Cancer Immunology, Immunotherapy

, Volume 54, Issue 5, pp 431–445

Epithelial tight junction proteins as potential antibody targets for pancarcinoma therapy

  • Sonja Offner
  • Armin Hekele
  • Ulrike Teichmann
  • Susanne Weinberger
  • Susanne Gross
  • Peter Kufer
  • Christian Itin
  • Patrick A. Baeuerle
  • Birgit Kohleisen
Original Article
  • 246 Downloads

Abstract

Recombinant monoclonal antibodies are beginning to revolutionize cancer therapy. In combination with standard chemotherapy, high response rates have been reported with antibodies of the human IgG1 isotype for treatment of non-Hodgkin’s lymphoma and breast cancer. It is becoming apparent that targets for antibody-based therapies do not necessarily need to be absent from normal tissues but can be present there either in low copy numbers or with binding epitopes shielded from the therapeutic antibody. Here, we studied whether claudin proteins that form tight junctions in normal epithelia are still expressed on carcinoma cells and whether their extracellular domains can be recognized by antibodies. We show that mRNAs of claudins 1, 3, 4, and 7 are all expressed in different human carcinoma cell lines, while claudin 8 was selectively expressed in breast and pancreas cancer lines. Chicken polyclonal antibodies were raised against peptides contained within predicted extracellular domains of claudins 1, 3, and 4. Affinity-purified IgG fractions for claudins 3 and 4 were monospecific and bound to human breast and colon carcinoma lines, but not to a line of monocytic origin. Claudin 3 antibodies also homogeneously stained human renal cell carcinoma tissue and micrometastatic tumor cells as identified by cytokeratin staining in bone marrow biopsies of breast cancer patients. Fluorescence-activated cell sorting and immunocytochemistry indicated that claudin antibodies bound to the surface of tumor cells. By analogy to other tumor-associated antigens that are differentially accessible to antibodies on tumor vs normal tissue, we propose that certain claudin proteins have potential as targets for novel antibody-based therapies of carcinomas.

Keywords

Antibody Carcinoma Claudin Gene expression Therapeutic target Tight junction 

Abbreviations

ADCC

Antibody-dependent cell-mediated cytotoxicity

AP

Alkaline phosphatase

CDC

Complement-dependent cytotoxicity

CDR

Complementarity-determining region

CLDN

Claudin

CPE

Clostridium perfringens enterotoxin

dNTP

Deoxynucleoside-triphosphate

ELISA

Enzyme-linked immunosorbent assay

Ep-CAM

Epithelial cell adhesion molecule

FACS

Fluorescence-activated cell sorting

FCS

Fetal calf serum

HPLC

High-performance liquid chromatography

IgG

Immunoglobulin G

KLH

Keyhole limpet hemocyanine

NK

Natural killer cell

PBS

Phosphate-buffered saline

PCR

Polymerase chain reaction

PNPP

Paranitrophenylphosphate

RT

Reverse transcription

TJ

Tight junction

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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Sonja Offner
    • 1
  • Armin Hekele
    • 2
  • Ulrike Teichmann
    • 1
  • Susanne Weinberger
    • 1
  • Susanne Gross
    • 1
  • Peter Kufer
    • 1
  • Christian Itin
    • 1
  • Patrick A. Baeuerle
    • 1
  • Birgit Kohleisen
    • 1
  1. 1.Micromet AGMunichGermany
  2. 2.Department of Microbiology and ImmunologyUniversity of CaliforniaSan FranciscoUSA

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