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==Bivalent and trivalent scFvs==
[[File:Polyvalent single-chain variable fragments.svg|thumb|300px|Structure of divalent (top) and trivalent (bottom) scFvs, tandem (left) and di-/trimerisation format (right)]]
''Divalent'' (or ''bivalent'') single-chain variable fragments (di-scFvs, bi-scFvs) can be engineered by linking two scFvs. This can be done by producing a single peptide chain with two V<sub>H</sub> and two V<sub>L</sub> regions, yielding ''tandem scFvs''.<ref>{{cite journal|title=Development of tumor targeting anti-MUC-1 multimer: effects of di-scFv unpaired cysteine ___location on PEGylation and tumor binding|first5=SJ|last5=Denardo|first4=GL|last4=Denardo|first3=XB|last3=Shi|first2=A|last2=Natarajan |last1=Xiong|first1=Cheng-Yi|journal=Protein Engineering Design and Selection|year=2006|volume=19|issue=8|pmid=16760193|pages=359–367|url=http://peds.oxfordjournals.org/cgi/content/full/19/8/359|doi=10.1093/protein/gzl020|doi-access=free}}</ref><ref>{{cite journal|title=A revival of bispecific antibodies|first1=Peter|last1=Kufer|first2=Ralf|last2=Lutterbüse|first3=Patrick A.|last3=Baeuerle|journal=Trends in Biotechnology|volume=22|issue=5|pages=238–244|year=2004|url=http://www.micromet.de/fileadmin/template/main/pdf/publications_147881aaf61df52304237f0ee7f0cf2a.pdf|doi=10.1016/j.tibtech.2004.03.006|pmid=15109810}}</ref> Another possibility is the creation of scFvs with linker peptides that are too short for the two variable regions to fold together (about five amino acids), forcing scFvs to dimerize. This type is known as ''diabodies''.<ref>{{cite journal|pmid=8341653|title="Diabodies": small bivalent and bispecific antibody fragments|last1=Hollinger|first1=Philipp|volume=90|issue=14|pmc=46948|date=July 1993|pages=6444–8|last2=Prospero|first2=T|last3=Winter|first3=G|journal=Proceedings of the National Academy of Sciences of the United States of America|doi=10.1073/pnas.90.14.6444|bibcode=1993PNAS...90.6444H}}</ref> Diabodies have been shown to have [[dissociation constant]]s up to 40-fold lower than corresponding scFvs, meaning that they have a much higher [[affinity (pharmacology)|affinity]] to their target. Consequently, diabody drugs could be dosed much lower than other therapeutic antibodies and are capable of highly specific targeting of tumors in vivo.<ref name="Adams">{{cite journal|pmid=9652755|year=1998|last1=Adams|first1=GP|last2=Schier|first2=R|last3=McCall|first3=AM|last4=Crawford|first4=RS|last5=Wolf|first5=EJ|last6=Weiner|first6=LM|last7=Marks|first7=JD|title=Prolonged in vivo tumour retention of a human diabody targeting the extracellular ___domain of human HER2/neu|volume=77|issue=9|pages=1405–12|pmc=2150193|journal=British Journal of Cancer|doi=10.1038/bjc.1998.233}}</ref> Still shorter linkers (one or two amino acids) lead to the formation of trimers, so-called ''triabodies'' or ''tribodies''. ''Tetrabodies'' have also been produced. They exhibit an even higher affinity to their targets than diabodies.<ref>{{cite journal|title=Di-, tri- and tetrameric single chain Fv antibody fragments against human CD19: effect of valency on cell binding|first4=M|last4=Little|first3=G|last3=Moldenhauer|journal=FEBS Letters|first2=SM|volume=453|last2=Kipriyanov|issue=1|pages=164–168|first1=F.|last1=Le Gall|pmid=10403395|doi=10.1016/S0014-5793(99)00713-9|year=1999|s2cid=20213440|doi-access=free}}</ref>
All of these formats can be composed from variable fragments with specificity for two different antigens, in which case they are types of [[bispecific antibodies]].<ref>{{cite journal|pmid=11388794|year=2001|last1=Dincq|first1=S|last2=Bosman|first2=F|last3=Buyse|first3=MA|last4=Degrieck|first4=R|last5=Celis|first5=L|last6=De Boer|first6=M|last7=Van Doorsselaere|first7=V|last8=Sablon|first8=E|title=Expression and purification of monospecific and bispecific recombinant antibody fragments derived from antibodies that block the CD80/CD86-CD28 costimulatory pathway|volume=22|issue=1|pages=11–24|doi=10.1006/prep.2001.1417|journal=Protein Expression and Purification}}</ref><ref>{{cite web|first1=C|last1=Kellner|url=http://www.opus.ub.uni-erlangen.de/opus/volltexte/2009/1235/|title=Entwicklung und Charakterisierung bispezifischer Antikörper-Derivate zur Immuntherapie CD19-positiver Leukämien und Lymphome|trans-title=Development and characterisation of bispecific antibody derivatives for the immunotherapy of CD19-positive leukaemia and lymphoma|language=de, en|publisher=Friedrich-Alexander-Universität|___location=Erlangen-Nürnberg|year=2008}}</ref> The furthest developed of these are bispecific tandem di-scFvs, known as [[bi-specific T-cell engager]]s (BiTE antibody constructs).
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