Rational design and engineering of therapeutic proteins

被引:147
作者
Marshall, SA [1 ]
Lazar, GA [1 ]
Chirino, AJ [1 ]
Desjarlais, JR [1 ]
机构
[1] Xencor, Monrovia, CA 91016 USA
关键词
D O I
10.1016/S1359-6446(03)02610-2
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
An increasing number of engineered protein therapeutics are currently being developed, tested in clinical trials and marketed for use. Many of these proteins arose out of hit-and-miss efforts to discover specific mutations, fusion partners or chemical modifications that confer desired properties. Through these efforts, several useful strategies have emerged for rational optimization of therapeutic candidates. The controlled manipulation of the physical, chemical and biological properties of proteins enabled by structure-based simulation is now being used to refine established rational engineering approaches and to advance new strategies. These methods provide clear, hypothesis-driven routes to solve problems that plague many proteins and to create novel mechanisms of action. We anticipate that rational protein engineering will shape the field of protein therapeutics dramatically by improving existing products and enabling the development of novel therapeutic agents.
引用
收藏
页码:212 / 221
页数:10
相关论文
共 68 条
[51]   RATIONAL DESIGN OF A RECEPTOR SUPER-ANTAGONIST OF HUMAN INTERLEUKIN-6 [J].
SAVINO, R ;
CIAPPONI, L ;
LAHM, A ;
DEMARTIS, A ;
CABIBBO, A ;
TONIATTI, C ;
DELMASTRO, P ;
ALTAMURA, S ;
CILIBERTO, G .
EMBO JOURNAL, 1994, 13 (24) :5863-5870
[52]   Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human FcγRIII and antibody-dependent cellular toxicity [J].
Shields, RL ;
Lai, J ;
Keck, R ;
O'Connell, LY ;
Hong, K ;
Meng, YG ;
Weikert, SHA ;
Presta, LG .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (30) :26733-26740
[53]   High resolution mapping of the binding site on human IgG1 for FcγRI, FcγRII, FcγRIII, and FcRn and design of IgG1 variants with improved binding to the FcγR [J].
Shields, RL ;
Namenuk, AK ;
Hong, K ;
Meng, YG ;
Rae, J ;
Briggs, J ;
Xie, D ;
Lai, J ;
Stadlen, A ;
Li, B ;
Fox, JA ;
Presta, LG .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (09) :6591-6604
[54]   Reversibly locking a protein fold in an active conformation with a disulfide bond:: Integrin αL I domains with high affinity and antagonist activity in vivo [J].
Shimaoka, M ;
Lu, CF ;
Palframan, RT ;
von Andrian, UH ;
McCormack, A ;
Takagi, J ;
Springer, TA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (11) :6009-6014
[55]   Computational design of an integrin I domain stabilized in the open high affinity conformation [J].
Shimaoka, M ;
Shifman, JM ;
Jing, H ;
Takagi, L ;
Mayo, SL ;
Springer, TA .
NATURE STRUCTURAL BIOLOGY, 2000, 7 (08) :674-678
[56]   An antagonistic vascular endothelial growth factor (VEGF) variant inhibits VEGF-stimulated receptor autophosphorylation and proliferation of human endothelial cells [J].
Siemeister, G ;
Schirner, M ;
Reusch, P ;
Barleon, B ;
Marmé, D ;
Martiny-Baron, G .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (08) :4625-4629
[57]   Computational protein design [J].
Street, AG ;
Mayo, SL .
STRUCTURE, 1999, 7 (05) :R105-R109
[58]   Potent antithrombin activity and delayed clearance from the circulation characterize recombinant hirudin genetically fused to albumin [J].
Syed, S ;
Schuyler, PD ;
Kulczycky, M ;
Sheffield, WP .
BLOOD, 1997, 89 (09) :3243-3252
[59]   An erythropoietin fusion protein comprised of identical repeating domains exhibits enhanced biological properties [J].
Sytkowski, AJ ;
Lunn, ED ;
Risinger, MA ;
Davis, KL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (35) :24773-24778
[60]   Structural correlates of an anticarcinoma antibody: Identification of specificity-determining residues (SDRs) and development of a minimally immunogenic antibody variant by retention of SDRs only [J].
Tamura, M ;
Milenic, DE ;
Iwahashi, M ;
Padlan, E ;
Schlom, J ;
Kashmiri, SVS .
JOURNAL OF IMMUNOLOGY, 2000, 164 (03) :1432-1441