Highlights from a live keynote by Antonio Lanzavecchia, Group Leader; SVP and Senior Research Fellow at National Institute of Molecular Genetics, INGM; Humabs BioMed
Candace Kastanis recaps this talk presented by Antonio Lanzavecchia, Group Leader; SVP and Senior Research Fellow at National Institute of Molecular Genetics, INGM; Humabs BioMed
Opening the presentation, we retraced some steps back to the origins of fighting emerging diseases.
It was very informational as we relearned the primary ways antibodies can be used. Dr. Lanzavecchia provided a great deal of insight.
He spoke eloquently about the evolution of antibody expressions and the relevance they have towards clinical and therapeutic interventions.
Dr. Lanzavecchia guided his talk regarding the basis of experiments based on four major components:
The Platform that has been developed in 2004 was ultimately built to deal with the SARS virus and:
Researchers then take the plasma or memory cells and high throughput screenings of secreted antibodies using multiple and functional assays.
There isn’t a need for defined or purified antigens (target agnostic). This methodology is designed to create an easier avenue to focus on the targeted antibodies, but we can also be target agnostic.
The first attempt at putting this platform into motion was to create a vaccine to fight emerging viruses.
As an example, the drug antibody Asuvimab was approved for use or the treatment of Ebola and was highly effective and neutralizing the MOA.
Mortality is reduced from 70% to less than 10% and is actively deployed for use in Zaire.
What is known by these early origins of antibody research, is that antibodies can be used with Zika, Ebola, Sars, Mers, SArs2. The scientific community is excited by the newly developed schematic.
It illustrates that you can develop the antibody as a drug but also as a tool or as a vaccine by identifying the cellular receptor of the target pathogen.
This helps discover the infectious mechanism of action and related cellular activity.
Antibody Guided Vaccine Design- The Pentameric Complex
Potent neutralizing antibodies identify the HCMV pentamer as a critical target for vaccine development.
A pentamer vaccine induces in mice, neutralizing titers 300-fold higher than those found in CMV infected patients one year after the infection.
This is a good example as it shows that by identifying the right molecule, you can develop a vaccine that induces a level of neutralizing antibodies that are much higher than that created via a natural infection.
Another example was given involving a collaborative effort of one of his team members and another research facility.
The discovery involved broadly neutralizing antibodies identifying a conserved epitope in the stem of the influenza hemagglutinin relevant for a universal influenza vaccine.
It is very difficult to find escaped mutants from this particular antibody.
They also found that most neutralizing antibodies recognize the prefusion of RSV F protein.
This lends to the rationale for developing stabilized trimers (3-unit polymers) as vaccines.
Likewise, the finding that three antibodies also recognize the RBD of SARS Cov2 also gives credence for developing a RBD based vaccine.
Paramyxoviruses and coronaviruses: Broadly Neutralizing Antibodies as a Barrier to Viral Evolution and Escape
The concept brought forward stretches the activity of the BNAs even further.
It is suggested that they recognize conserved sites that are less prone to mutate.
With regard to RSV, the problem is that the selection of escape mutants may limit the efficacy of clinical stage antibodies to RSV.
The MPE8, a BNA that binds to a conserved epitope in the prefusion F-protein of HSRV, HMPV, BRSV, and PVM, does not select escape mutants.
Dr. Lanzavecchia noted that he just published a paper on the cross-neutralization activity of four paramyxoviruses by a human monoclonal antibody. Genetic variation is continuing to be a challenging prevention.
Spillover of alpha and beta coronaviruses
An example was provided surrounding the coronaviruses and related virus family members i.e. - SARs, MERS, and SARS2. Widely diverse, the viruses still continue to evolve with a super variant.
In other words, there are mutations that continue to accumulate and there are sites where mutation is selected, in particular the RBM. This leads us to the question of how to deal with the problem.
Exploring the VIR7831 Variants
The VIR7831 showcases the following attributes:
Design Principles and Clinical Data of VIR 7831 now FDA approved for treatment in COVID 19
This new treatment was engineered successfully to have potent and long-lasting effects against SARS-CoV2 and other CoVs. The properties which make it function at an optimal level includes:
The research team found Isolated BNAs all Beta-Coronavirus mAbs from C-19 convalescent individuals. The noted broad reactivity against all beta coronaviruses and they were not as potent as 309.
Neutralize live virus, and variants of concern and show binding activity to the conserved S stem helix. These antibodies are quick potent at blocking cell to cell fusion.
The MOA of relative antibodies and it was discovered they present the following attributes:
This is important in vaccine design because identify an epitope that highly conserved among coronaviruses.
So, moving forward, they discovered the unmutated ancestor of this family S2P6 is specific to for HKU1.
This is relevant because the three clones acquired affinity and breadth through somatic mutations broad reactivity to coronaviruses.
Recent Data for Ongoing Experiments
Dr. Lanzavecchia expanded on an idea of his to search for pan coronavirus antibodies that bind to the fusion peptide.
It was informative to find that it is extremely rare to isolate an antibody that binds to BOTH the beta and the S type of coronaviruses.
The characteristics of the Pan antibodies are very interesting as well. Dr. Lanzavecchia noted that they tend to be modest in vitro neutralizing activity and they bind to the fusion peptide AND the prefusion spike conformation.
This parasite is responsible for the most severe form malaria infection.
It works the sporozites is introduced in minute amounts and travels quickly to the liver to give rise to blood stage parasites that express a different set of genes.
The sporozite surface protein CSP is conserved and does not induce an effective antibody response in infected individuals.
This more than likely occurred because there were not enough parasites. Therefore, it made sense to find a vaccine to block the infection.
However, the results were not positive as the efficacy of the vaccine was decidedly poor.
A CSP based vaccine could confer sterilizing immunity, but the efficacy of the current candidate is limited.
With an efficacy of only about 50%, the goal was centered around if the CSP vaccine could be improved.
Studies from multiple laboratories produced the same information regarding the activity of parasites.
They discovered that a public antibody lineage that potently inhibits malaria infection though dual binding to the circumporozite protein.
This encouraged the Humabs research team to search for antibodies that have been tested and capable of preventing infection, but at the same time show a strategy to improve the vaccine by using the recombinant proteins.
Once isolated, the Humabs team noticed the following reaction: though somatic mutations, the proteins show affinity, achieving breadth and binding to NPDP peptide.
Antigenic Variation / Variant Surface Antigen
Taking yet another deep dive into the specific antigenic properties of the NPDP proteins, they wondered if they could find antibodies that broadly recognize infected erythrocytes.
The takeaway of dissecting the antigenic variations and variant surface antigens, returned the direction of the Humabs team back to the behavior of parasitic activity.
Research shows that blood stage parasites express VSAs that mediate adhesion of infected erythrocytes to the endothelial.
However, Anti VSA antibodies protect from disease.
The high number of VSA genes with polymorphism and clonal expressions provide an effective escape mechanism.
Again, this provided a backdrop for how parasitic molecular activity lends itself to escape and prevent disease.
Through experimentation, a discovery of Isolated antibodies that display activity against the isolate were observed and notated that broadly reacted antibodies carry a mutated LAIR1 gene.
LAIR1 is a collagen binding inhibitory receptor encoded on chromosome 19. This led for further examination of the LAIR 1 antibodies and to discover how common they are.
LAIR1 Containing Antibodies
Through volunteer donors, our researcher team found a high prevalence and clonal dominance of LAIR1 antibodies in African donors.
The specific properties of the LAIR 1 containing antibodies prove to be very interesting.
This is important as a single clone can immortalize the memory cells and sequence the genomic DNA. This translates to the fact that in everyone, the antibodies are produced by a single clone.
Further exploration led to the discovery of RIFINS and LILRBI insertions.
These elements are very important as they harbor immune suppressive properties which prove critical to developing a new arm of antibody engineering.
RIFINS: Immune Suppression and Evasion Strategy
This last section detailed the MOA of both RIFINS, LAIR1 and LILRB1 containing antibodies.
RIFINS engage inhibitory receptors and evade the antibody response using multiple polymorphic and clonally expressed genes.
Antibodies with LAIR1 and LILRB1 insertions counteract pathogen escape strategies.
It is interesting to see how evolution took a path to identify and hone the creation of immune suppressive containing antibodies towards clinical applications.
As a closing point, Dr. Lanzavecchia referenced his proof-of-concept point regarding the use of bispecific antibodies.
He stated that it is possible to create extra binding sites that can be inserted into the antibodies in a particular elbow to create a new platform for antibody engineering.
