Therapeutic Targets

Oncology | Infectious Disease (MRSA) | Cardiovascular | Dermatology (Acne, Psoriasis, PG) | Type 2 Diabetes


Market Opportunity: Colorectal Cancer

Colorectal Cancer Markets

Mechanism of Action

"Inflamation contributes to the severity of most diseases, and cytokine-specific blocking treatments are well established for autoinflammatory and auto immune diseases1 However, cytokine-mediated inflammation also has a role in the pathogenesis of cancer; for example, in the immunosuppression of the 2. Cytokine mediated systematic inflammation is also a debilitating aspect of cancer. Many tumors produce inflammatory cytokines, which promote angiogenesis and tumour growth. Therefore, blocking a cytokine treatment lacks side-effects and tumours are unlikely to develop resistance to cytokine blockade. In The Lancet Oncology, David Hong and collegues3 report the effects of neutralising interleukin-1a in patients with end-stage cancers of various origins. The study is a unique contribution because it opens entire new areas in cancer therapeutics"

Excerpt from Commentary, Lancet Oncology Publication: Written by Dr. Charles Dinarello, Department of Medicine, University of Colorado

Neutralizing IL-1α activity with monoclonal antibody therapy is believed to have broad tumor suppressing activity. IL-1α has direct effects on tumor survival, angiogenesis, and tissue matrix remodeling.

By working against IL-1α mediated cancer associated sterile inflammation, Xilonix™ presents anti-cancer benefits at 3 levels:

  • 1. Primary (angiogenesis growth): Limits IL-1α activity in the tumor microenvironment, which includes blocking of VGEF, angiogenesis, matrix-metalloproteinases, and overall inhibition of tumor growth.
  • 2. Secondary (vascular endothelium metastasis): Prevents tumor-platelet-microemboli from escaping circulation and forming new sites of metastasis
  • 3. Distal: Reduces IL-1α activated CNS symptoms such as anxiety, fatigue, anorexia, and metabolic dysregulation



Primary IL-1α and other factors present on infiltrating leukocytes and platelets induce expression of MMPs, VEGF and other factors crucial to tumor survival, growth, and spread.

Tumor-platelet aggregates or "micro-emboli" are formed by the adherence of tumor cells and platelets via membrane glycoprotein interactions. IL-1α present on the surface of platelets plays a role in activating VE and facilitating transendothelial migration of tumors. Thus the platelet- IL-1α system provides a mechanism for invasion of circulating tumors into tissue to form new sites of metastasis


Relevance to Xilonix™ Therapy
Xilonix™ inhibits IL-1α and therefore reduces its effects on tumor growth, angeogenesis, tissue matrix remodeling, and metastatic potential.

Relevant Publications:

Dinarello, C. (2014). Interleukin-1α neutralisation in patients with cancer. The Lancet Oncology, 552-553.

Hong, D., Hui, D., Bruera, E., Janku, F., Naing, A., Falchook, G., . . . Kurzrock, R. (n.d.). MABp1, a first-in-class True Human™ antibody targeting interleukin-1α in refractory cancers: An open-label, phase 1 dose-escalation and expansion study. The Lancet Oncology, 656-666.

Hong, D., Janku, F., Naing, A., Falchook, G., Piha-Paul, S., Wheler, J., . . . Kurzrock, R. (2015). Xilonix™, a novel True Human™ antibody targeting the inflammatory cytokine interleukin-1 alpha, in non-small cell lung cancer. Investigational New Drugs, 621-631.

Infectious Disease
True Human™ antibodies are derived directly from human donors that have natural immunity to disease.

In addition to S. aureus, we have successfully generated an anti-Ebola therapeutic antibody candidate using our True Human™ technology by identifying and cloning the antibody directly from blood donations of patients who recovered from the Ebola infection.

Function of Antibodies

Antibodies can neutralize or kill bacteria in two important ways:

  • 1. When binding to the surface of bacteria, antibodies are designed to activate complement proteins, which are highly abundant in the blood, to form complexes that can literally punch holes in the germs. Complement mediated killing of bacteria is in most cases a highly efficient means of eradicating infections.
  • 2. Antibodies stuck on the surface of bacteria can enable the bacteria to be detected by white blood cells. Specialized receptors on white blood cells attach to antibodies, by grabbing onto the antibody like a handle, thereby pulling the bacteria into the cell. The ability of white blood cells to engulf and kill bacteria in this way is a critically important means of removing infection from blood or tissue.
The unprecedented speed and efficacy of the True Human™ technology platform in identifying and developing these therapies represents XBiotech’s core strength in efficient drug discovery, making the Company not only able to treat infectious diseases in general, but also uniquely capable to quickly respond to disease outbreaks.

XBiotech recently completed a groundbreaking clinical study in cardiovascular medicine. This Phase II randomized, multi-center clinical study evaluated a True HumanTM therapeutic antibody MABp1 for its ability to reduce adverse events after balloon angioplasty, atherectomy, or stent placement in patients undergoing revascularization procedures for blockage of a major artery. This drug development program has FDA Fast Track designation.

Phase II Randomized Study Results

  • Clinical results demonstrated a reduction in restenosis and reduced incidence of Major Adverse Cardiovascular Events (MACE) in treated patients compared to controls
  • Study suggests beneficial treatment effect at 15 weeks

Vascular disease is currently one of the most common causes of death in both developed countries and emerging economic regions. While there has been significant research, technology has largely centered around angioplasty and the use of stents to open affected arteries and maintain patency, respectively.

Limitation of Current Treatments:

  • Potential benefits are often only temporary
  • Treated arteries can re-occlude (restenosis)

Benefits of Using an Anti-IL-1α True Human™ Antibody:

  • Inhibit white blood cell infiltration of the artery
  • Reduce arterial inflammation after angioplasty procedures
  • Reduce incidence or severity of restenosis

Inflammatory skin conditions encompass a wide range of diagnoses from common conditions such as acne, eczema, and psoriasis, to more rare conditions such as pyoderma gangrenosum. One common factor unifying the pathophysiology of these conditions is Interleukin-1 alpha. IL-1α is an extremely potent pro-inflammatory cytokine, which has long been associated with the skin. Keratinocytes are large reservoirs for preformed, intracellular, and biologically active IL-1α, which is believed to be a key factor in the initiation of skin inflammation. Blockade of this inflammatory signal with MABp1 promises a safe and effective treatment for numerous dermatologic conditions.


XBiotech has completed a multicenter, phase II study of its True Human™ therapeutic antibody MABp1 in subjects with moderate to severe plaque psoriasis. Internationally recognized expert in dermatology research, Johann Gudjonsson MD, Ph.D., Assistant Professor Department of Dermatology, University of Michigan, headed the study.

Therapeutic Opportunity

Psoriasis, an inflammatory disease that primarily involves the skin, and secondarily the joints, affects about 2-3% percent of the population in the USA. Disease severity can vary substantially among individuals, from thin plaques involving limited areas, to thick lesions over large areas of the body. Treatments such as topical corticosteroids, topical vitamin D analogs, and emollients are used to treat mild disease; light based therapies, oral medications with anti-inflammatory or immunosuppressive medications can be used to treat more severe disease.

Previous Treatments and Shortcomings:

  • Four approved biological therapies: etanercept, infliximab, adulimumab, and ustekinumab
  • Often serious side effects
  • Loss of effectiveness over time
  • Costly
Anti-IL-1α Antibody Therapy

IL-1α has been identified as a key mediator of sterile inflammation and is abundantly present in psoriatic skin lesions. Excess IL-1α promotes the production of adhesion molecules and release of chemokines, which lead to infiltration of the tissues by white blood cells. This cycle of inflammation and infiltration by white blood cells likely plays a significant role in the chronic inflammatory component of psoriasis.

XBiotech's antibody directed against IL-1α has been found to be not only effective in treating psoriasis, but could be safer and better tolerated than the existing front line therapies for the disease. MABp1 therapy is potent and fast acting, offering the potential for an important and novel treatment option for the disease.

Relevant Publications:

Coleman, K., Gudjonsson, J., & Stecher, M. (2015). Open-Label Trial of MABp1, a True Human™ Monoclonal Antibody Targeting Interleukin 1α, for the Treatment of Psoriasis. JAMA Dermatology JAMA Dermatol, 555-555.


XBiotech is using a subcutaneous injectable formula of its True Human™ antibody to safely and conveniently stop the chronic inflammation associated with acne - to help resolve both skin lesions and mental health issues associated with the disease. The phase II clinical study evaluated treatment in moderate to severe acne vulgaris, headed by leaders in the dermatology community, including Dr. Ronald Moy, recent President of the American Academy of Dermatology, former Co-Chief of Dermatology, and Chief of Dermatological Surgery at UCLA Medical Center.

Therapeutic Opportunity

Acne vulgaris affects more than 40 million persons in the US. Most adolescents suffer from some degree of acne as well as up to 51% of adults into their fourth decade. The underlying cause of acne is not clear, inflammation of pilosebaceous follicles is known to be a central feature of the disease; where in severe cases, subsequent cyst and nodule formation result in permanent scarring.

While most everyone is familiar with the skin manifestations, relatively few are aware that acne vulgaris is associated with serious psychological disturbances and in some cases even mortality due to suicide. In fact, depression and anxiety associated with acne is reportedly more severe in acne patients than in many other serious chronic, non-psychiatric medical conditions.

Current treatments exist, but are often associated with:

  • Exacerbation of depression
  • Psychosis
  • Suicide ideation

No therapy currently exists to treat both the skin manifestations of acne as well as the psychological complications.

Anti-IL-1α Antibody Therapy

Several avenues of research point toward the chronic inflammatory cytokine IL-1α as playing a key role in microcomedone formation and hypercornification. Skin biopsies of acne vulgaris reveal the presence of IL-1α.

Antibody therapy, as a result, could be expected to reduce inflammatory acne lesions. Furthermore, in the hypothalamus, IL-1α can trigger the cells to signal the presence of danger signals resulting in perception of anxiety or depression.

The True Human™ antibody under development for the treatment of acne provides a highly targeted blockade of IL-1α. Results from a recent Phase I/II study have provided the basis to conduct advanced clinical study in this indication. The results showed continual improvement in lesions, with up to a 36% reduction after eight weeks, and statistically signficant improvement in patient anxiety.

Relevant Publications:

Carrasco et al., "An Open Label Phase 2 Study of MABp1 Monotherapy for the Treatment of Acne Vulgaris and Psychiatric Comorbidity." J Drugs Dermatol. June 2015;14(6):560-564.

Pyoderma Gangrenosum

The clinical study is a 28 day phase II, open label trial of anti-IL-1α therapeutic antibody in subjects with Pyoderma Gangrenosum. The study is lead by Principal Investigator, Dr. Armand Cognetta at Florida State University Division of Dermatology. Primary endpoints of study involve clinician's and patient's Global Assessment at day 28 from baseline. Patients found to be responding to therapy, but haven't yet experienced complete resolution of their lesion(s) after 28 days of therapy may participate in up to 2 additional 28 day cycles.

Therapeutic Opportunity

Pyoderma Gangrenosum (PG) is an inflammatory skin disorder that causes tissue necrosis and results in severe, painful ulcers, most commonly on the legs. While a rare condition (affecting approximately 1 in 100,00 persons), it is devastating to those afflicted. It is often secondary to underlying diseases such as inflammatory bowel disease, systemic arthritis, hematological diseases and malignancies.

The inflamed, ulcerated skin lesions characterized by PG are heavily infiltrated with neutrophils in the absence of infectious stimuli. While the exact pathogenesis of PG is unknown, an altered innate immune response is believed to play a role in the disease process. IL-1α is a key cytokine that drives sterile inflammation, in particular wound healing responses, and is also present in keratinocytes where it is thought to stimulate and propagate inflammation in response to tissue damage. IL-1α is therefore expected to play a key role in the pathogenesis of inflammatory dermatoses, such as PG.

Type 2 Diabetes

XBiotech has concluded a Phase II pilot study to test MABp1 in patients with Type 2 diabetes. The study was headed by world-leading diabetes expert Dr. Marc Donath, Head of Endocrinology, Diabetes and Metabolism at University Hospital of Basel, Switzerland. Remarkable findings in this study have provided the basis to advance clinical programs in Type 2 diabetes.

  • Completed at the Univeristy Hospital in Basel, Switzerland in 7 patients
  • Assessed safety and pharmacokinetics and if patients' diabetes improved, including pancreas function and glucose control
  • Treatment was well tolerated and no adverse events occurred
  • Analysis at day 60 showed reduction in HbA1C as well as increase in C-peptide and pro-insulin
Type 2 Diabetes Overview

Type 2 Diabetes is one of the fastest growing and most significant disease burdens among industrialized societies. New treatment options are needed to prevent progression of disease and loss of pancreatic function in type 2 diabetic patients.

System Inflammation

Inflammatory cells infiltrate white adipose tissue and the pancreas, resulting in the development of insulin resistance and loss of insulin production, respectively. When inflammation makes adipose cells insensitive to insulin, they can no longer take up sugar, making control of blood sugar levels difficult.

Pancreatitis (Acute Inflammation of the Pancreas)

The pancreas can initially compensate for reduced insulin sensitivity by increasing output of insulin. However, this increased load results in stress on the pancreas and an inflammatory process can ensue in the pancreas itself. Current drugs, such as Linagliptin, worsen this process by stimulating the pancreas to produce insulin and furthering stress on the pancreas.

xBiotech Antibody Therapy
XBiotech Antibody Therapy

The mechanism of action of XBiotech's antibody therapy - to reduce inflammation that compromises pancreas function and glycemic control - could enhance glycemic control by improving the overall status of the systemic inflammatory condition present in type 2 diabetics. This represents a breakthrough in management of the disease.

Relevant Publications:

Timper, K., Seelig, E., Tsakiris, D., & Donath, M. (2015). Safety, Pharmacokinetics, and Preliminary Efficacy of a specific Anti-IL-1alpha Therapeutic Antibody (MABp1) in Patients with Type 2 Diabetes Mellitus. Journal of Diabetes and Its Complications. June 15, 2015,