Antibody Fragments Directed against Different Portions of the Human Neural Cell Adhesion Molecule L1 Act as Inhibitors or Activators of L1 Function.docVIP

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Antibody Fragments Directed against Different Portions of the Human Neural Cell Adhesion Molecule L1 Act as Inhibitors or Activators of L1 Function.doc

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Antibody Fragments Directed against Different Portions of the Human Neural Cell Adhesion Molecule L1 Act as Inhibitors or Activators of L1 Function

AntibodyFragmentsDirectedagainstDifferentPortions oftheHumanNeuralCellAdhesionMoleculeL1Actas InhibitorsorActivatorsofL1Function YanWang1,GabrieleLoers2,Hong-ChaoPan1,RicardoGouveia3,Wei-JiangZhao1,Yan-QinShen1, RalfKleene2,JuliaCosta3,MelittaSchachner1,4* 1Center for Neuroscience, Shantou University Medical College, Shantou, Guangdong Province, People’s Republic of China, 2Zentrum fu¨r Molekulare Neurobiologie Hamburg, Universita¨t Hamburg, Hamburg, Germany, 3Instituto de Tecnologia Qu?′mica e Biolo′gica, Universidade Nova de Lisboa, Oeiras, Portugal, 4Keck Center for CollaborativeNeuroscienceandDepartmentofCellBiologyandNeuroscience,RutgersUniversity,Piscataway,NewJersey,UnitedStatesofAmerica Abstract The neural cell adhesion molecule L1 plays important roles in neuronal migration and survival, neuritogenesis and synaptogenesis.L1hasalsobeenfoundintumorsofdifferentorigins,withlevelsofL1expressioncorrelatingpositivelywith themetastaticpotentialoftumors.ToselectantibodiestargetingthevariedfunctionsofL1,wescreenedtheTomlinson library of recombinant human antibody fragments to identify antibodies binding to recombinant human L1 protein comprising the entire extracellular domain of human L1. We obtained four L1 binding single-chain variable fragment antibodies(scFvs),namedI4,I6,I13,andI27andshowedbyenzyme-linkedimmunosorbentassay(ELISA)thatscFvsI4and I6 have high affinity to the immunoglobulin-like (Ig) domains 1–4 of L1, while scFvs I13 and I27 bind strongly to the fibronectintypeIIIhomologous(Fn)domains1–3ofL1.ApplicationofscFvsI4andI6tohumanSK-N-SHneuroblastoma cellsreducedproliferationandtransmigrationofthesecells.TreatmentofSK-N-SHcellswithscFvsI13andI27enhancedcell proliferationandmigration,neuriteoutgrowth,andprotectedagainstthetoxiceffectsofH2O2byincreasingtheratioofBcl- 2/Bax.Inaddition,scFvsI4andI6inhibitedandscFvsI13andI27promotedphosphorylationofsrcandErk.Ourfindings indicatethatscFvsreactingwiththeimmunoglobulin-likedomains1–4inhibitL1functions,whereassc