Micromet Sticking To Research into Cell Adhesion Antibodies

[Christine]

Micromet is sticking to its research into cell adhesion antibodies to treat breast cancer and other tumours, hoping it will have more luck than GlaxoSmithKline and Centocor's failed attempt.

Epithelial cell adhesion molecule (EpCAM) is over expressed in several types of cancer, including breast, colon and gastric cancers. Although several companies are reported to have developed antibodies against this transmembrane protein, only GSK and Centocor have taken a drug to market: Panorex (edrecolomab).

In fact, when Panorex, a murine-based monoclonal antibody (mAb), was approved by German regulators back in 1995, it became the world's first anticancer mAb. However, the initial excitement didn't last and the drug was subsequently withdrawn due to lack of efficacy.

Dr Tobias Raum, who heads up lead discovery of antibodies for Micromet, believes this was because Panorex was a murine-based mAb, and so lost its efficacy quickly as it was broken down by human antibodies. He explained that Micromet's own drug, called adecatumumab (MT201), is a human antibody and so is "likely to be much more efficacious and non-immo-toxic."

He was speaking at the recent drug Discovery and Development of innovative Therapeutics conference in Boston, US, and took the opportunity to explain to delegates that this explains why the drug actually works better in vitro than Panorex, although both have a similar, intermediate, affinity to EpCAM.

This middling binding to its target ensures adecatumumab has a good safety profile, he explained. At first, the company developed a type I immunoglobulin (IgG1), the most abundant subclass of antibodies. However, its scientists soon discovered an IgG2a version worked much better and in a lung cancer model, the number of tumours was almost reduced to zero.

A subsequent Phase I clinical trial showed no grade four toxicities, no dose dependence of clearance, and perhaps most importantly, no human antibodies were found against the drug.

Micromet then moved it into a Phase II trial in metastatic breast cancer patients. The study had four arms with high and low doses and high and low doses of EpCAM expression. For ethical reasons, no control group was used, explained Raum.

However, no overall effective tumour response was observed, which was the primary endpoint of the trial. Despite this, there was some encouraging news for Micromet: in EpCAM positive patients, the time to disease progression was significantly longer in patients treated with the higher dose of the drug.

"The finding of better clinical outcome in patients with truly high EpCAM expressing tumours confirms the targeted nature of adecatumumab," said Dr Ahmad Awada, Head of the Medical Oncology Clinic at Institute Jules Bordet in Brussels, Belgium.

"[it] is in line with observations from other tumour-specific monoclonal antibodies in oncology like [Roche & Genentech's] Herceptin [trastuzumab]."

Raum said that a Phase IIb trial of the mAb in combination with chemotherapy (docetaxel) is currently ongoing.