Production and characterization of a camelid single domain antibody-urease enzyme conjugate for the treatment of cancer

Bioconjug Chem. 2015 Jun 17;26(6):1144-55. doi: 10.1021/acs.bioconjchem.5b00237. Epub 2015 May 14.

Abstract

A novel immunoconjugate (L-DOS47) was developed and characterized as a therapeutic agent for tumors expressing CEACAM6. The single domain antibody AFAIKL2, which targets CEACAM6, was expressed in the Escherichia coli BL21 (DE3) pT7-7 system. High purity urease (HPU) was extracted and purified from Jack bean meal. AFAIKL2 was activated using N-succinimidyl [4-iodoacetyl] aminobenzoate (SIAB) as the cross-linker and then conjugated to urease. The activation and conjugation reactions were controlled by altering pH. Under these conditions, the material ratio achieved conjugation ratios of 8-11 antibodies per urease molecule, the residual free urease content was practically negligible (<2%), and high purity (>95%) L-DOS47 conjugate was produced using only ultradiafiltration to remove unreacted antibody and hydrolyzed cross-linker. L-DOS47 was characterized by a panel of analytical techniques including SEC, IEC, Western blot, ELISA, and LC-MS(E) peptide mapping. As the antibody-urease conjugate ratio increased, a higher binding signal was observed. The specificity and cytotoxicity of L-DOS47 was confirmed by screening in four cell lines (BxPC-3, A549, MCF7, and CEACAM6-transfected H23). BxPC-3, a CEACAM6-expressing cell line was found to be most susceptible to L-DOS47. L-DOS47 is being investigated as a potential therapeutic agent in human phase I clinical studies for nonsmall cell lung cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / therapeutic use*
  • Camelids, New World*
  • Canavalia / enzymology*
  • Cell Line, Tumor
  • Enzyme Therapy
  • Humans
  • Immunoconjugates / chemistry
  • Immunoconjugates / therapeutic use*
  • Male
  • Mice, Nude
  • Molecular Sequence Data
  • Neoplasms / drug therapy*
  • Single-Domain Antibodies / chemistry
  • Single-Domain Antibodies / therapeutic use*
  • Urease / chemistry
  • Urease / therapeutic use*

Substances

  • Antineoplastic Agents
  • Immunoconjugates
  • Single-Domain Antibodies
  • Urease