XBiotech’s Pipeline: Anti-Inflammatory Antibodies
XBiotech’s discovery pipeline is built on the screening of thousands of human subjects for the presence of antibodies, particularly those targeting medically important cytokines. While our strategy has been to identify human antibodies that neutralize specific cytokines, our focus has been on identifying antibodies that neutralize cytokines that have already been “validated” as important targets in clinical trials—using mouse-derived therapeutic antibodies. NATHMAB™ therapeutic antibodies are expected to be significantly less immunogenic and thus superior drug products compared to mouse-derived antibodies. XBiotech believes that major market opportunities exist for next generation NATHMAB™ therapeutics targeting these cytokines.
Our early stage antibody pipeline targets various cytokines, each involved in diseases that represent significant unmet medical needs and high disease-related morbidity. Moreover, for each of these indications, the medical condition is expected to be chronic. In such situations, therapeutic antibody administration will likely be needed for a prolonged period of time, perhaps for the lifetime of the patient. Immunogenic antibodies are neutralized by the body’s immune system and have limited utility for long-term use. We believe that NATHMAB™ will not exhibit immunogenic characteristics in patients and thus will be particularly well suited for situations where long term administration of the drug is required.
From a development point of view, NATHMAB™ anti-cytokine therapeutics offer excellent risk benefit analysis and we believe this is a sound strategy for value creation in our therapeutic antibody portfolio. This thinking is supported from several viewpoints: positive clinical data has already been generated (by others using murine antibodies) that indicates we are going after medically important therapeutic targets; there are natural partnership opportunities with Big Pharma companies developing current generation, mouse-derived antibodies; clinical trial design and validation strategies have been “mapped-out” for these targets; and revenue potential (and hence value proposition) for a successful NATHMAB™ against these targets is somewhat established.
Together, the company believes that undertaking development against these targets represents low risk value creation with early partnership potential and revenue creation.
XBiotech’s Lead Therapeutic Antibody: Targeting Cancer
XBiotech’s cancer program targets a cytokine commonly expressed on cancer cells. PBMC are found in the area of inflammation that surrounds a tumor, making up what is called the “cellular infiltrate”, or invading white blood cells, of a growing tumor.
Understanding the dynamic between the body’s immune system and cancer—in order to elucidate the role the immune system plays in tumor progression or suppression—has been the topic of intense scientific interest for decades. It is generally understood that, with respect to cancer, there is a delicate balance between good and bad immune responses. On the one hand, inflammation may cause tumor destruction, on the other hand, inflammation can induce angiogenesis (new blood supply) and connective tissue breakdown, thereby helping to facilitate growth and spread of the tumor.
Targeting specific cytokines may alter the balance of inflammation in the tumor microenvironment, such that pro-tumor inflammatory effects are reduced, and the viability and metastatic potential of the tumor is impaired. Moreover, since there is considerable evidence that a tumor itself can produce specific cytokines, direct inhibition or antibody-directed killing of tumor cells may be anticipated in certain situations resulting from treatment with our therapeutic antibody.
It is well documented that cytokine expression is found in malignant tumor cells and tumor environments of many forms of cancer. Consequently, our therapeutic antibody may demonstrate therapeutic benefit for a number of different forms of cancer.
The Company will annouce later this year, after completion of its formal toxicology studies, the launch indication for its oncology candidate therapy. At present, the Company is focusing on the treatment of advanced stage prostate cancer, but is also exploring orphan indications that may facilitate expedited clinical testing and approval.
Significant cytokine expression has been well documented in prostate cancer, for which there is also a very large unmet medical need. Moreover, excellent surrogate markers exist to assess whether or not clinical responses are achieved. XBiotech's lead product candidate may ultimately be used to treat major cancer therapy indications where cytokine expression has been reported and/or inflammatory infiltrate may be expected to support tumor progression and metastasis. These indications include prostate, breast, lung, endometrial and pancreatic cancers.
Background of XBiotech’s Lead Therapeutic Antibody: Targeting Arterial Inflammation
XBiotech’s lead therapeutic product candidate acts to specifically block or neutralize a cytokine that appears to be a key trigger in the process of arterial inflammation. By blocking the action of this cytokine, the antibody may block inflammation involved in disease processes such as atherosclerosis, the major cause of heart disease, heart attack and stroke.
Inflammation appears to play a key role in the development of atherosclerosis. Atherosclerosis begins as a result of some form of damage or stress to the interior wall of an artery. The nature of this damage is not entirely clear, but some of the causes probably include elevated levels of unhealthy fats in the blood, infections, reactive chemical agents derived from cigarette smoking, and mechanical stress on the arterial wall due to high blood pressure.
Microscopic damage to the interior wall of arteries caused by these events results in arterial inflammation, which amounts to migration of white blood cells into the wall of the artery. With this begins the formation of a thickened interior lining, or “atheroma.”
The atheroma thus becomes an accumulation of fats and debris from the collection of dead and dying white blood cells that have collected in the lining of the artery wall. In response to the atheroma, smooth muscle cells surrounding the artery wall produce collagen fibers which cover the atheroma. The ensuing collection of fat, dead and dying cells covered by a collagen-fiber sheet is what is known as the “atherosclerotic plaque.”
Eventually, the atherosclerotic plaque of the arterial wall begins to take up space inside the artery and interfere with the passage of blood. The artery can expand to compensate for the blockage. But the fibrous cover over the atherosclerotic plaque may weaken and rupture, stimulating the formation of a blood clot and subsequent blockage of blood flow, possibly causing heart attack or stroke.
Recent scientific studies showed that cytokines play a crucial role in the progression of atherosclerosis-like lesions in animals. In mice that are highly susceptible to atherosclerosis-like lesions, high fat diet rapidly results in heavy plaque formation in major arteries. By inhibiting specific cytokine activity, plaque formation can be dramatically reduced in animal models. On the other hand, it has also been shown that in mice with overactive production of specific cytokines, or in mice subjected to infections thought to be associated with heart disease, plaque formation in arteries is dramatically accelerated.
XBiotech’s therapeutic antibody program involves using its NATHMAB™ product candidate to neutralize biological activity of a specific cytokine that appears to play a crucial role in arterial inflammation. Data from humans, pre-clinical and mouse modeling experiments, all suggest that our antibody may be an effective therapeutic for reducing arterial inflammation.