7Z3W

Crystal structure of the AAL160 Fab

Summary for 7Z3W

• Entry DOI: 10.2210/pdb7z3w/pdb
• Related: 7Z2M
• Descriptor: AAL160 Fab heavy-chain, AAL160 Fab light-chain, 2-{2-[2-2-(METHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL, ... (4 entities in total)
• Functional Keywords: monoclonal antibody, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 2
• Total formula weight: 49186.05

Authors

Rondeau, J.M.,Lehmann, S. (deposition date: 2022-03-02, release date: 2023-02-08, Last modification date: 2024-02-07)

Primary citation

Fischman, S.,Levin, I.,Rondeau, J.M.,Strajbl, M.,Lehmann, S.,Huber, T.,Nimrod, G.,Cebe, R.,Omer, D.,Kovarik, J.,Bernstein, S.,Sasson, Y.,Demishtein, A.,Shlamkovich, T.,Bluvshtein, O.,Grossman, N.,Barak-Fuchs, R.,Zhenin, M.,Fastman, Y.,Twito, S.,Vana, T.,Zur, N.,Ofran, Y.
"Redirecting an anti-IL-1 beta antibody to bind a new, unrelated and computationally predicted epitope on hIL-17A".
Commun Biol, 6:997-997, 2023

PubMed Abstract: Antibody engineering technology is at the forefront of therapeutic antibody development. The primary goal for engineering a therapeutic antibody is the generation of an antibody with a desired specificity, affinity, function, and developability profile. Mature antibodies are considered antigen specific, which may preclude their use as a starting point for antibody engineering. Here, we explore the plasticity of mature antibodies by engineering novel specificity and function to a pre-selected antibody template. Using a small, focused library, we engineered AAL160, an anti-IL-1β antibody, to bind the unrelated antigen IL-17A, with the introduction of seven mutations. The final redesigned antibody, 11.003, retains favorable biophysical properties, binds IL-17A with sub-nanomolar affinity, inhibits IL-17A binding to its cognate receptor and is functional in a cell-based assay. The epitope of the engineered antibody can be computationally predicted based on the sequence of the template antibody, as is confirmed by the crystal structure of the 11.003/IL-17A complex. The structures of the 11.003/IL-17A and the AAL160/IL-1β complexes highlight the contribution of germline residues to the paratopes of both the template and re-designed antibody. This case study suggests that the inherent plasticity of antibodies allows for re-engineering of mature antibodies to new targets, while maintaining desirable developability profiles.

PubMed: 37773269
DOI: 10.1038/s42003-023-05369-x

Experimental method

X-RAY DIFFRACTION (2 Å)