Adintrevimab: Cure for All Mutant Variants of SARS-CoV-2

Highlights

Adagio Therapeutics has notified that the monoclonal antibody adintrevimab (ADG20) that it is developing against the new coronavirus SARS-CoV-2 will maintain adequate neutralizing activity against the Omicron variant (B.1.1.529), which is listed as “variant of concern” by the World Health Organization (WHO).

Adagio is going to test this claim, but adintrevimab does appear to be effective against any currently known SARS-CoV-2 mutation, including the highly contagious Delta variant and the as yet thoroughly unexplored Omicron variant.

Adintrevimab, unlike other monoclonal antibodies against SARS-CoV-2, targets its epitope, which is highly conserved, immunoreactive, and not an easy target for endogenous neutralizing antibody response.

Adagio is developing adintrevimab with the goal of putting an effective cure in human hands that takes into account any future variants of the SARS-CoV-2.

If all goes well, adintrevimab will be commercially available in the second half of 2022. Adagio hopes that a single intramuscular injection of adintrevimab will be enough to reliably and durably (at least 6 months) prevent the development of symptomatic COVID-19 infection and to treat it if it does occur.

Despite the availability of many vaccines, there is still a high unmet need for drugs that can reverse the course of the COVID-19 pandemic.

 

Update #1

In mid-December 2021, Adagio reported that adintrevimab did not work against the Omicron variant. When this monoclonal antibody was tested in vitro on the coronavirus itself and in a pseudovirus system, adintrevimab’s neutralizing activity against Omicron dropped by more than 300 times. Adagio believes the failure is due to an abundance of mutations in the Omicron’s S protein, a combination of which helps the variant evade adintrevimab. ADG10, another experimental monoclonal antibody, also failed at suppressing Omicron. The disappointing news collapsed Adagio’s stock price by 75%.

 

Update #2

 A month later, in mid-January 2022, Adagio announced that a follow-up test confirmed adintrevimab’s efficacy against Omicron. The neutralizing activity of adintrevimab is said to be comparable to that of the few other monoclonal antibodies that have demonstrated efficacy against this variant of coronavirus.

Thus, the half-maximal inhibitory concentration (IC₅₀) of adintrevimab is 0.4–1.1 µg/ml, which compares with that of sotrovimab and Evusheld (AZD7442) as a combination of tixagevimab (AZD8895) and cilgavimab (AZD1061) developed respectively by GlaxoSmithKline/Vir Biotechnology and AstraZeneca.

 

What is Adintrevimab

Adintrevimab (ADG20) is a fully human IgG1 monoclonal antibody targeting the highly conserved epitope on the receptor-binding domain (RBD) of S (spike) protein of SARS-CoV-2. Due to its modified Fc region, adintrevimab is characterized by a long elimination half-life.

Adintrevimab is derived from memory B-cells’ antibodies of a patient who survived a severe acute respiratory syndrome caused by the SARS-CoV-1 coronavirus of 2003.

Adintrevimab is claimed to exhibit broad in vitro neutralizing activity against not only the new coronavirus SARS-CoV-2 but also other SARS-like coronaviruses of the Sarbecovirus subgenus, which penetrate host cells through high affinity for angiotensin-converting enzyme 2 (ACE2) and which have pandemic potential.

The uniqueness of adintrevimab targeting is such that it binds with high affinity to the RBD of multiple SARS-like coronaviruses at very low dissociation constants: from 0.24 to 1.12 nM. Monoclonal antibodies already commercialized (or about to be commercialized) and approved for the treatment of COVID-19 cannot do so. Thus, the protein-ligand binding dissociation constant for sotrovimab, imdevimab, casirivimab, etesevimab, and bamlanivimab is several times higher.

Adintrevimab retains high binding affinity (> 50% wild-type RBD) for currently circulating SARS-CoV-2 variants.

Adintrevimab exhibits neutralizing activity against strains of SARS-CoV-2 that are classified by the WHO as “variants of concern”, such as Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2), and its half-maximal inhibitory concentration (IC₅₀) is at or below that of other monoclonal antibodies.

Adintrevimab also works against new variants of SARS-CoV-2, including Delta plus (AY), Lambda (C.37), and Mu (B.1.621).

 

Prospects for Adintrevimab

Adintrevimab is in two phase 2/3 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trials, STAMP (NCT04805671) and EVADE (NCT04859517), which evaluate its potential in respectively treating and preventing COVID-19.

The STAMP invites adult volunteers infected with SARS-CoV-2 and with manifestation of mild-to-moderate COVID-19 symptoms no later than 5 days before randomization. Participants must be at high risk of progression to severe disease with hospitalization or death.

The EVADE recruits volunteers aged 12 years or older who have not previously had COVID-19 and who are at high risk of getting it: for example, from family members, the same household, a place of recreation, or work.

According to Adagio, adintrevimab will find use among four different subgroups of patients: to treat newly diagnosed COVID-19, for post-exposure prophylaxis of SARS-CoV-2 infection in the unvaccinated ones, as a supplement to vaccination, and for pre-exposure prophylaxis of infection in the unvaccinated ones.