PDBsum entry 1cz8

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Immune system PDB id
Protein chains
94 a.a. *
213 a.a. *
218 a.a. *
SO4 ×2
Waters ×419
* Residue conservation analysis
PDB id:
Name: Immune system
Title: Vascular endothelial growth factor in complex with an affinity matured antibody
Structure: Vascular endothelial growth factor. Chain: v, w. Fragment: receptor binding fragment. Engineered: yes. Light chain of neutralizing antibody. Chain: l, x. Fragment: fab fragment. Engineered: yes. Other_details: mutated form of a humanized murine antibody
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Mus musculus. House mouse. Organism_taxid: 10090. Expression_system_taxid: 562
Biol. unit: Hexamer (from PQS)
2.40Å     R-factor:   0.208     R-free:   0.267
Authors: Y.Chen,C.Wiesmann,G.Fuh,B.Li,H.W.Christinger,P.Mckay,A.M.De Vos,H.B.Lowman
Key ref:
Y.Chen et al. (1999). Selection and analysis of an optimized anti-VEGF antibody: crystal structure of an affinity-matured Fab in complex with antigen. J Mol Biol, 293, 865-881. PubMed id: 10543973 DOI: 10.1006/jmbi.1999.3192
01-Sep-99     Release date:   20-Mar-00    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P15692  (VEGFA_HUMAN) -  Vascular endothelial growth factor A
232 a.a.
94 a.a.
Protein chains
No UniProt id for this chain
Struc: 213 a.a.
Protein chains
No UniProt id for this chain
Struc: 218 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   1 term 
  Biochemical function     growth factor activity     1 term  


DOI no: 10.1006/jmbi.1999.3192 J Mol Biol 293:865-881 (1999)
PubMed id: 10543973  
Selection and analysis of an optimized anti-VEGF antibody: crystal structure of an affinity-matured Fab in complex with antigen.
Y.Chen, C.Wiesmann, G.Fuh, B.Li, H.W.Christinger, P.McKay, Vos, H.B.Lowman.
The Fab portion of a humanized antibody (Fab-12; IgG form known as rhuMAb VEGF) to vascular endothelial growth factor (VEGF) has been affinity-matured through complementarity-determining region (CDR) mutation, followed by affinity selection using monovalent phage display. After stringent binding selections at 37 degrees C, with dissociation (off-rate) selection periods of several days, high affinity variants were isolated from CDR-H1, H2, and H3 libraries. Mutations were combined to obtain cumulatively tighter-binding variants. The final variant identified here, Y0317, contained six mutations from the parental antibody. In vitro cell-based assays show that four mutations yielded an improvement of about 100-fold in potency for inhibition of VEGF-dependent cell proliferation by this variant, consistent with the equilibrium binding constant determined from kinetics experiments at 37 degrees C. Using X-ray crystallography, we determined a high-resolution structure of the complex between VEGF and the affinity-matured Fab fragment. The overall features of the binding interface seen previously with wild-type are preserved, and many contact residues are maintained in precise alignment in the superimposed structures. However, locally, we see evidence for improved contacts between antibody and antigen, and two mutations result in increased van der Waals contact and improved hydrogen bonding. Site-directed mutants confirm that the most favorable improvements as judged by examination of the complex structure, in fact, have the greatest impact on free energy of binding. In general, the final antibody has improved affinity for several VEGF variants as compared with the parental antibody; however, some contact residues on VEGF differ in their contribution to the energetics of Fab binding. The results show that small changes even in a large protein-protein binding interface can have significant effects on the energetics of interaction.
  Selected figure(s)  
Figure 2.
Figure 2. Radiolabeled VEGF binding assay. [ 125 I]VEGF was equilibrated (23 °C) with serial dilutions of unlabeled VEGF and (a) Fab-12 or (c) Y0317. Fabs were captured with an anti-Fab antibody-coated immunosorbant plate. Scatchard analysis (Munson & Rodbard, 1980) with a 1:1 binding model was used to calculate Kd of (b) 433 (±116) pM for Fab-12 and (d) 19.8(±4.3) pM for Y0317.
Figure 4.
Figure 4. Structure of the affinity-improved Y0317 Fab in complex with VEGF. A superposition of the structure (Muller et al., 1998a) of wild-type humanized antibody Fab-12 (gray) in complex with VEGF (gray) is shown with that of Fab Y0317 (green) in complex with VEGF (yellow). (a) Overall view of the complex, including one Fab molecule bound to one dimer of VEGF (a second Fab molecule is bound at left in the crystal) shows that the binding site for both antibody variants centers on the ``80's loop'' of VEGF. (b) A view of the four CDR changes between Fab-12 and Y0317 Fab shows that the new D28 and T100a side-chains do not directly contact antigen. However, H31 and Y97 form new contacts. (c) Interactions of H97 and an associated, buried water molecule in the Fab-12 complex, compared with those of Y97 in the Y0317 complex.
  The above figures are reprinted by permission from Elsevier: J Mol Biol (1999, 293, 865-881) copyright 1999.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21501594 L.Yu, X.H.Liang, and N.Ferrara (2011).
Comparing protein VEGF inhibitors: In vitro biological studies.
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21478869 R.S.Gaster, L.Xu, S.J.Han, R.J.Wilson, D.A.Hall, S.J.Osterfeld, H.Yu, and S.X.Wang (2011).
Quantification of protein interactions and solution transport using high-density GMR sensor arrays.
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21146229 U.Schmidt-Erfurth, B.Eldem, R.Guymer, J.F.Korobelnik, R.O.Schlingemann, R.Axer-Siegel, P.Wiedemann, C.Simader, M.Gekkieva, and A.Weichselberger (2011).
Efficacy and Safety of Monthly versus Quarterly Ranibizumab Treatment in Neovascular Age-related Macular Degeneration: The EXCITE Study.
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19730802 B.J.Ernst, A.J.Barkmeier, and L.Akduman (2010).
Optical coherence tomography-based intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration.
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20875152 D.Wu, J.Sun, T.Xu, S.Wang, G.Li, Y.Li, and Z.Cao (2010).
Stacking and energetic contribution of aromatic islands at the binding interface of antibody proteins.
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20337993 H.S.Park, S.Y.Kim, S.R.Kim, and Y.C.Lee (2010).
Targeting abnormal airway vascularity as a therapeutical strategy in asthma.
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20847101 R.J.Pantazes, and C.D.Maranas (2010).
OptCDR: a general computational method for the design of antibody complementarity determining regions for targeted epitope binding.
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20501651 S.Iyer, P.I.Darley, and K.R.Acharya (2010).
Structural insights into the binding of vascular endothelial growth factor-B by VEGFR-1(D2): recognition and specificity.
  J Biol Chem, 285, 23779-23789.
PDB code: 2xac
20924261 S.R.Sadda, G.Stoller, D.S.Boyer, B.A.Blodi, H.Shapiro, and T.Ianchulev (2010).
Anatomical benefit from ranibizumab treatment of predominantly classic neovascular age-related macular degeneration in the 2-year anchor study.
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18437176 A.OzkiriƟ (2009).
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19404665 C.Costagliola, F.Semeraro, U.Cipollone, M.Rinaldi, M.della Corte, and M.R.Romano (2009).
Changes in neovascular choroidal morphology after intravitreal bevacizumab injection: prospective trial on 156 eyes throughout 12-month follow-up.
  Graefes Arch Clin Exp Ophthalmol, 247, 1031-1037.  
19476398 F.Ziemssen, S.Grisanti, K.U.Bartz-Schmidt, and M.S.Spitzer (2009).
Off-label use of bevacizumab for the treatment of age-related macular degeneration: what is the evidence?
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19668560 J.P.Hubschman, S.Reddy, and S.D.Schwartz (2009).
Age-related macular degeneration: current treatments.
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19092732 M.Parravano, F.Oddone, M.Tedeschi, D.S.Lomoriello, A.Chiaravalloti, G.Ripandelli, and M.Varano (2009).
Retinal functional changes measured by microperimetry in neovascular age-related macular degeneration patients treated with ranibizumab.
  Retina, 29, 329-334.  
19407836 N.V.Chong (2009).
Should avastin be used to treat age-related macular degeneration in the NHS?--No.
  Eye, 23, 1250-1253.  
19079149 R.Rasier, O.Artunay, E.Yuzbasioglu, A.Sengul, and H.Bahcecioglu (2009).
The effect of intravitreal bevacizumab (avastin) administration on systemic hypertension.
  Eye, 23, 1714-1718.  
18766380 Y.Crawford, and N.Ferrara (2009).
VEGF inhibition: insights from preclinical and clinical studies.
  Cell Tissue Res, 335, 261-269.  
18388961 H.Dadgostar, and N.Waheed (2008).
The evolving role of vascular endothelial growth factor inhibitors in the treatment of neovascular age-related macular degeneration.
  Eye, 22, 761-767.  
19668384 M.S.Spitzer, F.Ziemssen, K.U.Bartz-Schmidt, F.Gelisken, and P.Szurman (2008).
Treatment of age-related macular degeneration: focus on ranibizumab.
  Clin Ophthalmol, 2, 1.  
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Current and emerging therapies for the treatment of age-related macular degeneration.
  Clin Ophthalmol, 2, 377-388.  
18404258 R.Simó, and C.Hernández (2008).
Intravitreous anti-VEGF for diabetic retinopathy: hopes and fears for a new therapeutic strategy.
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  19668726 S.Sivaprasad, N.Acharya, and P.Hykin (2008).
Pegaptanib sodium for neovascular age-related macular degeneration: clinical experience in the UK.
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18510737 Klerk, and D.H.Steel (2008).
Use of intravitreal bevacizumab in a patient with a Von Hippel-Lindau-associated retinal haemangioblastoma of the optic nerve head: a case report.
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19087303 Y.X.Huang, Y.L.Bao, S.Y.Guo, Y.Wang, C.G.Zhou, and Y.X.Li (2008).
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17685870 C.Hernández, and R.Simó (2007).
Strategies for blocking angiogenesis in diabetic retinopathy: from basic science to clinical practice.
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  19668481 D.P.Smit, and D.Meyer (2007).
Intravitreal bevacizumab: an analysis of the evidence.
  Clin Ophthalmol, 1, 273-284.  
17360669 H.P.Gerber, X.Wu, L.Yu, C.Wiesmann, X.H.Liang, C.V.Lee, G.Fuh, C.Olsson, L.Damico, D.Xie, Y.G.Meng, J.Gutierrez, R.Corpuz, B.Li, L.Hall, L.Rangell, R.Ferrando, H.Lowman, F.Peale, and N.Ferrara (2007).
Mice expressing a humanized form of VEGF-A may provide insights into the safety and efficacy of anti-VEGF antibodies.
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17477812 I.Benhar (2007).
Design of synthetic antibody libraries.
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17151070 I.Mayrose, T.Shlomi, N.D.Rubinstein, J.M.Gershoni, E.Ruppin, R.Sharan, and T.Pupko (2007).
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18046235 J.Gaudreault, D.Fei, J.C.Beyer, A.Ryan, L.Rangell, V.Shiu, and L.A.Damico (2007).
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17675348 J.Morfill, K.Blank, C.Zahnd, B.Luginbühl, F.Kühner, K.E.Gottschalk, A.Plückthun, and H.E.Gaub (2007).
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17933418 K.Hida, J.Hanes, and M.Ostermeier (2007).
Directed evolution for drug and nucleic acid delivery.
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17628122 M.V.Emerson, and A.K.Lauer (2007).
Emerging therapies for the treatment of neovascular age-related macular degeneration and diabetic macular edema.
  BioDrugs, 21, 245-257.  
17052163 N.Ferrara, R.D.Mass, C.Campa, and R.Kim (2007).
Targeting VEGF-A to treat cancer and age-related macular degeneration.
  Annu Rev Med, 58, 491-504.  
17330108 N.V.Chong, and T.Adewoyin (2007).
Intravitreal injection: balancing the risks.
  Eye, 21, 313-316.  
17891008 P.A.Quiram, T.S.Hassan, and G.A.Williams (2007).
Treatment of naïve lesions in neovascular age-related macular degeneration with pegaptanib.
  Retina, 27, 851-856.  
17628683 P.K.Kaiser, B.A.Blodi, H.Shapiro, and N.R.Acharya (2007).
Angiographic and optical coherence tomographic results of the MARINA study of ranibizumab in neovascular age-related macular degeneration.
  Ophthalmology, 114, 1868-1875.  
17313620 P.K.Kaiser, and D.V.Do (2007).
Ranibizumab for the treatment of neovascular AMD.
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17237677 R.C.Lin, and P.J.Rosenfeld (2007).
Antiangiogenic therapy in neovascular age-related macular degeneration.
  Int Ophthalmol Clin, 47, 117-137.  
  17951895 R.Kim (2007).
Introduction, mechanism of action and rationale for anti-vascular endothelial growth factor drugs in age-related macular degeneration.
  Indian J Ophthalmol, 55, 413-415.  
17891135 S.M.Lippow, K.D.Wittrup, and B.Tidor (2007).
Computational design of antibody-affinity improvement beyond in vivo maturation.
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17655610 U.M.Schmidt-Erfurth, G.Richard, A.Augustin, W.G.Aylward, F.Bandello, B.Corcòstegui, J.Cunha-Vaz, A.Gaudric, A.Leys, and R.O.Schlingemann (2007).
Guidance for the treatment of neovascular age-related macular degeneration.
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17027972 A.A.Moshfeghi, P.J.Rosenfeld, C.A.Puliafito, S.Michels, E.N.Marcus, J.D.Lenchus, and A.S.Venkatraman (2006).
Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twenty-four-week results of an uncontrolled open-label clinical study.
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17049020 D.J.Pieramici, and R.L.Avery (2006).
Ranibizumab: treatment in patients with neovascular age-related macular degeneration.
  Expert Opin Biol Ther, 6, 1237-1245.  
16763865 F.Ziemssen, K.U.Bartz-Schmidt, and S.Grisanti (2006).
[(Side) effects of VEGF inhibition]
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16373345 G.Fuh, P.Wu, W.C.Liang, M.Ultsch, C.V.Lee, B.Moffat, and C.Wiesmann (2006).
Structure-function studies of two synthetic anti-vascular endothelial growth factor Fabs and comparison with the Avastin Fab.
  J Biol Chem, 281, 6625-6631.
PDB codes: 2fjf 2fjg 2fjh
16483659 J.S.Heier, A.N.Antoszyk, P.R.Pavan, S.R.Leff, P.J.Rosenfeld, T.A.Ciulla, R.F.Dreyer, R.C.Gentile, J.P.Sy, G.Hantsbarger, and N.Shams (2006).
Ranibizumab for treatment of neovascular age-related macular degeneration: a phase I/II multicenter, controlled, multidose study.
  Ophthalmology, 113, 633.e1-633.e4.  
17031284 N.Ferrara, L.Damico, N.Shams, H.Lowman, and R.Kim (2006).
Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration.
  Retina, 26, 859-870.  
17000017 P.Dufner, L.Jermutus, and R.R.Minter (2006).
Harnessing phage and ribosome display for antibody optimisation.
  Trends Biotechnol, 24, 523-529.  
16487065 P.Gupta, M.Saleemuddin, and R.H.Khan (2006).
Hydrophobic interactions are the prevalent force in bromelain:Fab' complex.
  Biochemistry (Mosc), 71, S31-S37.  
16581423 P.J.Rosenfeld, J.S.Heier, G.Hantsbarger, and N.Shams (2006).
Tolerability and efficacy of multiple escalating doses of ranibizumab (Lucentis) for neovascular age-related macular degeneration.
  Ophthalmology, 113, 623.e1.  
17060799 P.U.Dugel (2006).
Ranibizumab treatment of patients with ocular diseases.
  Int Ophthalmol Clin, 46, 131-140.  
17011951 R.L.Avery, J.Pearlman, D.J.Pieramici, M.D.Rabena, A.A.Castellarin, M.A.Nasir, M.J.Giust, R.Wendel, and A.Patel (2006).
Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy.
  Ophthalmology, 113, 1695.e1-1695.15.  
16770255 R.M.Rich, P.J.Rosenfeld, C.A.Puliafito, S.R.Dubovy, J.L.Davis, H.W.Flynn, S.Gonzalez, W.J.Feuer, R.C.Lin, G.A.Lalwani, J.K.Nguyen, and G.Kumar (2006).
Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration.
  Retina, 26, 495-511.  
17078173 R.Narayanan, B.D.Kuppermann, C.Jones, and P.Kirkpatrick (2006).
  Nat Rev Drug Discov, 5, 815-816.  
16278208 W.C.Liang, X.Wu, F.V.Peale, C.V.Lee, Y.G.Meng, J.Gutierrez, L.Fu, A.K.Malik, H.P.Gerber, N.Ferrara, and G.Fuh (2006).
Cross-species vascular endothelial growth factor (VEGF)-blocking antibodies completely inhibit the growth of human tumor xenografts and measure the contribution of stromal VEGF.
  J Biol Chem, 281, 951-961.  
15939870 A.Rajpal, N.Beyaz, L.Haber, G.Cappuccilli, H.Yee, R.R.Bhatt, T.Takeuchi, R.A.Lerner, and R.Crea (2005).
A general method for greatly improving the affinity of antibodies by using combinatorial libraries.
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16211515 C.Shea, L.Bloedorn, and M.A.Sullivan (2005).
Rapid isolation of single-chain antibodies for structural genomics.
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16151404 H.R.Hoogenboom (2005).
Selecting and screening recombinant antibody libraries.
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  15630447 J.M.Butler, S.M.Guthrie, M.Koc, A.Afzal, S.Caballero, H.L.Brooks, R.N.Mames, M.S.Segal, M.B.Grant, and E.W.Scott (2005).
SDF-1 is both necessary and sufficient to promote proliferative retinopathy.
  J Clin Invest, 115, 86-93.  
15709915 M.A.Groves, and J.K.Osbourn (2005).
Applications of ribosome display to antibody drug discovery.
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16355214 N.Ferrara, and R.S.Kerbel (2005).
Angiogenesis as a therapeutic target.
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15967101 S.Ran, K.A.Mohamedali, T.A.Luster, P.E.Thorpe, and M.G.Rosenblum (2005).
The vascular-ablative agent VEGF(121)/rGel inhibits pulmonary metastases of MDA-MB-231 breast tumors.
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16054718 T.Hey, E.Fiedler, R.Rudolph, and M.Fiedler (2005).
Artificial, non-antibody binding proteins for pharmaceutical and industrial applications.
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15306681 F.A.Fellouse, C.Wiesmann, and S.S.Sidhu (2004).
Synthetic antibodies from a four-amino-acid code: a dominant role for tyrosine in antigen recognition.
  Proc Natl Acad Sci U S A, 101, 12467-12472.
PDB codes: 1tzh 1tzi
15155907 M.Gullberg, S.M.Gústafsdóttir, E.Schallmeiner, J.Jarvius, M.Bjarnegård, C.Betsholtz, U.Landegren, and S.Fredriksson (2004).
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Molecular studies of anti-HLA-A2 using light-chain shuffling: a structural model for HLA antibody binding.
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PDB code: 1ur7
15136787 N.Ferrara, K.J.Hillan, H.P.Gerber, and W.Novotny (2004).
Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer.
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Structural basis for recognition by an in vitro evolved affibody.
  Proc Natl Acad Sci U S A, 100, 3191-3196.
PDB code: 1lp1
12634013 S.A.Marshall, G.A.Lazar, A.J.Chirino, and J.R.Desjarlais (2003).
Rational design and engineering of therapeutic proteins.
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Crystal structure of an in vitro affinity- and specificity-matured anti-testosterone Fab in complex with testosterone. Improved affinity results from small structural changes within the variable domains.
  J Biol Chem, 277, 44021-44027.
PDB codes: 1l7s 1l7t 1vpo
12204693 L.Xu, P.Aha, K.Gu, R.G.Kuimelis, M.Kurz, T.Lam, A.C.Lim, H.Liu, P.A.Lohse, L.Sun, S.Weng, R.W.Wagner, and D.Lipovsek (2002).
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11447282 A.J.Chmura, M.S.Orton, and C.F.Meares (2001).
Antibodies with infinite affinity.
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11134506 L.Jermutus, A.Honegger, F.Schwesinger, J.Hanes, and A.Plückthun (2001).
Tailoring in vitro evolution for protein affinity or stability.
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Directed evolution of antibody fragments with monovalent femtomolar antigen-binding affinity.
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Antibody engineering.
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11102799 N.Ferrara (2000).
VEGF: an update on biological and therapeutic aspects.
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Phage display in pharmaceutical biotechnology.
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The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.