Granulocyte colony-stimulating factor (G-CSF), a recombinantdrug intended to mitigate the most horrendous side effect ofcancer chemotherapy, turns out to pack a potent tumor-killingpunch of its own.
Hair loss and nausea make anti-tumor drug regimens an agony,but are not in themselves life threatening. Infection is. Theanti-metabolites that modern medicine sends in to fightmalignancy also decimate the immune system, causing -- mostnotably -- neutropenia, or depletion of the body's neutrophils.
These effector cells, filled with pathogen-slaying granules, arethe most populous contingent of the blood's white cells. That'swhy G-CSF is becoming a major adjunct to chemotherapy,permitting higher doses of anti-cancer drugs and shorteninghospital stays caused by infection.
A team of Dutch and German immunologists and oncologistsreported discovering G-CSF's unexpected role as a cancer killerin the the current issue of the twice-monthly journal Blood.Their paper's title tells the story: "Involvement of the High-Affinity Receptor for IgG (FcyRI:CD64) in Enhanced Tumor CellCytotoxicity of Neutrophils During Granulocyte Colony-Stimulating Factor Therapy."
"What our paper tells first of all," explained its senior author,immunologist Jan G.J. Van de Winkel of Utrecht UniversityHospital, "is that when you isolate neutrophils from patientstreated in vivo with G-CSF, you get a very high expression of amyeloid trigger molecule, FcyRI, which neutrophils do notnormally express."
Van de Winkel told BioWorld that "these directed neutrophilsare incredibly active in directing lysis of tumor cells."
To demonstrate how this exotic IgG surface receptor works, thebinational team introduced the neutrophils in vitro to bispecificantibodies engineered to put them in touch with target tumorcells and destroy them.
They obtained the two-pronged, designer cut-off antibodies(MDX-210) from Medarex Inc. of Princeton, N.J. These semi-artificial components consist of two monoclonal fragments, eachwith its own antigen-seeking active site. Medarex's presidentand chief executive officer, Donald Drakeman, explained:"Fragment A binds to the tumor target, an oncogene calledHER2, which overexpresses in breast and ovarian cells.Fragment B binds to the trigger molecules on the neutrophils."
Medarex makes these Siamese-twin antibodies by reducingeach one to a predesigned fragment, using enzymic digestion,then coupling the two truncated sections chemically.
Fragment B, which recognizes the exotic G-CSF-instigated FcyRIreceptors aboard the neutrophils, is patent protected. "Ourpiece of the intellectual-property rock," Drakeman toldBioWorld, "is the unique triggering antibody, which is able tobind to and direct killing through these receptors in a far moreefficient way than even normal human antibodies."
Recruiting and arming these new neutrophils alongside the lessnumerous cytotoxic monocytes and phagocytes, Drakeman said,"is like adding another several battalions to your army. Youstarted with the army and navy, then you send in the marines.It's that kind of analogy."
As Blood reported, Van de Winkel and his associates testedMDX-210 in vitro with neutrophils of head-and-neck, testicularand hematological cancer patients treated with G-CSF(Neupogen obtained from Amgen Inc.). They also tested celllines for glioblastoma and ovarian carcinoma. In both groups,the bispecific/G-CSF combination produced a fivefold increasein tumor-cell destruction.
"What we show in this paper," Van de Winkel said, "is thatneutrophils are more potent even than T cells in directing thekilling of these tumor cells. So it may be a very wise idea tocombine treatment with G-CSF with bispecifics, enabling thoseeffector cells to be targeted physically toward the tumor cells.That is a new idea."
Will he test the idea in clinical trials?
"We are doing that. We will absolutely go forward and trywhether we can indeed use these potent trigger molecules inpatients treated with G-CSF." Such a trial, he added, "wouldbegin between now and a year from now."
Drakeman said the Blood results also will prompt Medarex "toexplore a separate clinical trial protocol using the two elements,MDX-210 and G-CSF, in combination." Meanwhile, two monthsago, Medarex began a Phase I/II study of the bispecific aloneat Dartmouth-Hitchcock Medical Center. This open-label, dose-escalation trial in breast and ovarian cancer patients resistantto chemotherapy will test the antibody's ability to recruitmonocytes and macrophages. It is currently enrolling a patienta week toward a planned 30 or 40 in the protocol.
Also two months ago, Chiron Corp. launched a Phase I trial ofits bispecific antibody at Fox Chase Cancer Center. One prongpicks up the FcyRI: receptor on white cells and the othertargets the erbB2 antigen on breast tumors.
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.