Cancer Research - Europa

Keywords | Monoclonal antibodies | bispecifi c | bifunctional | nanoparticles | genetic engineering |
leukaemia and lymphoma | cancer therapy |
BMC
Bispecifi c Monoclonal Antibody
Technology Concept
Summary
Monoclonal antibodies (mAbs) represent a new form of
protein-based drug having demonstrated a signifi cant
impact on the treatment of several types of cancers. Their
specifi city towards cell surface receptors makes them able
to target and destroy tumour cells. However, much progress
is still necessary to understand the mechanism of the binding
and activity of antibodies in order to improve their
targeting capabilities and their effi ciency. To reach these
objectives, the BMC project will:
• develop a recombinant bispecifi c mAb with tetrameric
binding sites, directed against two diff erent antigens
expressed on the same target tumour cell;
• develop new bispecifi c or bifunctional molecules with
the property of cross-linking two diff erent receptors on
the surface of the cell;
• modify the carbohydrate moiety of bispecifi c antibodies
and the tumour targeting of the complement regulator
molecule, properdin, to trigger the activation of the
complement enzymatic cascade at the tumour site.
The recombinant molecules are directed against a selected
target antigen for mAb therapy, CD5, as well as a B-cell
marker to be selected, in order to treat a specifi c type of
leukaemia, the B-CLL. However, the described innovative
cancer immunotherapy strategy will also be extended to
the treatment of many other types of cancers, especially all
carcinomas.
The consortium is made up of nine partners:
• six RTDs specialising in genetic engineering (CNRS), innovative
molecule design (UNIL), antibody vectorisation with
nanoparticles (HUJI), CDC activity improvement and cell
line and animal model development (UBO), mechanisms
of therapeutic antibodies on patients’ cells (OORRBG),
toxicology studies and standardisation (ITEM);
• two biotechnology SMEs specialising in therapeutic
antibody development (MAT) and antibodies in vitro
production (MABGENE);
• one company dedicated to the project management
– ALMA.
EARLY DETECTION, DIAGNOSIS AND PROGNOSIS
Problem
Monoclonal antibodies given as a single modality treatment
induce tumour remissions in less than 50 % of patients with
well-selected type of cancer; complete tumour remissions
are scarce. Thus, while the rapid introduction of mAbs for
cancer therapy is very encouraging in favour of the use
of this type of biological molecule, much progress is still
necessary to understand the mechanism of the action of
therapeutic mAbs in order to make them more specifi c and
effi cient in a broader range of cancer types. Indeed, it is
a paradox that despite the great success of some wellselected
mAbs in the treatment of some cancer types, the
principal mechanism by which mAbs are inducing the
destruction of cancer cells has not yet been completely elucidated.
Furthermore, the reasons why some patients
respond to mAbs therapy, while others with almost the same
tumour do not, is not yet understood. The possible causes
for a poor response to mAbs therapy include a low density
of target antigen on the surface of tumour cells, which limits
the activity of complement mediated cytotoxicity (CDC),
and of antibody dependent cell-mediated immunity (ADCC),
a low sensitivity of tumour cells to an apoptosis signal or a
poor accessibility of the injected mAbs to the tumour cells.
Aim
The global aim of the project is to improve the monoclonal
antibody therapy with special emphasis on B-Chronic Lymphocytic
Leukaemia and Mantle zone B-cell lymphoma,
which will be achieved by:
• a link between targeting and activity: increase of understanding
of apoptosis signalling;
• exploitation of the complement activity on tumoural cells
as it is known to function on bacteria, overcoming the
known inhibitory molecules present in eukaryotic cells;
• development of novel approaches to optimise the targeting
and destruction of tumoural cells by:
• engineering new constructs of recombinant bispecifi c or
bifunctional antibodies reacting with two diff erent antigens
on the same tumour cells;
• developing new strategies for the induction of complementdependant
cytotoxicity (CDC), either through modifi cations
of the glycosylation of bispecifi c monoclonal antibodies, or
by genetically fusing properdin to recombinant monoclonal
antibodies;
• chemical conjugation of antibodies of diff erent specifi cities
on emulsion nanoparticles;
• evaluation and validation of the novel tumour targeting
strategies proposed in the BMC project on tumour cells
from patients with CD5 + B-cell lymphoproliferative diseases,
as well as in an experimental model of SCID mice
grafted with CD5 + B-cell lines.
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