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Blood, 15 November 2000, Vol. 96, No. 10, pp. 3544-3552
NEOPLASIA
Therapeutic efficacy of Fc RI/CD64-directed
bispecific antibodies in B-cell lymphoma
Jamie Honeychurch,
Alison
L. Tutt,
Thomas Valerius,
Ingmar A. F. M. Heijnen,
Jan G. J. Van de
Winkel, and
Martin J. Glennie
From the Cancer Sciences Division, School of Medicine,
General Hospital, Southampton, United Kingdom; Department of Medicine
III, University of Erlangen-Nurnberg, Nuremberg, Germany; and
Department of Immunology and Medarex Europe, University Medical Center,
Utrecht, The Netherlands.
CD64 (Fc RI) receptors represent highly potent trigger
molecules for activated polymorphonuclear cells (PMN) and mediate lysis of a range of tumors in the presence of appropriate monoclonal antibodies. An huCD64 transgenic mouse model designed to analyze the
therapeutic activity of a panel of bispecific F(ab')2
(BsAb) in retargeting granulocyte-colony-stimulating factor
(G-CSF)-activated PMN against syngeneic B-cell lymphomas is reported.
This model allows careful analysis of the individual elements of the
therapeutic process. BsAb were directed against immunoglobulin-idiotype
(Id), major histocompatibility class II (MHC II), or CD19 on the tumors and huCD64 on the effectors. In vitro cytotoxicity assays and in vivo
tumor tracking showed that, provided effectors were activated with
G-CSF, all 3 derivatives destroyed and cleared lymphoma cells, with
(huCD64 × MHC II) proving by far the most cytotoxic in vitro. However, though all derivatives delivered some survival advantage, only
the [huCD64 × Id] BsAb provided long-term protection to
tumor-bearing animals. These results demonstrate that CD64-recruited
cytotoxic effectors operate in vivo but that the (huCD64 × Id)
conferred an additional anti-tumor function essential for long-term
protection. T-cell depletion studies demonstrated that this extra
therapeutic activity with [huCD64 × Id] was totally dependent on
CD4 and CD8 T cells and that mice, once "cured" with BsAb, were
resistant to tumor rechallenge. These findings indicate that CD64 is an effective trigger molecule for delivering cytokine-activated PMN against tumor in vivo and that, provided tumor targets are selected appropriately, CD64-based BsAb can establish long-term T-cell immunity.
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