Various coarse-grained (CG) models have become increasingly common in studies of antibody-antibody interactions in solution. These models appear poised to enter development pipelines in the near future to help predict and understand how antibody-antibody interactions influence the suitability of a given monoclonal antibody (mAb) for mass production and delivery as an antibody therapy. This blog post is a non-exhaustive summary of some of the highlights I found during a recent literature search.
Continue readingTag Archives: Antibodies
The SARS-CoV-2 protein spike glycosylation not only shields but primes binding by providing structural stability too
Yep, it is very well known that the sugar coating (aka glycosylation) of viruses makes them invisible to the immune system, a strategy so effective that like in the case of HIV, whose spike is almost entirely covered by glycans, makes it so difficult to target by the human immune system.
Unsurprisingly, coronaviruses such as SARS, MERS, and SARS-CoV-1(2) not only benefit from this evolutionary strategy but there is evidence now that sugars provide stability to their spikes to be effective binders by glueing the spike chains, hence making them infectious.
This is the major finding of this paper that introduces very interesting results from all-atom MD simulations of a fully glycosylated model of the SARS-CoV-2 spike protein embedded in a realistic viral membrane. Researchers aimed to look into the stability of the protein spike (A, B, and C) chains in the “open” and “closed” conformation and how these changed upon key residue mutations to test how glycans sitting in the inter-chain space affect stability. It also aimed at quantifying glycans’ shielding effect from molecules ranging from 2 to 15 Angstroms, i.e., from small-sized to peptide- and antibody-sized molecules.
Continue readingA to Z of Alternative Antibody Formats: Next-Generation Therapeutics
Do you know your diabodies from your zybodies?
Antibodies are a highly important class of therapeutics used to treat a range of diseases. Given their success as therapeutics, a wide variety of alternative antibody formats have been developed – these are driving the next generation of antibody therapeutics.
To note, this is not an exhaustive list but rather intended to demonstrate the range of existing antibody formats.
Inspired by this article in The Guardian: “Rachel Roddy’s A-Z of pasta“
Many of these figures were adapted from Spiess et al., 2015. Additionally, some of these formats have multiple variations or further possible forms (e.g., trispecific antibodies) – in these cases, one example is given here.
A – Antibodies
Antibodies – a fitting place to start this post. Antibodies are proteins produced by our immune systems to detect and protect against foreign pathogens. The ability of antibodies to bind molecules strongly and specifically – properties essential to their role in our immune defence – also make them valuable candidates for therapeutics. Antibody therapies have been developed for the treatment of various diseases, including cancers and viruses, and form a market estimated at over $100 billion1.
Continue readingAntibody Binding is Mediated by a Compact Vocabulary of Paratope-Epitope Interactions
While my own research focuses mainly on what happens in an antibody before it binds its antigen, I recently came across a paper by Akbar et al [1] that examines antibody-antigen interactions using an elegant approach to identify a set of structural motifs that antibodies use to interact with their epitopes. Since I am interested in emergent properties that arise when a sequence is mapped onto an antibody structure, this paper was very exciting. I will also shamelessly admit that I’m a sucker for a pretty figure and this paper has many! Regardless, on to the findings!
The Coronavirus Antibody Database: 10 months on, 10x the data!
Back in May 2020, we released the Coronavirus Antibody Database (‘CoV-AbDab’) to capture molecular information on existing coronavirus-binding antibodies, and to track what we anticipated would be a boon of data on antibodies able to bind SARS-CoV-2. At the time, we had found around 300 relevant antibody sequences and a handful of solved crystal structures, most of which were characterised shortly after the SARS-CoV epidemic of 2003. We had no idea just how many SARS-CoV-2 binding antibody sequences would come to be released into the public domain…
10 months later (2nd March 2021), we now have tracked 2,673 coronavirus-binding antibodies, ~95% with full Fv sequence information and ~5% with solved structures. These datapoints originate from 100s of independent studies reported in either the academic literature or patent filings.
It’s been here all along: Analysis of the antibody DE loop
In my work, I mainly look at antigen-bound antibodies and this means a lot of analysing interfaces. Specifically, I spend a lot of my time examining the contributions of complementarity-determining regions (CDRs) to antigen binding, but what about antibodies where the framework (FW) region also contributes to binding? Such structures do exist, and these interactions are rarely trivial. As such, a recent preprint I came across where the authors examined the DE loops of antibodies was a great motivator to broaden my horizons!
Continue readingIdentifying shared antibodies using deep learning
Antibody convergence is the presence of similar antibodies in different individuals – suggesting that the individuals have had exposure to a common antigen, which has stimulated the production of similar, antigen-specific antibodies. We want to be able to identify these shared antibodies, sometimes referred to as ‘public clones’, as it could lead to development of immunodiagnostic tests against the shared antibodies, and potentially assist in the design of vaccines and therapeutic antibodies. A recent paper on bioRxiv by Sai Reddy’s group[i] has applied deep learning techniques – variational autoencoders (VAE) and support vector machines (SVM) – to the problem of how to identify shared antibodies.
Continue readingComparative analysis of the CDR loops of antigen receptors
Allow me to present our recently accepted paper: Comparative analysis of the CDR loops of antigen receptors, to appear in Frontiers in Immunology [1]. In the blog post I will give a quick five-minute summary of the key messages in this work.
Continue readingDo we need the constant regions of Antibodies and T-cell receptors in molecular simulations?
At this week’s journal club I presented my latest results on the effect of the constant regions of antibodies (ABs) and T-cell receptors (TCRs) on the dynamics of the overall system. Not including constant regions in such simulations is a commonly used simplification that is found throughout the literature. This is mainly due a massive saving in computational runtime as illustrated below: 
The constant regions contain about 210 residues but an additional speed up comes from the much smaller solvation box. If a cubic solvation box is used then the effect is even more severe:
But the question is: “Is is OK to remove the constant regions of an AB or TCR and simulate without them?”.
Using replica simulations we found that simulations with and without constant regions lead to (on average) significantly different results. The detail of our analysis will soon be submitted to a scientific journal. The current working title is “Why constant regions are essential in antibody and T-cell receptor Molecular Dynamics simulations”.