Targeting future variants: a keynote presentation by Dr Laura Walker at Adimab, LLC
Dr Laura Walker, Senior Director of Antibody Sciences at Adimab, LLC., discussed her work on engineering antibodies to fight rapidly emerging diseases.
Currently, neutralizing antibodies have a range of applications in prophylaxis, therapy, and vaccine design in HIV-1, ebolavirus, and SARS-CoV-2.
However, the challenge of emerging diseases is a rapid emergence and the current ‘proactive’ approaches to the emerging viruses are too slow to prevent a pandemic.
For example, the monoclonal antibodies to SARS-CoV-2 have been abandoned despite the much more rapid development than usual.
An alternative approach would be a ‘preemptive’ approach that could work against a broad spectrum of viruses and diseases. For instance, had there been a pan-coronavirus vaccine available prior to the SARS-CoV-2, there would be a tool available to use when the pandemic emerged.
A strategy for the development of broadly neutralizing antibodies (bNAbs) is to target conserved epitopes on viral envelope proteins, against for example HIV-1 or influenza. Over the past few years, advances in large-scale donor screening followed by FACS screening and single-cell technologies led to the identification of bNAbs to many viral pathogens.
Illustrating her point with an example, Dr Walker explained that only a handful of bNAbs had been identified that broadly neutralized HIV, none of which had been very potent.
However, following large-scale donor screening, a small subset of HIV patients was found to develop highly potent bNAbs to HIV, called elite neutralizers. A collaboration with Theraclone Biosciences allowed screening memory B cells directly for neutralization, screening potential IgGs for neutralization.
Dr Walker identified PG9 and PG16 antibodies that had a remarkable breadth and potency to target HIV (Walker et al., Science, 2009). Building upon Dr Walker’s work, dozens of HIV bNAbs have been identified to date, revealing multiple targets for vaccine design. Currently, HIV-1 bNAbs are being explored in both treatment and prevention.
In the second part of her talk, Dr Walker focused on ebolavirus species. There are 6 ebolavirus species and each treatment/measure is species-specific, meaning that it would not work against another ebolavirus species.
Broadly neutralizing anti-ebolavirus antibodies must target conserved surfaces on the GP protein. Dr Walker’s group developed a workflow for the identification and engineering of a pan-ebolavirus antibody cocktail (MBP134).
This was done by taking samples from ebolavirus survivor PBMCs, followed by single B cell cloning and isolation of bNAbs that would bind to the GP protein. The resulting molecule MBP134 is in Phase 1 clinical trials.
MBP134 shows a neutralizing activity against a novel, divergent ebolavirus, Bombali virus (Wec et al., 2019, Cell Host Microbe). This is of proof-of-principle that bNAbs could work against future emerging antibodies.
In the final part of her talk, Dr Walker talked about her work on coronaviruses. Novel coronaviruses will likely emerge in the future, highlighting the need for pan-neutralizing coronavirus vaccines.
The difficulty with SARS-CoV-2 is that there is a continuous emergence of new variants that escape common classes of neutralizing antibodies, due to the escape mutations affecting the spike protein.
Many of the antibodies isolated until now that are in clinical stages or EUA authorized target common epitopes and fail to neutralize other coronavirus variants. Dr Walker suggested that inherent features of broadly neutralizing antibodies should offer a high barrier to resistance.
Dr Walker’s group obtained blood samples from a convalescent SARS donor, and through single B cell sorting, antibodies that would demonstrate cross-neutralizing activity were isolated. 3 of the 7 antibodies were affinity matured, increasing the neutralization potency of the antibodies, leading to three potential therapeutic candidates.
The antibodies were Fc modified to extend their half-life and two of the antibodies were demonstrated to show broad and potent neutralizing in vitro activity across diverse SARS-related coronaviruses.
Typically, bNAbs target epitopes distinct from those recognized by commonly elicited antibodies, enabling a pan-coronavirus neutralizing activity. bNAbs maintain neutralizing activity against Alpha, Beta, Gamma, and Delta SARS-CoV-2 variants of concern (Dejnirattisai et al., Cell 2021, Liu et al., Cell 2021).
Out of these, many bNAbs maintain some of their activity against the Omicron variant, unlike the monoclonal antibodies that were developed in the early stages of the pandemic.
The bNAbs identified by Dr Walker’s group is now in clinical trials and their pharmacokinetics and potential for prolonged protection are being assessed. bNAbs could potentially become platforms for a pan-SARS vaccine design.
