Structure prediction and characterisation

In the absence of structural data, we perform sequence-to-structure predictions for all proteins and biologics. As part of characterisation, we predict protein-protein interaction sites on the surface of proteins in aid of identifying the mechanism of action of a biologic. When working with antibodies we predict residues that comprise the paratope and use this information to make informed predictions about potential epitopes. If multiple antibodies are to be analysed, we perform epitope binning and determine epitope overlap.

Structure Prediction

Biophysical characterisation

PPI site prediction

Epitope Prediction

Paratope Prediction

CDR numbering

Discovery and de novo design

When developing a novel biologic for a target protein, we perform structure-based virtual screening of our structural libraries in order to identify potential hits with preliminary complementarity in shape and chemistry. Alternatively, we design libraries of de novo protein scaffolds using the structure of the target protein. This process can involve a predefined region or epitope on the target protein or a predicted PPI site or epitope.

De novo binder design

De novo antibody design

Structure-based screening

Affinity maturation

Our proprietary binding affinity optimisation process utilises structural information of the drug-target complex, taking into account amino acid mutations themselves as well as their surrounding environment. If the goal of a project is to improve the species cross-reactivity of a biologic for studies in animal models, we provide simultaneous affinity maturation based on several homologous target proteins at once. We de-risk the affinity maturation process by filtering out mutations that would deleteriously affect the solubility or stability of the biologic.

Saturation mutagenesis

Alanine scanning

Cross species reactivity

Improve affinity

Reduce affinity

Humanisation

In instances where biologics have been obtained from non-human sources, we analyse the sequence and introduce mutations that resemble the closest human-germline reference sequence. Alternatively, we graft regions of the biologic, such as the CDR loops, onto a human framework. In these processes, we increase the “humanness” of the sequence with the goal of reducing immunogenicity. We validate that the changes introduced do not have a deleterious effect on the structural integrity of the biologic by predicting the structure of the newly developed sequence.

CDR grafting

Germline reversion

Humanised structure prediction

Humanness scoring

Developability assessment and optimisation

We consider key characteristics of candidate biologics in order to mitigate downstream developability issues. We assess the structure of the candidate in order to quantify features such as hydrophobic and charged patches; key factors relating to aggregation and colloidal stability. We further assess the sequence of the candidate for post-translational modification liabilities which can result in downstream issues during the drug development process.

Glycosylation

Phosphorylation

Ubiquitination

And other PTMs

Aggregation hotspots

Colloidal stability