A universal combinatorial design of antibody framework to graft distinct CDR sequences: A bioinformatics approach
Correction(s) for this article
-
A universal combinatorial design of antibody framework to graft distinct CDR sequences: A bioinformatics approach
- Jaafar N. Haidar,
- Qing-An Yuan,
- Lin Zeng,
- Mark Snavely,
- Xenia Luna,
- Haifan Zhang,
- Wei Zhu,
- Dale L. Ludwig,
- Zhenping Zhu,
- Volume 81Issue 9Proteins: Structure, Function, and Bioinformatics
- pages: 1677-1677
- First Published online: August 23, 2013
Corresponding Author
Jaafar N. Haidar
Department of Antibody Technology, ImClone Systems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Alexandria Center for Life Sciences, New York, New York 10016
Jaafar N. Sleiman Haidar and Qing-An Yuan contributed equally to this work.
Jaafar N. Haidar, Department of Antibody Technology, ImClone Systems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Alexandria Center for Life Sciences, New York, New York 10016===Search for more papers by this authorQing-An Yuan
Department of Antibody Technology, ImClone Systems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Alexandria Center for Life Sciences, New York, New York 10016
Search for more papers by this authorLin Zeng
Department of Antibody Technology, ImClone Systems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Alexandria Center for Life Sciences, New York, New York 10016
Search for more papers by this authorMark Snavely
Department of Antibody Technology, ImClone Systems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Alexandria Center for Life Sciences, New York, New York 10016
Search for more papers by this authorXenia Luna
Department of Antibody Technology, ImClone Systems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Alexandria Center for Life Sciences, New York, New York 10016
Search for more papers by this authorHaifan Zhang
Department of Antibody Technology, ImClone Systems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Alexandria Center for Life Sciences, New York, New York 10016
Search for more papers by this authorWei Zhu
Department of Antibody Technology, ImClone Systems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Alexandria Center for Life Sciences, New York, New York 10016
Search for more papers by this authorDale L. Ludwig
Department of Antibody Technology, ImClone Systems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Alexandria Center for Life Sciences, New York, New York 10016
Search for more papers by this authorZhenping Zhu
Department of Antibody Technology, ImClone Systems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Alexandria Center for Life Sciences, New York, New York 10016
Search for more papers by this authorCorresponding Author
Jaafar N. Haidar
Department of Antibody Technology, ImClone Systems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Alexandria Center for Life Sciences, New York, New York 10016
Jaafar N. Sleiman Haidar and Qing-An Yuan contributed equally to this work.
Jaafar N. Haidar, Department of Antibody Technology, ImClone Systems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Alexandria Center for Life Sciences, New York, New York 10016===Search for more papers by this authorQing-An Yuan
Department of Antibody Technology, ImClone Systems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Alexandria Center for Life Sciences, New York, New York 10016
Search for more papers by this authorLin Zeng
Department of Antibody Technology, ImClone Systems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Alexandria Center for Life Sciences, New York, New York 10016
Search for more papers by this authorMark Snavely
Department of Antibody Technology, ImClone Systems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Alexandria Center for Life Sciences, New York, New York 10016
Search for more papers by this authorXenia Luna
Department of Antibody Technology, ImClone Systems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Alexandria Center for Life Sciences, New York, New York 10016
Search for more papers by this authorHaifan Zhang
Department of Antibody Technology, ImClone Systems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Alexandria Center for Life Sciences, New York, New York 10016
Search for more papers by this authorWei Zhu
Department of Antibody Technology, ImClone Systems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Alexandria Center for Life Sciences, New York, New York 10016
Search for more papers by this authorDale L. Ludwig
Department of Antibody Technology, ImClone Systems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Alexandria Center for Life Sciences, New York, New York 10016
Search for more papers by this authorZhenping Zhu
Department of Antibody Technology, ImClone Systems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Alexandria Center for Life Sciences, New York, New York 10016
Search for more papers by this authorAbstract
Antibody (Ab) humanization is crucial to generate clinically relevant biologics from hybridoma-derived monoclonal antibodies (mAbs). In this study, we integrated antibody structural information from the Protein Data Bank with known back-to-mouse mutational data to build a universal consensus of framework positions (10 heavy and 7 light) critical for the preservation of the functional conformation of the Complimentarity Determining Region of antibodies. On the basis of FR consensus, we describe here a universal combinatorial library suitable for humanizing exogenous antibodies by CDR-grafting. The six CDRs of the murine anti-human EGFR Fab M225 were grafted onto a distinct (low FR sequence similarity to M225) human FR sequence that incorporates at the 17 FR consensus positions the permutations of the naturally observed amino acid diversities. Ten clones were selected from the combinatorial library expressing phage-displayed humanized M225 Fabs. Surprisingly, 2 of the 10 clones were found to bind EGFR with stronger affinity than M225. Cell-based assays demonstrated that the 10 selected clones retained epitope specificity by blocking EGFR phosphorylation and thus hindering cellular proliferation. Our results suggest that there is a universal and structurally rigid near-CDR set of FR positions that cooperatively support the binding conformation of CDRs. Proteins 2011. © 2012 Wiley Periodicals, Inc.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
| Filename | Description |
|---|---|
| PROT_23246_sm_SuppInfo.pdf226.9 KB | Supporting Information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1CarterPJ.Potent antibody therapeutics by design.Nat Rev Immunol2006; 6: 343–357.
- 2KozlowskiS,WoodcockJ,MidthunK,ShermanRB.Developing the nation's biosimilars program.N Engl J Med2011; 365: 385–388.
- 3KohlerG,HengartnerH,ShulmanMJ.Immunoglobulin production by lymphocyte hybridomas.Eur J Immunol1978; 8: 82–88.
- 4MorrisonSL,JohnsonMJ,HerzenbergLA,OiVT.Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains.Proc Natl Acad Sci USA1984; 81: 6851–6855.
- 5SahaganBG,DoraiH,Saltzgaber-MullerJ,ToneguzzoF,GuindonCA,LillySP,McDonaldKW,MorrisseyDV,StoneBA,DavisGL,McIntoshPK,MooreGP.A genetically engineered murine/human chimeric antibody retains specificity for human tumor-associated antigen.J Immunol1986; 137: 1066–1074.
- 6RiechmannL,ClarkM,WaldmannH,WinterG.Reshaping human antibodies for therapy.Nature1988; 332: 323–327.
- 7HwangWY,FooteJ.Immunogenicity of engineered antibodies.Methods2005; 36: 3–10.
- 8ShawlerDL,BartholomewRM,SmithLM,DillmanRO.Human immune response to multiple injections of murine monoclonal IgG.J Immunol1985; 135: 1530–1535.
- 9JaffersGJ,FullerTC,CosimiAB,RussellPS,WinnHJ,ColvinRB.Monoclonal antibody therapy. Anti-idiotypic and non-anti-idiotypic antibodies to OKT3 arising despite intense immunosuppression.Transplantation1986; 41: 572–578.
- 10LiJ,SaiT,BergerM,ChaoQ,DavidsonD,DeshmukhG,DrozdowskiB,EbelW,HarleyS,HenryM,JacobS,KlineB,LazoE,RotellaF,RouthierE,RudolphK,SageJ,SimonP,YaoJ,ZhouY,KavuruM,BonfieldT,ThomassenMJ,SassPM,NicolaidesNC,GrassoL.Human antibodies for immunotherapy development generated via a human B cell hybridoma technology.Proc Natl Acad Sci USA2006; 103: 3557–3562.
- 11GreenLL,HardyMC,Maynard-CurrieCE,TsudaH,LouieDM,MendezMJ,AbderrahimH,NoguchiM,SmithDH,ZengY,DavidNE,SasaiH,GarzaD,BrennerDG,HalesJF,McGuinnessRP,CaponDJ,KlapholzS,JakobovitsA.Antigen-specific human monoclonal antibodies from mice engineered with human Ig heavy and light chain YACs.Nat Genet1994; 7: 13–21.
- 12ClacksonT,HoogenboomHR,GriffithsAD,WinterG.Making antibody fragments using phage display libraries.Nature1991; 352: 624–628.
- 13MarksJD,HoogenboomHR,BonnertTP,McCaffertyJ,GriffithsAD,WinterG.By-passing immunization. Human antibodies from V-gene libraries displayed on phage.J Mol Biol1991; 222: 581–597.
- 14RoguskaMA,PedersenJT,KeddyCA,HenryAH,SearleSJ,LambertJM,GoldmacherVS,BlattlerWA,ReesAR,GuildBC.Humanization of murine monoclonal antibodies through variable domain resurfacing.Proc Natl Acad Sci USA1994; 91: 969–973.
- 15Dall'AcquaWF,DamschroderMM,ZhangJ,WoodsRM,WidjajaL,YuJ,WuH.Antibody humanization by framework shuffling.Methods2005; 36: 43–60.
- 16LazarGA,DesjarlaisJR,JacintoJ,KarkiS,HammondPW.A molecular immunology approach to antibody humanization and functional optimization.Mol Immunol2007; 44: 1986–1998.
- 17JonesPT,DearPH,FooteJ,NeubergerMS,WinterG.Replacing the complementarity-determining regions in a human antibody with those from a mouse.Nature1986; 321: 522–525.
- 18QueenC,SchneiderWP,SelickHE,PaynePW,LandolfiNF,DuncanJF,AvdalovicNM,LevittM,JunghansRP,WaldmannTA.A humanized antibody that binds to the interleukin 2 receptor.Proc Natl Acad Sci USA1989; 86: 10029–10033.
- 19VerhoeyenM,MilsteinC,WinterG.Reshaping human antibodies: grafting an antilysozyme activity.Science1988; 239: 1534–1536.
- 20KettleboroughCA,SaldanhaJ,HeathVJ,MorrisonCJ,BendigMM.Humanization of a mouse monoclonal antibody by CDR-grafting: the importance of framework residues on loop conformation.Protein Eng1991; 4: 773–783.
- 21CarterP,PrestaL,GormanCM,RidgwayJB,HennerD,WongWL,RowlandAM,KottsC,CarverME,ShepardHM.Humanization of an anti-p185HER2 antibody for human cancer therapy.Proc Natl Acad Sci USA1992; 89: 4285–4289.
- 22BacaM,PrestaLG,O'ConnorSJ,WellsJA.Antibody humanization using monovalent phage display.J Biol Chem1997; 272: 10678–10684.
- 23WallJG,PluckthunA.The hierarchy of mutations influencing the folding of antibody domains in Escherichia coli.Protein Eng1999; 12: 605–611.
- 24ChothiaC,LeskAM.Canonical structures for the hypervariable regions of immunoglobulins.J Mol Biol1987; 196: 901–917.
- 25MianIS,BradwellAR,OlsonAJ.Structure, function and properties of antibody binding sites.J Mol Biol1991; 217: 133–151.
- 26FooteJ,WinterG.Antibody framework residues affecting the conformation of the hypervariable loops.J Mol Biol1992; 224: 487–499.
- 27PrestaLG,ChenH,O'ConnorSJ,ChisholmV,MengYG,KrummenL,WinklerM,FerraraN.Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders.Cancer Res1997; 57: 4593–4599.
- 28ShalabyMR,ShepardHM,PrestaL,RodriguesML,BeverleyPC,FeldmannM,CarterP.Development of humanized bispecific antibodies reactive with cytotoxic lymphocytes and tumor cells overexpressing the HER2 protooncogene.J Exp Med1992; 175: 217–225.
- 29PrestaLG,LahrSJ,ShieldsRL,PorterJP,GormanCM,FendlyBM,JardieuPM.Humanization of an antibody directed against IgE.JImmunol1993; 151: 2623–2632.
- 30EigenbrotC,GonzalezT,MayedaJ,CarterP,WertherW,HotalingT,FoxJ,KesslerJ.X-ray structures of fragments from binding and nonbinding versions of a humanized anti-CD18 antibody: structural indications of the key role of VH residues 59 to 65.Proteins1994; 18: 49–62.
- 31MartinAC.Accessing the Kabat antibody sequence database by computer.Proteins1996; 25: 130–133.
10.1002/(SICI)1097-0134(199605)25:1<130::AID-PROT11>3.0.CO;2-L CAS PubMed Web of Science® Google Scholar
- 32BermanHM,WestbrookJ,FengZ,GillilandG,BhatTN,WeissigH,ShindyalovIN,BournePE.The protein data bank.Nucleic Acids Res2000; 28: 235–242.
- 33HoneggerA,PluckthunA.Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool.J Mol Biol2001; 309: 657–670.
- 34LefrancMP,GiudicelliV,GinestouxC,Jabado-MichaloudJ,FolchG,BellahceneF,WuY,GemrotE,BrochetX,LaneJ,RegnierL,EhrenmannF,LefrancG,DurouxP.IMGT, the international ImMunoGeneTics information system.Nucleic Acids Res2009; 37: D1006–D1012.
- 35FanZ,MasuiH,AltasI,MendelsohnJ.Blockade of epidermal growth factor receptor function by bivalent and monovalent fragments of 225 anti-epidermal growth factor receptor monoclonal antibodies.Cancer Res1993; 53: 4322–4328.
- 36PrewettM,RockwellP,RockwellRF,GiorgioNA,MendelsohnJ,ScherHI,GoldsteinNI.The biologic effects of C225, a chimeric monoclonal antibody to the EGFR, on human prostate carcinoma.J Immunother Emphasis Tumor Immunol1996; 19: 419–427.
- 37AbhinandanKR,MartinAC.Analysis and improvements to Kabat and structurally correct numbering of antibody variable domains.Mol Immunol2008; 45: 3832–3839.
- 38MacCallumRM,MartinAC,ThorntonJM.Antibody-antigen interactions: contact analysis and binding site topography.J Mol Biol1996; 262: 732–745.
- 39AllcornLC,MartinAC.SACS—self-maintaining database of antibody crystal structure information.Bioinformatics2002; 18: 175–181.
- 40TatusovaTA,MaddenTL.BLAST 2 Sequences, a new tool for comparing protein and nucleotide sequences.FEMS Microbiol Lett1999; 174: 247–250.
- 41KraussJ,ArndtMA,MartinAC,LiuH,RybakSM.Specificity grafting of human antibody frameworks selected from a phage display library: generation of a highly stable humanized anti-CD22 single-chain Fv fragment.Protein Eng2003; 16: 753–759.
- 42EwertS,HuberT,HoneggerA,PluckthunA.Biophysical properties of human antibody variable domains.J Mol Biol2003; 325: 531–553.
- 43HoetRM,CohenEH,KentRB,RookeyK,SchoonbroodtS,HoganS,RemL,FransN,DaukandtM,PietersH,van HegelsomR,NeerNC,NastriHG,RondonIJ,LeedsJA,HuftonSE,HuangL,KashinI,DevlinM,KuangG,SteukersM,ViswanathanM,NixonAE,SextonDJ,HoogenboomHR,LadnerRC.Generation of high-affinity human antibodies by combining donor-derived and synthetic complementarity-determining-region diversity.Nat Biotechnol2005; 23: 344–348.
- 44RichRL,MyszkaDG.Advances in surface plasmon resonance biosensor analysis.Curr Opin Biotechnol2000; 11: 54–61.
- 45SadickMD.Kinase receptor activation (KIRA): a rapid and accurate alternative to endpoint bioassays.Dev Biol Stand1999; 97: 121–133.
- 46LiuB,FangM,SchmidtM,LuY,MendelsohnJ,FanZ.Induction of apoptosis and activation of the caspase cascade by anti-EGF receptor monoclonal antibodies in DiFi human colon cancer cells do not involve the c-jun N-terminal kinase activity.Br J Cancer2000; 82: 1991–1999.
- 47KabatEA, National Institutes of Health (U.S.). Office of the Director. Sequences of proteins of immunological interest: tabulation and analysis of amino acid and nucleic acid sequences of precursors, V-regions, C-regions, J-chain, T-cell receptors for antigenm T-cell surface antigens, [beta]2-microglobulins,major histocompatibility antigens, Thy-1, complement, C-reactive protein, thymopoietin, integrins, post-gamme globulin, α2-macroglobulins, and other related proteins.Bethesda, MD (Bethesda, 20892):U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health;1991.
- 48LefrancMP.Unique database numbering system for immunogenetic analysis.Immunol Today1997; 18: 509.
- 49LefrancMP,GiudicelliV,GinestouxC,BodmerJ,MullerW,BontropR,LemaitreM,MalikA,BarbieV,ChaumeD.IMGT, the international ImMunoGeneTics database.Nucleic Acids Res1999; 27: 209–212.
- 50RuizM,GiudicelliV,GinestouxC,StoehrP,RobinsonJ,BodmerJ,MarshSG,BontropR,LemaitreM,LefrancG,ChaumeD,LefrancMP.IMGT, the international ImMunoGeneTics database.Nucleic Acids Res2000; 28: 219–221.
- 51HanesJ,SchaffitzelC,KnappikA,PluckthunA.Picomolar affinity antibodies from a fully synthetic naive library selected and evolved by ribosome display.Nat Biotechnol2000; 18: 1287–1292.
- 52NiebaL,HoneggerA,KrebberC,PluckthunA.Disrupting the hydrophobic patches at the antibody variable/constant domain interface: improved in vivo folding and physical characterization of an engineered scFv fragment.Protein Eng1997; 10: 435–444.
- 53WornA,PluckthunA.Different equilibrium stability behavior of ScFv fragments: identification, classification, and improvement by protein engineering.Biochemistry1999; 38: 8739–8750.
- 54WornA,PluckthunA.Stability engineering of antibody single-chain Fv fragments.J Mol Biol2001; 305: 989–1010.
- 55ZhangC,VasmatzisG,CornetteJL,DeLisiC.Determination of atomic desolvation energies from the structures of crystallized proteins.J Mol Biol1997; 267: 707–726.
- 56MiyazawaS, JerniganRL.Estimation of effective inter-residue contact energies from protein crystal structures: quasi-chemical approximation.Macromolecules1985; 18: 534–552.
- 57TempestPR,WhiteP,ButtleM,CarrFJ,HarrisWJ.Identification of framework residues required to restore antigen binding during reshaping of a monoclonal antibody against the glycoprotein gB of human cytomegalovirus.Int J Biol Macromol1995; 17: 37–42.
- 58NakanishiT,TsumotoK,YokotaA,KondoH,KumagaiI.Critical contribution of VH-VL interaction to reshaping of an antibody: the case of humanization of anti-lysozyme antibody, HyHEL-10.Protein Sci2008; 17: 261–270.
- 59TramontanoA,ChothiaC,LeskAM.Framework residue 71 is a major determinant of the position and conformation of the second hypervariable region in the VH domains of immunoglobulins.J Mol Biol1990; 215: 175–182.
- 60LegerOJ,YednockTA,TannerL,HornerHC,HinesDK,KeenS,SaldanhaJ,JonesST,FritzLC,BendigMM.Humanization of a mouse antibody against human alpha-4 integrin: a potential therapeutic for the treatment of multiple sclerosis.Hum Antibodies1997; 8: 3–16.
- 61ProbaK,WornA,HoneggerA,PluckthunA.Antibody scFv fragments without disulfide bonds made by molecular evolution.J Mol Biol1998; 275: 245–253.
- 62LiS,SchmitzKR,JeffreyPD,WiltziusJJ,KussieP,FergusonKM.Structural basis for inhibition of the epidermal growth factor receptor by cetuximab.Cancer Cell2005; 7: 301–311.
- 63SaulFA,PoljakRJ.Structural patterns at residue positions 9, 18, 67 and 82 in the VH framework regions of human and murine immunoglobulins.J Mol Biol1993; 230: 15–20.
- 64WornA,PluckthunA.Mutual stabilization of VL and VH in single-chain antibody fragments, investigated with mutants engineered for stability.Biochemistry1998; 37: 13120–13127.
- 65FongCJ,SherwoodER,MendelsohnJ,LeeC,KozlowskiJM.Epidermal growth factor receptor monoclonal antibody inhibits constitutive receptor phosphorylation, reduces autonomous growth, and sensitizes androgen-independent prostatic carcinoma cells to tumor necrosis factor alpha.Cancer Res1992; 52: 5887–5892.
- 66NgM,CunninghamD.Cetuximab (Erbitux)—an emerging targeted therapy for epidermal growth factor receptor-expressing tumours.Int J Clin Pract2004; 58: 970–976.
- 67FanZ,LuY,WuX,MendelsohnJ.Antibody-induced epidermal growth factor receptor dimerization mediates inhibition of autocrine proliferation of A431 squamous carcinoma cells.J Biol Chem1994; 269: 27595–27602.
- 68SpanglerJB,NeilJR,AbramovitchS,YardenY,WhiteFM,LauffenburgerDA,WittrupKD.Combination antibody treatment down-regulates epidermal growth factor receptor by inhibiting endosomal recycling.Proc Natl Acad Sci USA2010; 107: 13252–13257.
- 69PedersenMW,JacobsenHJ,KoefoedK,HeyA,PykeC,HaurumJS,KraghM.Sym004: a novel synergistic anti-epidermal growth factor receptor antibody mixture with superior anticancer efficacy.Cancer Res2010; 70: 588–597.
- 70WuX,FanZ,MasuiH,RosenN,MendelsohnJ.Apoptosis induced by an anti-epidermal growth factor receptor monoclonal antibody in a human colorectal carcinoma cell line and its delay by insulin.J Clin Invest1995; 95: 1897–1905.
- 71ThorpeIF,BrooksCL,III.Molecular evolution of affinity and flexibility in the immune system.Proc Natl Acad Sci USA2007; 104: 8821–8826.
- 72MohanS,KourentziK,SchickKA,UeharaC,LipschultzCA,AcchioneM,DesantisME,Smith-GillSJ,WillsonRC.Association energetics of cross-reactive and specific antibodies.Biochemistry2009; 48: 1390–1398.
Citing Literature
