5f3b | pdb_00005f3b
Structure of myostatin in complex with chimeric RK35 antibody
Structural highlights
Disease[GDF8_HUMAN] Myostatin-related muscle hypertrophy. The disease is caused by mutations affecting the gene represented in this entry. Function[GDF8_HUMAN] Acts specifically as a negative regulator of skeletal muscle growth. Publication Abstract from PubMedAntibodies 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. Beyond CDR-grafting: Structure-guided humanization of framework and CDR regions of an anti-myostatin antibody.,Apgar JR, 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 MAbs. 2016 Oct;8(7):1302-1318. Epub 2016 Sep 13. PMID:27625211[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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