug development people.”

In late June, Gerngross led a group of executives from inside and outside Adimab in spinning out Adagio, transferring to it all of Adimab’s coronavirus-related assets. Among the executives was Walker, who joined Adagio as co-founder and CSO. Adagio has since grown its workforce to about 30 people—a staff that is “probably going to double” over the next year, Gerngross said.

Future funding

Next year, Adagio anticipates seeking to raise additional capital beyond the $130 million in financing it has already garnered—first through an additional financing, then by going public.

“We need to build inventory for a potential launch in 2022, and that’s going to be in the tens of millions of dollars. We will be going out to the capital markets again early in the year,” Gerngross said. “As soon as we’re in the clinic, we’ll launch our Series C crossover round to raise more capital to finance that.”

About 90% of the money raised by Adagio so far has gone into clinical manufacturing, inventory building, and paying for clinical trials directly. The company launched on July 16 with a $50-million Series A financing led by Polaris Partners and Mithril Capital, with other investors including Fidelity, OrbiMed, M28 Capital, and GV (formerly Google Ventures).

GV stepped up its investment in Adagio last month, leading the company’s $80-million Series B round. Joining GV were existing investors Polaris, Mithril, Fidelity, and OrbiMed, as well as two new investors, Population Health Partners and Omega Funds. “We told them (GV) the story, and really laid out the historic case for the problem, and the historic case is just remarkable,” Gerngross said.

That story, he said, stretches back to research published in 2015 by Ralph S. Baric, PhD, of UNC Gillings School of Global Public and Shi Zhengli, PhD, of the Wuhan Institute of Virology about coronaviruses originating in bats that posed potential harm to humans. In July, Shi—nicknamed the “Bat Woman” by Chinese state-owned media—denied assertions by President Donald Trump that SARS-CoV-2 escaped from the Institute, with Shi telling Science that the contention “totally contradicts the facts. It jeopardizes and affects our academic work and personal life. He owes us an apology.”

“When there is no pandemic, nobody gives a shit. When there’s a pandemic, all of a sudden, people pay attention,” Gerngross said. “So, if you don’t do it now, and if you don’t put in place the measures to prevent this in the future now, where there is a high public alertness and interest by politicians, at least in functioning democracies, then we’re not going to get it done. So, I think this is the time to do it.”

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