Details

Autor(en) / Beteiligte

• Apgar, James R
• Mader, Michelle
• Agostinelli, Rita
• Benard, Susan
• Bialek, Peter
• Johnson, Mark
• Gao, Yijie
• Krebs, Mark
• Owens, Jane
• Parris, Kevin
• St Andre, Michael
• Svenson, Kris
• Morris, Carl
• Tchistiakova, Lioudmila

Titel

Beyond CDR-grafting: Structure-guided humanization of framework and CDR regions of an anti-myostatin antibody

Ist Teil von

• mAbs, 2016-10, Vol.8 (7), p.1302-1318

Ort / Verlag

United States: Taylor & Francis

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.