Cancer Immunology, Immunotherapy

, Volume 54, Issue 4, pp 315–327 | Cite as

Carcinoembryonic antigen antibody inhibits lung metastasis and augments chemotherapy in a human colonic carcinoma xenograft

  • Rosalyn D. Blumenthal
  • Lou Osorio
  • Marianne K. Hayes
  • Ivan D. Horak
  • Hans J. Hansen
  • David M. Goldenberg
Original Article

Abstract

Purpose: In addition to its use as a blood marker for many carcinomas, elevated expression of carcinoembryonic antigen (CEA, CD66e, CEACAM5) has been implicated in various biological aspects of neoplasia, especially tumor cell adhesion, metastasis, the blocking of cellular immune mechanisms, and having antiapoptosis functions. However, it is not known if treatment with anti-CEA antibodies can affect tumor metastasis or alter the effects of cytotoxic drugs. Methods: In vitro, human colon cancer cell lines were treated with anti-CEA MAb IgG1, hMN-14 (labetuzumab), to assess direct effects on proliferation, as well as antibody-dependent cellular cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). In vivo studies were undertaken in nude mice bearing s.c. (local growth) or i.v. (metastatic model) GW-39 and LS174T human colon cancer grafts, to evaluate the MAb alone and in combination with either CPT-11 or 5-fluorouracil (5FU). Results: In vitro, labetuzumab did not induce apoptosis, nor did it affect tumor cell proliferation directly or by CDC, but it did inhibit tumor cell proliferation by ADCC. In vivo, labetuzumab did not increase median survival in the GW-39 metastatic model unless the mice were pretreated with GM-CSF to increase their peripheral WBC counts; GM-CSF alone was ineffective. Also, if GW-39 tumors were pretreated with IFN-γ to up-regulate CEA expression threefold prior to i.v. injection, labetuzumab significantly increased median survival of the mice. When nude mice received labetuzumab with CPT-11 or 5FU, median survival increased significantly as compared to the drug or antibody alone. Conclusions: Labetuzumab, a CEA-specific MAb, induces effector-cell function in vitro against CEA-positive colonic tumor cells, and also inhibits growth of lung metastasis when CEA expression is up-regulated or if peripheral WBCs are increased. The MAb also shows chemosensitizing properties.

Keywords

ADCC Apoptosis CD66e CPT-11 5-Fluorouracil Immunotherapy 

Abbreviations

ADCC

Antibody-dependent cellular cytotoxicity

CDC

Complement-dependent cytotoxicity

BrdU

Bromodeoxyuridine

CDR

Complementarity-determining region

CEA

Carcinoembryonic antigen

EDTA

Ethylenediaminetetraacetic acid

EGFR

Epidermal growth factor receptor

ELISA

Enzyme-linked immunosorbent assay

5FU

5-Fluorouracil

GM-CSF or rM-GM-CSF

Recombinant murine granulocyte-macrophage colony-stimulating factor

HRP

Horseradish peroxidase

IFN-γ

Gamma interferon

LAK cells

Lymphokine-activated killer cells

LDH

Lactate dehydrogenase

MAb

Monoclonal antibody

MTD

Maximum tolerated dose

NK cells

Natural killer cells

PBMC

Peripheral blood mononuclear cell

pWBC

Peripheral white blood cell

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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Rosalyn D. Blumenthal
    • 1
  • Lou Osorio
    • 1
  • Marianne K. Hayes
    • 2
  • Ivan D. Horak
    • 2
  • Hans J. Hansen
    • 2
  • David M. Goldenberg
    • 1
  1. 1.Center for Molecular Medicine and ImmunologyGarden State Cancer CenterBellevilleUSA
  2. 2.Immunomedics, Inc.Morris PlainsUSA

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