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Three-dimensional structures of a humanized anti-IFN-ϒ Fab (HuZAF) in two crystal forms.
- Source :
- Acta Crystallographica: Section D (Wiley-Blackwell); Oct2004, Vol. 60 Issue 10, p1761-1769, 9p
- Publication Year :
- 2004
-
Abstract
- Three-dimensional structures were determined for two crystal forms (orthorhombic P2<subscript>1</subscript>2<subscript>1</subscript>2<subscript>1</subscript> and monoclinic C2) of the Fab from the humanized version of a murine monoclonal antibody (AF2) that possesses binding and potent neutralizing activity against human interferon γ (IFN-γ). This humanized antibody (HuZAF; USAN name fontolizumab) is currently in phase II clinical trials for the treatment of Crohn's disease. HuZAF exhibits binding and IFN-γ neutralizing capacities that closely approximate those of the original antibody. It is shown that HuZAF, whose VH domain was designed using a best-sequence-fit approach, is closer structurally to its mouse precursor than is a version whose VH was constructed using a human sequence with lower homology to the original mouse sequence. This work thus offers direct structural evidence in support of the best-sequence-fit approach and adds to previous results of biological and biochemical evaluations of distinctly engineered antibodies that also favored the use of a best-sequence-fit strategy. A second crystal type appeared during attempts to crystallize the Fab-IFN-γ complex. The antibody-antigen complex that existed in solution dissociated in the crystallization mixture. A conformationally altered but unliganded HuZAF protein crystallized in a different space group (C2), with two Fab molecules in the asymmetric unit. In this crystal lattice, no space was available for accommodating the IFN-γ antigen. Thus, there are currently three slightly different structures of the HuZAF Fab. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 09074449
- Volume :
- 60
- Issue :
- 10
- Database :
- Complementary Index
- Journal :
- Acta Crystallographica: Section D (Wiley-Blackwell)
- Publication Type :
- Academic Journal
- Accession number :
- 14528070
- Full Text :
- https://doi.org/10.1107/S0907444904018670