8AON

Oxidoreductase fragment of human QSOX1 in complex with a Fab fragment of a humanized anti-QSOX1 antibody

This is a non-PDB format compatible entry.

Summary for 8AON

• Entry DOI: 10.2210/pdb8aon/pdb
• Related: 4IJ3 5D96
• Descriptor: Oxidoreductase fragment of human QSOX1, Heavy chain, Light chain, ... (5 entities in total)
• Functional Keywords: antibody, humanized, fab, qsox1, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 74361.47

Authors

Khmelnitsky, L.,Fass, D. (deposition date: 2022-08-08, release date: 2023-08-02, Last modification date: 2026-03-04)

Primary citation

Tennenhouse, A.,Khmelnitsky, L.,Khalaila, R.,Yeshaya, N.,Noronha, A.,Lindzen, M.,Makowski, E.K.,Zaretsky, I.,Sirkis, Y.F.,Galon-Wolfenson, Y.,Tessier, P.M.,Abramson, J.,Yarden, Y.,Fass, D.,Fleishman, S.J.
Computational optimization of antibody humanness and stability by systematic energy-based ranking.
Nat Biomed Eng, 8:30-44, 2024

PubMed Abstract: Conventional methods for humanizing animal-derived antibodies involve grafting their complementarity-determining regions onto homologous human framework regions. However, this process can substantially lower antibody stability and antigen-binding affinity, and requires iterative mutational fine-tuning to recover the original antibody properties. Here we report a computational method for the systematic grafting of animal complementarity-determining regions onto thousands of human frameworks. The method, which we named CUMAb (for computational human antibody design; available at http://CUMAb.weizmann.ac.il ), starts from an experimental or model antibody structure and uses Rosetta atomistic simulations to select designs by energy and structural integrity. CUMAb-designed humanized versions of five antibodies exhibited similar affinities to those of the parental animal antibodies, with some designs showing marked improvement in stability. We also show that (1) non-homologous frameworks are often preferred to highest-homology frameworks, and (2) several CUMAb designs that differ by dozens of mutations and that use different human frameworks are functionally equivalent.

PubMed: 37550425
DOI: 10.1038/s41551-023-01079-1

Experimental method

X-RAY DIFFRACTION (2.1 Å)