Micromet AG,
Staffelseestr. 2, 81477 Munich, Germany
patrick.baeuerle@micromet.de
The concept of bispecific antibodies
is highly attractive for the treatment of human diseases such as cancer, and
autoimmune and pro-inflammatory diseases. Bispecific antibodies can transiently
link target cells with otherwise inactive immune cells for induction of an
antigen-dependent redirected lysis of target cells. Over the past 15 years,
hundreds of publications and several phase I clinical trials have explored
the potential of bispecific antibodies recruiting cytotoxic T lymphocytes
(CTL). Many distinct bispecific formats have been developed including quadroma
antibodies, diabodies, Fab2 fragments and single-chain antibodies.
However, none of the many approaches has been fruitful in the development
of marketed drugs. Notorious problems were (i) production of sufficient and
homogeneous amounts of protein; (ii) the requirement for additional stimuli
to activate T cells; (iii) the need for excess amounts of T cells over target
cells; and (iv) disappointing efficacy and lack of therapeutic window in clinical
trials.
We have developed a novel bispecific
format that has seemingly overcome most problems encountered with previous
formats. We refer to this format as “bispecific T cell engager” (BiTE). One
example is MT103, a single-chain CD19/-CD3-bispecific antibody for the treatment
of human B cell malignancies which currently is in several phase 1 trials.
MT103 can at a high rate deplete tumor cells in blood samples from lymphoma
patients by recruiting the low amounts of endogenous T effector cells. MT103
does not require additional stimuli of CTL but can inherently activate a large
proportion of T cells as long as appropriate CD19-positive target cells are
present. Half maximal tumor cell elimination by MT103 is seen at low pico-molar
concentrations. The basis for the high potency of BiTEs is the initiation
of regular cytolytic synapses between T and tumor cells which requires only
very few BiTE molecules.
The particular features of MT103
are preserved when BiTEs are equipped with single chain antibodies recognizing
other targets for treatment of other diseases. BiTEs for treatment of solid
adenocarcinoma are being developed (for more information see www.micromet.de).