In the field of oncology, Positron Emission Tomography (PET) is a relatively new type of diagnostic tool, having only really been used in a regular clinical setting since the mid 1990s. the method involves introducing a tracer, a radioactive chemical, into a patient’s body, and then monitoring the movement and activity of said tracer using a computer/scanner system designed to detect the tracer in question.
The method has a number of major advantages over alternative forms of imaging in oncology; methods such as X-rays and and computerized tomography (CT) scans. They are more accurate, based on their selectivity to the target cells, and can provide a much clearer picture (both literally and figuratively) as to the stage of development of the cancer in question, and the degree to which said cancer has metastasized. The image is also three dimensional (if the imager requires), making it far easier to locate and identify tumors and other satellite cancerous cells residing in difficult to reach areas of the body.
The benefits aren’t without balance, however.
The tracer used in PET imaging has a number of risks associated with it, based on its radioactivity. It’s not generally regarded as unsafe, but the half life means a patient can only undertake a limited number of PET scans, and the method isn’t suitable for particularly at-risk patients (pregnant women, elderly or very ill).
Overall, the benefits outweigh the risks, but there’s always room for improvement, and a number of companies are seeking to develop a second generation of PET tracers that reduce risk, and top the balance further in favor of the benefits.
One of the leaders in this endeavor right now is MabVax Therapeutics Holdings, Inc. (NASDAQ:MBVX).
Before getting into why, a quick introduction to MabVax.
The company is a junior biotech with a primary focus on pancreatic cancer. It is developing its pipeline in collaboration with Memorial Sloan Kettering Cancer Center (MSKCC), giving it something of a unique positioning within the space. The partnership derives from the long time (30 years) employment by the latter of MabVax’s now Chief Scientific Officer, Philip O. Livingston, M.D. Livingston spent his time at MSKCC investigating various targeted approaches to immunotherapy in oncology patients, and the construction of conjugate vaccines specifically designed to augment antibody responses against these targets. Through this link, MSCKK now provides MabVax with a supply of antibodies derived from patients who have undergone immunotherapy. MabVax then identifies the most promising of these antibodies to develop its own targeted immunotherapy drugs. Its current lead candidate is called MVT-5873, and it harnesses an antibody called HuMab-5B1 in an attempt to deliver targeted radiotherapy to pancreatic cancer cells.
The lead investigation of this asset just advanced into the second stage of a two stage phase one, and is under investigation as a combination first line treatment in the above mentioned pancreatic cancer.
That side of the pipeline isn’t what we are here to discuss, however. With that said, while the potential of HuMab-5B1 as an immunotherapy agent isn’t the focal point of this piece, the antibody itself, and more specifically its potential as an imaging agent, is.
MabVax has spent the last eighteen months presenting preclinical data from investigative studies of a second generation PET agent – the first of its kind – called MVT-2163. MVT-2163 is a combination of the HuMab-5B1 antibody and a radioactive label (combined to create the “tracer” mentioned above) that the company is aiming to use to improve accuracy of pancreatic cancer PET imaging. The HuMab-5B1 antibody has a high affinity to a type of antigen, called CA 19-9, which expressed by pancreatic cancer cells (and, importantly, in very few other types of cells) in abundance. Once introduced into the body, the antibody gets to work tracking down its favorite antigen, and when it finds it, it locks onto it. This locking secures the radiolabel to the cancer cell, and when a physician uses the PET camera to image the patient, the image is a very detailed representation of where the cancerous cells are, and the degree to which they have spread.
Preclinical studies (and an ongoing early stage clinical investigation) have suggested the accuracy of MVT-2163 based PET is far higher than that of the current SOC PET imaging compound; that alone is not what makes it a second generation treatment, however.
The second generation tag derives from the way in which the treatment can be used to reduce the radiation exposure associated with the imaging method. MabVax has shown, and presented at numerous imaging conferences (examples here and here) that the imaging process can be split in to two steps, based on the high affinity of the HuMab-5B1 antibody to the pancreatic cancer cells.
The first step introduces the antibody and a linker in to the patient systemically. This combination gets to work seeking out the cancerous cells, and the antibody locks in to the antigens, just as described above (although without the radiolabel attached). Once this process is complete, the second step initiates, with the physician administering the radiolabel and a second linker that complements the first. The radiolabel used has a far shorter half life than in traditional PET, and this reduces the radiation a patient is exposed to. The second linker seeks out the first linker, and the two attach, forming a – proxy – connection between the HuMab-5B1 antibody and the imaging agent.
That’s not all.
This type of second generation treatment is difficult to achieve at high accuracy, because the high affinity of the antibody used (in this instance the HuMab-5B1 antibody) to the antigens expressed by the cancerous cells can throw the imaging off. Why? Because cancer cells shed antigens, and these antigens end up free floating around the system. The antibody cannot differentiate between free floating and cancer-attached antigens, and so the imaging can highlight free floating antigens that look like cancer cells when imaged.
MabVax has found a solution to this, which looks set to enable it to use highly selective targets without the concern of mislabeling, and it’s a pretty neat fix.
The company introduces small amounts of the HuMab-5B1 antibody into the system that hasn’t been linked to a radioactive tracer or a linker. This pre-dose soaks up all of the free floating antigens. When viewed through the PET imaging technology, none of these free floating antigens will show up, because the HuMab-5B1 that is linked to them doesn’t have a radiolabel attached to it.
Where is the company in the development process?
It’s still early days, but the company initiated a phase I trial at the MSKCC investigating MVT-2163 as a pancreatic cancer PET imaging compound in the second quarter of this year. The trial is primarily a safety study, but the company is also looking at a few key pharmacokinetic elements of the drug, with plasma concentration, bio-distribution and optimal visualization dose/time all areas of focus.
Primary completion is slated for April 2017, with study completion set for a couple of months later in June 2017.
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