1CE1

1.9A STRUCTURE OF THE THERAPEUTIC ANTIBODY CAMPATH-1H FAB IN COMPLEX WITH A SYNTHETIC PEPTIDE ANTIGEN

Summary for 1CE1

• Entry DOI: 10.2210/pdb1ce1/pdb
• Descriptor: PROTEIN (CAMPATH-1H:LIGHT CHAIN), PROTEIN (CAMPATH-1H:HEAVY CHAIN), PROTEIN (PEPTIDE ANTIGEN), ... (4 entities in total)
• Functional Keywords: therapeutic, antibody, cd52, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 47575.07

Authors

James, L.C.,Hale, G.,Waldmann, H.,Bloomer, A.C. (deposition date: 1999-03-12, release date: 1999-06-25, Last modification date: 2024-11-06)

Primary citation

James, L.C.,Hale, G.,Waldmann, H.,Bloomer, A.C.
1.9 A structure of the therapeutic antibody CAMPATH-1H fab in complex with a synthetic peptide antigen.
J.Mol.Biol., 289:293-301, 1999

PubMed Abstract: CAMPATH-1 antibodies have a long and successful history in the treatment of leukaemia, autoimmune disease and transplant rejection. The first antibody to undergo "humanisation", CAMPATH-1H, permits treatment with limited patient anti-globulin response. It recognises the CD52 antigen which is a small glycosylphosphatidylinositol(GPI)-anchored protein expressed on lymphocytes and mediates cell depletion. We present the 1.9 A structure of the CAMPATH-1H Fab complexed [corrected] with an analogue of the antigenic determinant of CD52. Analysis of the CAMPATH-1H binding site reveals that in contrast to most antibodies CDR L3 plays a dominant role in antigen binding. Furthermore CDR H3, which is essential for effective antigen recognition in most antibodies, participates in only two main-chain interactions in CAMPATH-1H. The CAMPATH-1H binding site is highly basic; ionic interaction with the enthanolamine phosphate of the CD52 GPI anchor has long been hypothesised to be important in antigen binding. The structure reveals a number of important specific ionic interactions, including Lys53H but not Lys52bH as had previously been suggested. Prolonged treatment with CAMPATH-1H can lead to patient anti-idiotype responses which may be exacerbated by the unusually high number of basic residues in the antibody. This suggests that a strategy where redundant basic residues are replaced with neutral counterparts may be effective in further reducing the immunogenicity of this versatile and widely used antibody.

PubMed: 10366506
DOI: 10.1006/jmbi.1999.2750

Experimental method

X-RAY DIFFRACTION (1.9 Å)