"DYNAMIC DUO TO SAVE HUMANITY FROM EVIL BAT VIRUS" would make a good headline in the Daily Planet. Unfortunately for humanity, while the bat virus is real the Caped Crusader and his sidekick are not. OK, while some will go to their grave insisting that the virus is imaginary, most people believe that it exists and is a serious threat to human life.
Confession: this is a long post, but the story merits it IMO. It's not about super-heroes but super-antibodies, in particular a dynamic duo designed to solve problems that beset earlier monoclonal antibody combinations targeting the Covid virus.
The slightly more realistic headline "SUPER ANTIBODIES COULD CURB COVID-19 AND HELP AVERT FUTURE PANDEMICS" appeared a month ago in the journal Nature Biotechnology nature.com/articles/s41587-...
"...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... The antibody therapy [Sotrovimab] 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...And although sales opportunities should diminish for all these products as vaccination rates increase worldwide, Nadeau anticipates there will be a sustained market for COVID-19 mAbs to help treat individuals who, for medical reasons, can’t mount an appropriate immune response to vaccination or, for whatever reason, elect not to get the shot."
For CLL patients, access to effective super-antibodies could be a game-changer, giving us a similar level of protection enjoyed by the majority of folk vaccinated against Covid.
Sotrovimab, aka VIR-7831, is the leading super-antibody at the moment, being authorised for use in the USA and the European Union.
"The EMA, following the completion of its review of the mAb, has concluded that VIR-7831 can be used for the treatment of confirmed COVID-19 in adults and adolescents aged 12 years and older who are at risk of progressing to severe disease and who do not require supplemental oxygen... The recommendations come following a review of data, including from a study evaluating the effects of VIR-7831 in adult outpatients with mild COVID-19 symptoms... VIR-7831 reduced the risk of hospitalisation for more than 24 hours or death by 85% compared to placebo". pmlive.com/pharma_news/ema_...
Nature Biotechnology again:
"In lab studies, sotrovimab seems to maintain its neutralization capacity against all circulating variants of concern, including some of the most worrying versions of the virus, first identified in South Africa, Brazil and India. Several of the leading phase 3 mAb candidates—including Adagio’s ADG20, AstraZeneca’s AZD7442 and Brii Biosciences’ BRII-196 and BRII-198—do as well. But Eli Lilly’s two-mAb cocktail is hobbled by escape mutations found in these variants, as is one of the agents, casirivimab, in Regeneron’s mAb combination. The other Regeneron agent, imdevimab, retains its activity, in large part because the mAb targets an epitope that does not overlap with that of its cocktail companion.
But an even better variant evasion tactic, asserts Adagio CSO Laura Walker, is what her company and Vir have done: both organizations independently screened for ultra-rare broadly neutralizing mAbs that recognize highly conserved epitopes found across the entire family of SARS-like coronaviruses.
The scarcity of these antibodies limits the evolutionary selection pressure for escape mutations in nature, Walker points out. And because conserved residues typically serve essential protein functions, “the virus often can’t mutate those residues without suffering a fitness cost,” she says, “which means the barrier to escape is typically higher for these broadly neutralizing antibodies.”"
Hold on a minute, this is all about one drug, Sotrovimab, aka VIR-7831. Didn't I mention a Dynamic Duo? Yes, and for now the other half of the duo is called (guess what) VIR-7832.
"“But antibodies are not merely things that bind to and neutralize a viral protein,” notes Vir CSO Skip Virgin. Through their Fc domain, mAbs also induce innate and adaptive immune responses that help destroy infected cells—and those Fc-mediated activities, Virgin says, “are fundamentally important for treatment of SARS and COVID-19.”
Mouse studies published in Cell, in the Journal of Experimental Medicine and as a preprint in recent months now support this idea. But last year, as the COVID-19 mAb race was just heating up, many companies—including AstraZeneca, Eli Lilly, Abpro and others—chose instead to dial down effector functions in their mAbs. They wanted to minimize the risk of antibody-dependent enhancement of viral infection, a phenomenon in which virus-specific antibodies can promote, rather than inhibit, disease. This can be a real problem with certain pathogens, including the respiratory syncytial virus and the dengue virus, but Virgin and his colleagues realized early on that it did not seem to be an issue with SARS-CoV-2. So Vir doubled down on the need for strong Fc receptor binding. Not only did the company leave the effector functions intact for sotrovimab, but it also engineered its successor, the follow-on mAb VIR-7832, to have even greater Fc binding activity.
“The concept is to make the antibody vaccinal,” explains Virgin. “We’re trying to make the antibody so it not only protects the individual, but it also generates an immune response that outlasts it” through the generation of pathogen-specific CD4+ and CD8+ T cells responses. The Vir team joined forces last year with Jeffrey Ravetch’s lab at Rockefeller University in New York City to demonstrate the Fc engineering concept with an anti-influenza mAb tested in mice.
“These are predicted benefits. They haven’t been observed in people,” Virgin acknowledges, “but that’s why we’re taking the antibody forward.” VIR-7832 and sotrovimab—both of which possess an Fc mutation that confers extended half-life and enhances drug distribution to the lungs—are now part of a master protocol study taking place in the United Kingdom."
The study platform for the VIR-7831 and -7832 trials goes by the name AGILE, and first patients were dosed last April. agiletrial.net/first-patien...
"The latest candidate to be tested, VIR-7832, will be given to patients who have tested positive for COVID-19 and have mild to moderate symptoms. Based on pre-clinical data, VIR-7832 has three potential mechanisms of action: it can neutralize the virus; target already infected cells for destruction by our immune system; and importantly, it can stimulate a T cell response that can further control the infection. These attributes may be important for both the treatment and prevention of COVID-19. The AGILE study marks the first in-human phase 1 trial of VIR-7832, which aims to establish an optimal dose. When established, the trial will seamlessly move into a second phase with another monoclonal antibody (VIR-7831) which is already being evaluated in two Phase 3 clinical trials.
The trial is currently open in Liverpool and Southampton and will extend to other CRF sites across the UK". For study design etc, see clinicaltrials.gov/ct2/show...
Commercialisation efforts meanwhile proceed fiercepharma.com/pharma/gsk...
"As far as supply is concerned, the companies currently have about 450,000 sotrovimab doses on hand, Vir’s Scangos said. The companies are also revving up their manufacturing network to crank out roughly 2 million doses for the first year of emergency supply in the U.S. The antibody itself is made by WuXi and Samsung Biologics in China and South Korea, respectively, before it’s finished and distributed from GSK’s facility in Parma, Italy, Scangos said. Samsung is currently coming online with high-volume manufacturing, and the companies “think in the following year, we can make many more than two million doses available,” he added.
The partners are also working on a formulation that can be delivered as an intramuscular injection, which many patients and healthcare providers prefer over infusions, Williams noted".
Keep an eye on developments!
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