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In the past Prohost Letter, we highlighted the biotech firm Micromet (MITI) and its extremely elegant BiTE monoclonal antibody technology. The BiTE antibody creates an immunological synapse between the cytotoxic T cells and the cancer cell in the same manner it happens naturally in the body. The cytolytic synapses mediate the delivery of cell poisonous proteins - perforin and granzymes - from the cytotoxic T cells into the cancer cells, leading these cells to self-destruct, a process referred to as apoptosis, or programmed cell death.

The concept is elegant. It is a breakthrough. But, like most breakthroughs, the BiTE approach needed to be validated. Slowly, but surely, validation is being made. This validation began with the observation that in the presence of BiTE antibodies, T cells have demonstrated their full cancer killing capability as they have serially eliminated tumor cells. More over, through the killing process, T cells were observed to proliferate, as judged by their increase in number at the site of attack.

Recently, an interesting validation was presented in a poster at the 51ST Annual Meeting of the American Society of Hematology (ASH) in New Orleans, Louisiana. The published poster contained new data from the ongoing phase 1 clinical trial of BiTE antibody, blinatumomab, for non-Hodgkin's lymphoma (NHL). The presentation demonstrated that at a dose level of 60 microgram/squaremeter per day, the drug realized partial or complete responses after the first 4-8 weeks of treatment. The responses were confirmed by independent review.

Biotechnology companies aim at creating breakthrough molecules that are expected to become therapeutic molecules (drugs). However, before they reach that goal, i.e., can be given to patients as treatments of diseases, they have to demonstrate safety at an effective dose. Molecules developed by Micromet are no exception. Its Blinatumomab molecules, the topic of the poster, had a problem. At its effective 60 microgram/squaremeter per day dose, the molecules have caused transient neurological adverse events. Researchers at Micromet observed that these neurological symptoms were fully reversible. They did not stay still. The scientists looked for a predictive marker for these adverse events in patients with NHL and identified them in a low ratio of B to T cells in peripheral blood.

Micromet did not lose time. It designed and effectively developed a biomarker-guided dosing schedule to decrease these early neurological events and provide all patients with the opportunity to reach the dose of 60 micrograms/squaremeter per day. This is a small sample of what biotechnology firms can do to overcome their product problems.

From the presentation, we also learned that at the effective 60-microgram dose level, the remaining common adverse events of any grade were fever, lymphopenia, leukopenia, increased C-reactive protein, and headache. Most have been of early occurrence and improved or resolved during treatment. As for the response rate, it can be described as high and very promising, which cheered the firm’s scientists and made them plan larger studies to confirm the encouraging results. They expect that the biomarker-guided dosing schedule will accelerate the clinical development of blinatumomab in all relevant B-cell lymphoma indications.

More detailed readings: Nagorsen, D. et al. (2009) Confirmation of Safety, Efficacy and Response Duration in Non-Hodgkin's Lymphoma Patients Treated with 60 Microgram/Squaremeter per Day of BiTE Antibody Blinatumomab. ASH Annual Meeting, abstract no. 2723.

We are witnessing a breakthrough attempt to unleash the immune system’s capability to fight diseases the same way as therapeutic vaccines attempt to do. The BiTE antibody builds a bridge for the immune system cytotoxic T cells to reach the cancer cells and kill them. The transformation of fascinating breakthrough molecules into therapeutic products is unfolding in front of our eyes. If scientists would have been asked whether an antibody could facilitate the immune system task of killing cancer cells before the validation of Micromet’s BiTE technology, the answer would have surely been, it is a beautiful approach, yet, practically unachievable. We are anxiously following up on Micromet’s moves.

Two of Micromet's BiTE antibodies and three of its conventional antibodies are currently in clinical trials. Micromet’s preclinical product pipeline includes several novel BiTE antibodies generated with its proprietary BiTE antibody platform technology.

Collaborators: Sanofi-Aventis (SNY), Bayer Schering Pharma (BYERF.PK), Nycomed, Merck Serono (MRK), and MedImmune.

The question expected to be asked is, what is BiTE antibody? The answer is, it is not a whole antibody. It consists of the small binding domains by which an antibody recognizes its antigens on T cells or target cells. In the BiTE antibody, all domains are linked together on one polypeptide chain using Micromet's proprietary single-chain antibody technology. BiTE antibodies can be produced in mammalian cell culture systems as fully functional proteins with high stability and homogeneity.

The stock: In June, 2009, MITI was trading a little above $4. Slowly, but surely, while yo-yoing a little bit on the road, the stock has climbed up to over $6. Now, the stock trades at $6.43.

Disclosure: No Positions

Source: Micromet: Opportunity Lies in Breakthrough BiTE Antibody