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Novo Annual Report 2015
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novo ventures invests in a european biopharmaceutical company. merus: boosting natural
antibodies
. m erus is a clinical-stage immuno-oncology company that specialises in the development of
bispecific
antibodies
for oncology. its lead programme has entered clinical trials in solid tumours, and the second programme is getting ready to enter clinical trials in 2016 for the treatment of acute myeloid leukaemia.
bispecific
antibodies
natural monoclonal
antibodies
are symmetric and monospecific, i.e. both arms of the
antibody
bind to the same target. merus?
bispecific
human
antibodies
have been modified to bind to two different targets to enable novel and more potent modes of action.
bispecific
antibodies
can be designed to simultaneously block multiple receptors that drive tumour cell growth and survival. this approach has been used for the design of mcla-128, merus? her2xher3
bispecific
antibody
, which is in phase i/ii clinical testing for the treatment of patients with her2-expressing solid tumours. in another approach,
bispecific
antibodies
can be used to mobilise the patient?s immune response by activating various killer cells to eradicate tumours. micromet was the first company to truly advance this concept into clinical proof of concept, and their lead programme, blinatumomab was approved by the fda in december 2014 for the treatment of acute lymphoblastic leukaemia. however, the problem with blinatumomab is that it is composed of
antibody
fragments and has a very short half-life of two hours. several other biotech and pharma companies are working on other
bispecific
formats with a view to improving half-life, reducing immunogenicity, and ensuring good manufacturability, high stability and tuneable immune activation. merus is leading this field with biclonics ® , the first
bispecific
antibody
format to represent a normal full-length human igg
antibody
and meet all the desired attributes at the same time.
bispecific
antibody
treatment of aml one of merus? very promising programmes focuses on the treatment of patients with acute myeloid leukaemia (aml). aml is a cancer of the myeloid line of blood cells, characterised by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. as an acute leukaemia, aml progresses rapidly and is typically fatal within months if left untreated. cause of death is often related to infections. merus?
bispecific
antibody
, mcla-117 could potentially treat more than 90 per cent of aml patients. mcla-117 binds to two different targets: clec12a, whose expression is restricted to myeloid cells present in peripheral blood and bone marrow; and cd3, which is expressed on t cells. mcla-117 brings the t cells in close proximity to the cancer cell to facilitate tumour cell killing. pre-clinical data on patient tumour samples show impressive kill efficacy, while the
bispecific
antibody
does not harm other cell types in vitro. many complementary technologies merus uses its proprietary transgenic mouse, memo ® and state- of-the art phage display libraries of human fab fragments for the generation of panels of common light chain
antibodies
. large and diverse panels of high affinity
antibodies
have been generated against a broad variety of targets. ? the memo ® mouse . this technology has a knock-in of single human vl gene incapable of undergoing somatic hypermutation, and a knock-in of human vh locus capable of rearrangements and somatic hypermutation. the mouse also has a knock-out of endogenous murine immunoglobulin heavy and light chain loci. this results in the memo ® mice generating high affinity, fully human mabs encoded by the germline vl and a somatically mutated vh. ? biclonics ® high-throughput functional screening. the panels of target-specific human common light chain
antibodies
are introduced as pairs of dna constructs into cells. the common light chain format and engineered ch3 domains of the
antibody
constant region ensure the secretion of essentially pure biclonics ® into the cell culture medium. the medium of thousands of cell cultures is harvested and used for rapid screening in cell- and tissue- based functional assays.
bispecific
antibodies
are expected to play a key role in cancer immuno-therapy treatments in the future. the dutch biotech, merus is a leading player in this field, developing innovative
bispecific
antibody
therapeutics to treat ? and potentially cure ? cancer patients. novo ventures novo a/s 38
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