Experimental drug harnesses T-cell’s tumor-killing powers	June 2009

By Michael Christel

Christian Itin, Ph.D., president and CEO of Micromet Inc., spoke with R&D Directions about the biotech company’s experimental and potentially revolutionary new class of constructed monoclonal antibodies, drugs designed to direct a patient’s T-cells to attack and kill tumor cells that hide beneath the bone marrow. MT103, also known as blinatumomab, is Micromet’s lead drug in this class and is in the early-to-mid stages of clinical development for leukemia and lymphoma. According to Dr. Itin, the company is planning to begin a registration trial for MT103 in acute lymphoblastic leukemia in 2010. Maryland-based Micromet, which runs its R&D center in Munich, Germany, is partnering with MedImmune and Bayer Schering Pharma on the technology behind MT103, which the company has coined BiTE, or Bi-specific T-Cell Engager.  

Q: What indications is MT103 specifically targeting and what are your goals for the drug?

A: MT103 in being studied in acute lymphoblastic leukemia (ALL) in one trial and the other trial in non-Hodgkin’s lymphoma. This month at the European Hematology Association (EHA) annual meeting we announced that we have met our primary endpoint in the trial for ALL. That’s a Phase II clinical trial where we treat adult patients that have undergone chemotherapy regimens which left them with no tumor cells left in the blood, but they still have remaining tumor cells sitting in the bone marrow.

What’s been shown for these patients is that if you can’t get rid of these tumor cells in the bone marrow, that they have a very high probability of relapse and a very aggressive development of the disease thereafter. An estimated 61% to 94% of patients who have such detectable cells after chemotherapy typically relapse, compared to 0 to 6% for patients who have no detectable levels of tumor cells after traditional chemotherapy

What we’re doing in these patients is we treat them with MT103 with the goal to eliminate the remaining tumor cells in the bone marrow below detection limit. Although the trial is still enrolling patients, we have already exceeded our primary endpoint and will move to a pivotal trial next year.

We also have new results from our non-Hodgkin’s lymphoma trial. At the EHA meeting, we provided updated data that show that 11 out of 12 of patients at the current dosing cohort have gone into complete or partial remission. These are patients who have relapsed and have failed on multiple prior treatments. These data are a follow up to the study published last summer in the journal Science. We’re continuing to work on that trial and continue to enroll patients.

Q: Can you explain the BiTE platform behind MT103 and what makes its mechanism of action unique?

A: The simplest way you can think about a BiTE antibody is like a little protein adapter that connects two cells. One of the two cells is a T-cell, which is the patient’s most potent immune effector cell. That’s one of our key lines of defense in our immune system, probably the most potent cell in our body often referred to as killer cells. On the other side, the BiTE antibody binds to a tumor cell, and by making that connection between the two cells, it actually instructs the T-cell to attack the tumor cell and kill it.

As you can imagine, by binding different structures of tumor cells, we can make BiTE antibodies that can specifically see a non-Hodgkin’s lymphoma cancer cell, as in the case of MT103, where the structure we’re binding to on the surface of the tumor cell is called CD19. We’re working on others that go after solid tumors. One of the surface structures we’re going after is epithelial cell adhesion molecule, or EpCAM, which is another clinical program. On the preclinical program side, we’re targeting structures like EGFR (epidermal growth factor receptor), the same structure that is also targeted by Erbitux and Vectibix, two marketed drugs. We’re also targeting HER2, which is well known from the drug Herceptin, and others that allow us to really address various types of tumors by directly engaging the patients’ own T-cells to take those tumor cells out.

Q:  How many sites are involved in the testing of MT103?

A: We’re working on the ALL study with the German ALL study group, which, is organized in such a away that all acute lymphoblastic leukemia patients in Germany are treated through the study group. They’re obviously focused on a number of centers across Germany, which is what we’re using in that particular trial.

Q: Conventional antibodies have traditionally had difficulty engaging T-cells, so how is it different with MT103? 

A: In the past we couldn’t redirect T-cells to the tumor the way we can now do that with BiTE antibodies because cancer cells have been able to evade recognition. What we needed to come up with is a way to make tumor cells visible to any T-cell in the body, and this led us to develop the BiTE antibodies which serve as these adapters.

What’s striking about T cells is that they are constantly patrolling the body, constantly moving through all our tissue, and when they can recognize cells that are not supposed to be there, they eliminate them very efficiently.

When T-cells recognize cells that are not supposed to be there, they can efficiently develop a very significant potency by forming small colonies locally, surrounding the tissue that needs to be taken out. The realization then for us was that we’d like to leverage these capabilities to patrol and also to develop high potency. BiTE antibodies accomplish these goals.

Q: What about the state of cancer R&D in general? What progress had been made and what continues to be major challenges in developing effective cancer treatments?

A: When we look at the field – particularly with the use of chemotherapy in combination with conventional antibodies – is that in a number of indications we manage to actually improve either survival time or time to progression, and often can do that now at a reasonable quality of life for these patients. There is progress we’ve seen over the last 10 years, particularly through those combinations. Some of the other advances that we’ve seen are through the targeting of the supplying blood vessels to the tumor, making sure that the tumor doesn’t get a sufficient amount of nutrients and therefore the growth can be slowed down. If you reach the tumor at the right point in time, you may actually also get the tumor to die off all well.

The key challenge that remains is that while we manage to buy some time for patients, we still have made very little progress in actually curing patients. If you look at late-stage disease, there is a point that we reach with all cancer patients, where the tumor outgrows any therapeutic approach we currently have available. That’s why we still have so many patients die of cancer – we cannot control the growth of the tumor with any of the approaches we have currently available. We still need more potent, more targeted approaches to tackle these fast growing tumors at the end of the disease.

When you look at the opportunity to improve cures in cancer, what we need to look at are the early stages of the disease. Some of the significant progress we’ve seen is related to early diagnosis and the ability to actually eliminate the early forms of the cancer that are forming prior to the cancer having reached many other organs, which then becomes much more difficult to treat

The concept there is that you try to get rid of this initial tumor lesion, often by surgery or radiation, and then you need to follow up with what’s called adjuvant treatment, a therapy that takes care of the tumor cells that have spread throughout the body. This is where some very nice progress has been made, for example in breast cancer, with the use of Herceptin in the adjuvant setting.

We really have to improve on both ends of the spectrum – on one end, catching up with rapid growth rates of cancers in late-stage disease, but also getting a lot better at detecting tumor cells that are hiding some place in the tissue of patients in the early setting of disease. It’s this line of thinking that led us to actually develop BiTE antibodies and to think about the utility of T-cells in that approach.