Abstract Book 2010 - CIMT Annual Meeting

066 Dettmar | New targets & new leads
Identification of clinically useful combinations of trifunctional
antibodies with chemotherapy using different preclinical
models
Kirsten Dettmar 1 , Petra Schroeder 2 , Carsten Lindemann 2 , Andrea Eberhardt 1 , Franziska
Hirschhaeuser 3 , Diane Seimetz 1 , Judith Atz 1
1 Fresenius Biotech GmbH, Munich, Germany
2 EUFETS GmbH, Idar-Oberstein, Germany
3 Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg-University
Mainz, Germany
The trifunctional bispecific antibodies catumaxo-
mab (anti-EpCAM x anti-CD3) and ertumaxomab
(anti-HER-2/neu x anti-CD3) exert their mechanism
of action by simultaneous recruitment and activation
of two different types of immune effector cells
(T-cells and accessory cells) at the tumor site. Thus
tumor cells and immune effector cells are brought
into close proximity leading to physiological co-stimulation
of T-cells, improved tumor cell elimination
by different immunologic killing mechanisms
and phagocytosis, as well as processing and presentation
of tumor material by bound and activated
accessory cells.
Despite the development of different antibody therapies,
chemotherapy (CTX) still represents the mainstay
of cancer therapy. Therefore many antibodies
are either used in combination with the established
chemotherapeutic therapies or in short intervals afterwards.
However, the commonly observed hematological
toxicities of chemotherapeutics are regularly associated
with some degree of immunosuppression.
On the other hand, some of these chemotherapeutic
agents are reported to support or even enhance the
anti-tumor effect of immunotherapeutic drugs in
certain doses.
A largely intact immune system is the key for trifunctional
antibodies to exhibit their full mode of action.
Since chemotherapy might impact the number and
/ or function of immune effector cells, we evaluated
in different preclinical in vitro models whether the
efficacy of trifunctional bispecific antibodies would
be influenced when combined with chemotherapeutic
drugs from different drug classes.
The preclinical studies performed included in vitro
cytotoxicity assays with established tumor cell lines
evaluating potential synergy by using the method
of Chou and Talalay. Furthermore, results from 3D
tumor spheroids and from an autologous human
ex vivo setting are presented. In addition, immune
cells from cancer patients were obtained at different
time points before, during and after chemotherapy
and were assessed for their in vitro cytotoxicity mediated
by trifunctional antibodies.
So far the results from the different in vitro assay
systems used indicate synergy for the combination
of the trifunctional antibodies with 5-Fluorouracil
(5-FU), cisplatin and epirubicin. Furthermore, no
negative influence of these chemotherapeutic drugs
was observed on the trifunctional mode of action
in vitro. Catumaxomab and ertumaxomab were
able to mediate an effective killing of tumor cells
with immune cells from chemotherapy patients
shortly after chemotherapy. The respective patients
immune cells can be activated by these bispecific
antibodies one week after chemotherapy with pyrimidine
antagonists (5-FU) and alkylating agents
(cisplatin) resulting in significant tumor cell killing
in vitro.
These results provide a basis for the possible combination
of these drugs with trifunctional antibodies
in the clinical setting.
111