Advancing the state of antibody 3D modelling

1. 22 September, 2015
The need for antibody structures
Pharma perspective
Pistoia alliance webinar
Sebastian Kelm (UCB), Guy Georges (Roche), Bojana Popovic
(MedImmune)

2. ©PistoiaAlliance
Why do we need more Ab structures?
• PDB contains ~ 2000 ab structures
– < 1000 non-identical structures
– Ab diversity is >1012
• Tools for Ab modeling exists in different flavors
– commercial, academic, owned by industrial research
groups
– quality is increasing, but highly dependent on PDB
• Abs among the top-grossing therapeutics
– growing interest since more than a decade!
– Bi-specifics and Ab fusion and coupling as second
generation therapeutics

3. ©PistoiaAlliance
Common uses of antibody structures in
pharma
• Analysing, predicting and engineering molecular properties:
– Structure
• Visual analysis
• Computational prediction of antibody-antigen interactions
– Mode-of-action
• Affinity/specificity determining residues
• Protein-protein interactions blocked by antibody
• Species cross-reactivity
– Biophysical and immunogenic properties
• Humanisation
• Developability (can impact BPD and manufacturing of drugs)
• Better coverage and quality of structures in the PDB means:
– better models of antibody structure
– better predictions of activity and biophysical properties that help us
generate better medicines

4. ©PistoiaAlliance
Large numbers enable statistics
Prediction of VH-VL domain orientation for antibody variable domain modeling.
Bujotzek A, Dunbar J, Lipsmeier F, Schaefer W, Antes I, Deane CM, Georges G.
Proteins: Stucture, Function, and Bioinformatics. 2015, 83, 681-695.
Predictors are retrained while database
is growing, accuracy increases!

5. ©PistoiaAlliance
Large numbers enable statistics
MoFvAb: modeling the Fv region of antibodies
Bujotzek A, Fuchs A, Qu C, Klostermann S, Antes A, Georges G.
mAbs. 2015, 7(5), 838-852.
crystal structure
unrefined MoFvAb
neighborhood-refined
MoFvAb
Knowledge-based
positioning accuracy will
grow when increasing
the database size

6. ©PistoiaAlliance
Large numbers enable statistics
Improving B-cell epitope prediction and its application to global antibody-
antigen docking. Krawczyk K, Liu X, Baker T, Shi J and Deane CM.
Bioinformatics. 2014, 30(16):2288-2294.
Intramolecular distances can be used to predict antibody-antigen contacts

7. ©PistoiaAlliance
Initiative to get more Abs into the PDB
• Collect non published structures within big
Pharmas (“dead” projects or sleeping data) for
deposition into the PDB
• Convince the whole community to act similarly
• Define gaps and provide sequences. Diversity!
– How to define “diversity”?
• Exotic CDRs
• Non canonical CDRs
• Flexible/rigid, highly/less stable, prone or not to aggregation,
long/short PK properties, …
– Companies to contribute their own lists of sequences

8. info@pistoiaalliance.org @pistoiaalliance www.pistoiaalliance.org