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Bispecific antibodies target operationally tumor-specific antigens in two
leukemia relapse models
H Lindhofer, H Menzel, W Gunther, L Hultner and S Thierfelder
Forschungszentrum fur Umwelt und Gesundheit (GSF)-Institut fur Immunologie,
Munich, Germany.
Despite improved procedures in chemotherapy and bone marrow transplantation
(BMT), post-BMT leukemia relapse rates have remained rather constant in the
last decade. Immunotherapy with monoclonal or bispecific antibodies (bsAb)
is a promising approach to improve this situation, but is hampered by the
absence of tumor-specific antigens on the majority of tumors. To evade this
problem, we developed a new tumor- specific approach in which bispecific
antibodies exploit chimerism after allogeneic BMT by redirecting donor T
cells against recipient- specific antigens on tumor cells. Two different
leukemia relapse models were established using a T-cell lymphoma (ST-1) and
a B-cell lymphoma (BCL1) to evaluate the efficiency of such a therapy. In
these experiments, irradiated BALB/c (Thy-1.2+, I-Ad) mice were
transplanted with C57BL/6 Thy-1.1 (I-Ab) BM cells under the protection of
graft- versus-host disease-preventing monoclonal antibodies. Forty-five
days after BMT, the chimeric mice were injected with either 2 x 10(4)
recipient-type, Thy-1.2+, CD3- ST-1 cells or major histocompatability
complex (MHC) class II+ (I-Ad)-BCL1 cells. Four days later, the mice were
treated with 8 microg bsAb G2 (anti-CD3 x anti-Thy-1.2) or 10 microg (+10
microg, day 6) bsAb BiC (anti-CD3 x anti-I-Ad), respectively. These
combinations guaranteed exclusive binding of the bsAbs target arms to tumor
cells, leaving the surrounding, donor-type hematopoietic cells unbound.
Compared with the parental antibodies, the bsAbs markedly reduced tumor
mortality. Between 34% and 83% of mice survived in the bsAb groups compared
with 0% of the control groups treated with parental antibodies, clearly
documenting the benefit of the redirection principle. Furthermore, cytokine
release (interleukin- 6) after anti-CD3 antibody or bsAb treatment was
decreased by administering a low-dose antibody preinjection. We have shown
(1) that 6 weeks after BMT, when donor T-cell reconstitution is still in
progress, T-cell-redirecting bsAb are clearly superior to parental
antibodies in terms of tumor cell elimination; and (2) that the
polymorphism of a common antigen such as Thy-1 or a clinically more
relevant target antigen such as MHC class II can be used as an operational
tumor-specific antigen after allogeneic BMT.
Volume 88,
Issue 12,
pp. 4651-4658,
12/15/1996
Copyright © 1996 by The American Society of Hematology
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