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-Receptor I (CD89) Recruits Neutrophils as Effector Cells for CD20-Directed Antibody Therapy1
*
Division of Hematology/Oncology, Department of Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany;
Medarex, Annandale, NJ;
Tenovus Research Laboratory, Southampton, U.K.; and
Department of Immunology and Medarex Europe BV, University Hospital Utrecht, Utrecht, The Netherlands
CD20 Abs induce clinical responses in lymphoma patients, but there
are considerable differences between individual patients. In
51Cr release assays with whole blood as effector source,
RAJI cells were effectively killed by a mouse/human chimeric IgG1
construct of CD20 Ab 1F5, whereas ARH-77 proved resistant to killing by
this Ab. When whole blood was fractionated into plasma, mononuclear
cells, or granulocytic effector cells, RAJI cells were effectively
killed in the presence of complement-containing plasma, whereas the
mature B cell line ARH-77 proved complement resistant. However, with a
bispecific Ab (BsAb) against the myeloid receptor for IgA (CD89;
Fc
RI) and CD20, a broad range of B cell lines were effectively
killed. FcRI is expressed on monocytes/macrophages, neutrophils, and
eosinophils. As the numbers of these effector cells and their
functional activity can be enhanced by application of G-CSF or GM-CSF,
lysis via (FcRI x CD20) BsAb was significantly enhanced in
blood from patients during therapy with these myeloid growth factors.
Interestingly, the major effector cell population for this BsAb were
polymorphonuclear neutrophils, which proved ineffective in killing
malignant B cells with murine, chimeric IgG1, or Fc
RI- or
FcRIII-directed BsAbs against CD20. Experiments with blood from
human FcRI/FcRI double-transgenic mice showed corresponding
results, allowing the establishment of relevant syngenic animal models
in these mice. In conclusion, the combination of myeloid growth factors
and an (FcRI x CD20) BsAb may represent a promising approach
to improve effector cell recruitment for CD20-directed lymphoma
therapy.
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