5F3H

Structure of myostatin in complex with humanized RK35 antibody

Summary for 5F3H

• Entry DOI: 10.2210/pdb5f3h/pdb
• Related: 5F3B
• Descriptor: humanized RK35 antibody heavy chain, humanized RK35 antibody light chain, Growth/differentiation factor 8 (3 entities in total)
• Functional Keywords: myostatin, antibody, complex, signaling protein-immune system complex, signaling protein/immune system
• Biological source: Mus musculus; More
• Cellular location: Secreted: O14793
• Total number of polymer chains: 12
• Total formula weight: 236204.50

Authors

Parris, K.D.,Mosyak, L. (deposition date: 2015-12-02, release date: 2016-09-28, Last modification date: 2024-10-23)

Primary citation

Apgar, J.R.,Mader, M.,Agostinelli, R.,Benard, S.,Bialek, P.,Johnson, M.,Gao, Y.,Krebs, M.,Owens, J.,Parris, K.,St Andre, M.,Svenson, K.,Morris, C.,Tchistiakova, L.
Beyond CDR-grafting: Structure-guided humanization of framework and CDR regions of an anti-myostatin antibody.
Mabs, 8:1302-1318, 2016

PubMed Abstract: Antibodies are an important class of biotherapeutics that offer specificity to their antigen, long half-life, effector function interaction and good manufacturability. The immunogenicity of non-human-derived antibodies, which can be a major limitation to development, has been partially overcome by humanization through complementarity-determining region (CDR) grafting onto human acceptor frameworks. The retention of foreign content in the CDR regions, however, is still a potential immunogenic liability. Here, we describe the humanization of an anti-myostatin antibody utilizing a 2-step process of traditional CDR-grafting onto a human acceptor framework, followed by a structure-guided approach to further reduce the murine content of CDR-grafted antibodies. To accomplish this, we solved the co-crystal structures of myostatin with the chimeric (Protein Databank (PDB) id 5F3B) and CDR-grafted anti-myostatin antibody (PDB id 5F3H), allowing us to computationally predict the structurally important CDR residues as well as those making significant contacts with the antigen. Structure-based rational design enabled further germlining of the CDR-grafted antibody, reducing the murine content of the antibody without affecting antigen binding. The overall "humanness" was increased for both the light and heavy chain variable regions.

PubMed: 27625211
DOI: 10.1080/19420862.2016.1215786

Experimental method

X-RAY DIFFRACTION (2.7 Å)