4KY1: Humanized Hp1/2 Fab

Citation:
Abstract
Antibodies are key components of the adaptive immune system and are well-established protein therapeutic agents. Typically high-affinity antibodies are obtained by immunization of rodent species that need to be humanized to reduce their immunogenicity. The complementarity-determining regions (CDRs) contain the residues in a defined loop structure that confer antigen binding, which must be retained in the humanized antibody. To design a humanized antibody, we graft the mature murine CDRs onto a germline human acceptor framework. Structural defects due to mismatches at the graft interface can be fixed by mutating some framework residues to murine, or by mutating some residues on the CDRs' backside to human or to a de novo designed sequence. The first approach, framework redesign, can yield an antibody with binding better than the CDR graft and one equivalent to the mature murine, and reduced immunogenicity. The second approach, CDR redesign, is presented here as a new approach, yielding an antibody with binding better than the CDR graft, and immunogenicity potentially less than that from framework redesign. Application of both approaches to the humanization of anti-alpha4 integrin antibody HP1/2 is presented and the concept of the hybrid humanization approach that retains "difficult to match" murine framework amino acids and uses de novo CDR design to minimize murine amino acid content and reduce cell-mediated cytotoxicity liabilities is discussed.
PDB ID: 4KY1Download
MMDB ID: 112095
PDB Deposition Date: 2013/5/28
Updated in MMDB: 2013/08
Experimental Method:
x-ray diffraction
Resolution: 2.97  Å
Source Organism:
Similar Structures:
Biological Unit for 4KY1: dimeric; determined by author and by software (PISA)
Molecular Components in 4KY1
Label Count Molecule
Proteins (2 molecules)
1
Immunoglobulin Igg1 Fab, Light Chain
Molecule annotation
1
Immunoglobulin Igg1 Fab, Heavy Chain
Molecule annotation
* Click molecule labels to explore molecular sequence information.

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