Recombinant anti-carcinoembryonic antigen antibodies for targeting cancer.
Antibodies can be used to target cancer therapies to malignant tissue; the approach is attractive because conventional treatments such as chemo- and radiotherapy are dose limited due to toxicity in normal tissues. Effective targeting relies on appropriate pharmacokinetics of antibody-based therapeutics, ideally showing maximum uptake and retention in tumor and rapid clearance from normal tissue. We have studied the factors influencing these dynamics for antibodies against carcinoembryonic antigen (CEA). Protein engineering of anti-CEA antibodies, in vivo biodistribution models, and mathematical models have been employed to improve understanding of targeting parameters, define optimal characteristics for the antibody-based molecules employed, and develop new therapies for the clinic. Engineering antibodies to obtain the desired therapeutic characteristics is most readily achieved using recombinant antibody technology, and we have taken the approach of immunizing mice to provide high-affinity anti-CEA single-chain Fv antibodies (sFvs) from filamentous bacteriophage libraries. MFE-23, the most characterized of these sFvs, has been expressed in bacteria and purified in our laboratory for two clinical trials: a gamma camera imaging trial using 123I-MFE-23 and a radioimmunoguided surgery trial using 125I-MFE-23, where tumor deposits are detected by a hand-held probe during surgery. Both these trials showed that MFE-23 is safe and effective in localizing tumor deposits in patients with cancer. We are now developing fusion proteins that use the MFE-23 antibody to deliver a therapeutic moiety; MFE-23:: carboxypeptidase G2 (CPG2) targets the enzyme CPG2 for use in the antibody-directed enzyme prodrug therapy system and MFE::tumor necrosis factor alpha (TNFalpha) aims to reduce sequestration and increase tumor concentrations of systemically administered TNFalpha.
Chester
K A
KA
Department of Oncology, Royal Free & University College Medical School, London, UK. k.chester@ucl.ac.uk
Mayer
A
A
Bhatia
J
J
Robson
L
L
Spencer
D I
DI
Cooke
S P
SP
Flynn
A A
AA
Sharma
S K
SK
Boxer
G
G
Pedley
R B
RB
Begent
R H
RH
D000818:Animals; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D007128:Immunoglobulin Fragments / Q000276:immunology* / Q000378:metabolism / Q000627:therapeutic use; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D011994:Recombinant Proteins / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use
D002272:Carcinoembryonic Antigen; D018796:Immunoconjugates; D007128:Immunoglobulin Fragments; D011994:Recombinant Proteins