Production of soluble ScFvs with C-terminal-free thiol for site-specific conjugation or stable dimeric ScFvs on demand

Bioconjug Chem. 2004 Jan-Feb;15(1):16-26. doi: 10.1021/bc030018+.

Abstract

ScFv recombinant antibody fragments can provide specific tumor binding modules for targeting drugs. In the process of building multimeric tumor targeting pharmaceuticals, a prerequisite is the conservation of functional scFv antigen binding domains, thereby excluding scFv random conjugation to a carrier molecule or to another scFv. The pCANTAB 5E phage display/expression vector was genetically engineered to express any scFv gene as scFv with an additional C-terminal cysteine (scFv-Cys) such that the specific conjugation site is removed from the binding domain. Selected scFvs derived from an anti-MUC-1 scFv phage library were expressed in pCANTAB 5E and its modified version pCANTAB 5E Cys vectors, and compared for key characteristics. Production yields of scFv and scFv-Cys in shaker flask and biofermentor were compared. In the absence of a reducing agent, stable dimers (covalent scFv homodimers (scFv-Cys)2) were the major form of scFv-Cys. These diabodies provided substantial signal enhancement for immunohistochemical staining of tissues. In the presence of a reducing agent, scFv-Cys molecules remained monomeric, with the free SH available for conjugation to a PEG(maleimide)2 scaffold to form immunoreactive PEG(scFv)2 bioconjugates. ScFv expression from pCANTAB 5E Cys allowed for the production of soluble scFv-Cys protein from E.coli, either as stable scFv-Cys or (scFv-Cys)2. ScFv-Cys can be used for conjugation to PEG to form bivalent PEG (scFv-Cys)2 molecules or used as (scFv-Cys)2 for increased sensitivity in IHC.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antibodies, Monoclonal / chemistry*
  • Cell Line, Tumor
  • Cloning, Molecular
  • Cysteine / chemistry
  • Electrophoresis, Polyacrylamide Gel
  • Enzyme-Linked Immunosorbent Assay
  • Escherichia coli / genetics
  • Female
  • Fermentation
  • Genetic Vectors
  • Humans
  • Immunoglobulin Fragments / chemistry*
  • Immunoglobulin Variable Region / biosynthesis
  • Immunoglobulin Variable Region / chemistry*
  • Immunohistochemistry
  • Indicators and Reagents
  • Mutagenesis
  • Peptide Library
  • Polyethylene Glycols
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry*
  • Reducing Agents / chemistry
  • Sulfhydryl Compounds / chemistry*
  • Sulfhydryl Reagents

Substances

  • Antibodies, Monoclonal
  • Immunoglobulin Fragments
  • Immunoglobulin Variable Region
  • Indicators and Reagents
  • Peptide Library
  • Recombinant Proteins
  • Reducing Agents
  • Sulfhydryl Compounds
  • Sulfhydryl Reagents
  • Polyethylene Glycols
  • Cysteine