Suppressing granulocyte macrophage colony-stimulating factor (GM-CSF) to tackle inflammatory and autoimmune diseases is the concept behind a new worldwide collaboration between German-American biopharmaceutical company Micromet and Denmark's Nycomed.
The agreement centres on Micromet's MT203, a human antibody expected to enter clinical trials in 2008. According to the new partners, MT203 neutralises GM-CSF, a cytokine known to play a significant role in autoimmune and inflammatory disease. Preclinical studies conducted by Micromet make a case for developing MT203 as a treatment for rheumatoid arthritis, multiple sclerosis, psoriasis, asthma and chronic obstructive pulmonary disease, they say.
Under the collaboration, Micromet will receive an upfront licence fee of €5m and additional payments and research and development (R&D) reimbursements of more than €120m in aggregate on achieving development milestones. The company is also eligible for royalties on worldwide sales of MT203 and any other products that may emerge from the agreement.
Micromet will take most of the responsibility for preclinical testing, process development and manufacturing of MT203 for early clinical trials, while Nycomed will be responsible for clinical development and commercialisation worldwide. Nycomed will also bear the cost of development activities and will reimburse Micromet for any expenses incurred in connection with the development programme.
Neutralising GM-CSF "presents a new biology concept in inflammatory processes and may have the potential to improve the lives of patients suffering from severe chronic inflammatory and autoimmune diseases," said Anders Ullman, Nycomed's executive vice-president R&D.
A human, high-affinity IgG1 antibody, MT203 was generated by Micromet using phage display-guided selection. The results of in vitro studies published last May in the journal Molecular Immunology showed that MT203 bound with picomolar affinity to an epitope on human and macaque GM-CSF involved in high-affinity receptor interaction.
As a consequence, the Micromet researchers said, the antibody potently prevented both GM-CSF-induced proliferation of TF-1 cells (these are used in proliferation bioassays for a number of cytokines and neutralising antibodies) and production of the chemokine IL-8 by U937 cells. MT203 significantly reduced both the survival and activation of peripheral human eosinophils, "as may be required for effective treatment of inflammatory lung diseases," they noted.
Another encouraging finding was that the antibody did not show any detectable loss of neutralising activity after five days in human serum at a temperature of 37°C.
In late June 2006, Micromet reported results from a study in arthritic mice challenged with streptococcus cell-wall fragments, in which a GM-CSF neutralising monoclonal was compared with the TNF (tumour necrosis factor)-alpha blocker etanercept, sold by Wyeth as Enbrel.
The monoclonal antibody (mAb) was found to be more potent than etanercept at reducing swelling of affected knee joints. While both the mAb and etanercept decreased the number of inflammatory cells in the joints, only the mAb cut levels of interleukin-1 beta (IL-1 beta) and reduced proteoglycan loss from the articular knee cartilage, Micromet pointed out.
IL1-beta mediates cartilage and bone destruction via secretion of metalloproteinases and decreases the synthesis of proteoglycan, one of the main components of the articular cartilage that cushions the body's joints.
These results suggested, therefore, that antibody neutralisation of GM-CSF might not only reduce inflammation but also protect cartilage from the destruction characteristic of arthritis - and that it might do so in TNF-alpha independent disease.
For Nycomed, the deal on MT203 highlights the company's strategic interest in inflammatory research and is the first example of its "strong commitment" to external collaborations at all stages of drug development as a key component of a new R&D strategy.
Following its acquisition of Germany's Altana Pharma in September 2006, Nycomed announced details earlier this year of an integration programme and strategic realignment that included redefining its R&D model to make it more flexible, results-oriented and "able to forge strong partnerships with external partners."