Abstracts (complete list) - Wissenschaft Online

Dafne Müller, Bettina Meißburger, Katharina Frey, Anette Karle, Ines Höfig, Roland
Stork, Roland E. Kontermann
Generation of an improved recombinant bispecific antibody
molecule and B7 fusion proteins for targeted cancer
immunotherapy
The recombinant bispecific antibody format single-chain diabody (scDb) has shown to
be able to retarget T lymphocytes to tumor cells, leading to their destruction. However,
therapeutic efficacy is hampered by the short serum half-life of this small molecule (55
kDa). Thus, improvement of the pharmacokinetic properties of small bispecific antibody
formats is required to enhance efficacy in vivo. We have generated a fusion protein of
single chain diabody and human serum albumin (scDb-HSA) and analyzed this molecule
for biological activity and pharmacokinetic properties. The scDb-HSA, which is directed
against the tumor antigen carcinoembryonic antigen (CEA) and the T cell receptor
complex molecule CD3, retained full binding capacity to both antigens and showed
strong increase in circulation time compared to the unfused scDb molecule. In order to
provide a tumor target specific costimulatory signal, fusion proteins of the extracellular
domain of B7.2 (CD86) and single chain Fv or diabody against CEA were generated.
This constructs showed specific binding to CEA and CD28/CTLA-4. Costimulatory
properties were assayed in combination with the scDb (providing the first stimulatory
signal) by monitoring IL-2 release after incubation with PBMCs. Here, B7-Db showed to
be superior to B7-scFv. Thus, in combination with B7-Db an enhancement of tumor
antigen-specific retargeting and activation of T cells could be achieved for scDb and
scDb-HSA. In summary, combining recombinant bispecific antibodies with improved
pharmacokinetic properties and tumor directed costimulatory fusion proteins might be a
promising approach for efficient retargeting and activation of cytotoxic T lymphocytes in
cancer immunotherapy.