Oncology

Xilonix™ is a first-in-class True Human™ monoclonal (IgG1k) antibody that neutralizes biological activity of interleukin-1α. Xilonix™ is called a True Human™ monoclonal antibody to differentiate it from other antibodies, such as so called "fully human," that are in fact not derived from a mature human antibody sequence. Unlike previous generations of humanized or fully human antibodies, Xilonix™ was cloned from an affinity matured, human immune response-with no in vitro sequence modifications to improve binding affinity. In vitro sequence modifications cause immunogenicity that leads to infusion reactions, risk of anaphylaxis, anti-product antibodies and poor therapy performance.

As a True Human™ antibody, Xilonix™ may be used as a monotherapy without concomitant medications to reduce adverse reactions. The safety results to date suggest a unique safety profile for monoclonal antibody therapy. Based on these data and the True Human™ derivation of Xilonix™, the treatment is expected to be among the best tolerated therapies ever used in oncology. The product is thus ideally suited for treating advanced cancer patients with reduced tolerance for toxic therapy.

Specific antagonism of IL-1α through Xilonix™ therapy is viewed as a unique, broad acting tumor suppression strategy that encompasses significant activity to ameliorate symptoms associated with the disease. IL-1α is unique in its involvement in so many processes related to tumor progression and collateral symptomatic effects of malignancy. The excellent safety and tolerability profile of the agent make it an ideal treatment option in advanced stage disease, particularly where the use of cytotoxic or other therapies with considerable toxicity are not supported by cost benefit analysis.


monotherapy

Figure IL-1α is expressed constitutively on monocytes and platelets and may be expressed by tumors. IL-1α activity promotes tumor growth and spread through multiple pathways.

MECHANISM OF ACTION

Neutralizing IL-1α activity with a monoclonal antibody therapy is believed to have broad antineoplastic activity. Depending on the site of action, IL-1α mediates a number of crucial physiological processes related to response to injury (e.g. tumor growth). At the site of injury (such as in the microenvironment of the growing tumor) IL-1α induces the expression of vascular growth factors including vascular endothelial growth factor (VEGF), thereby mediating growth and angiogenesis. IL-1α also induces expression of matrix metalloproteinases that in turn have pleiotropic activities including tissue matrix breakdown, regulation of FAS mediated apoptosis and inflammation.

Through its role on platelets, IL-1α also regulates interactions between endothelial cells and leukocytes, driving activation of vascular endothelial cells and transendothelial migration of inflammatory cells into the tumor microenvironment. Similarly, tumor-platelet micro-emboli formed between platelets and circulating tumor cells, provide tumor cells with enhanced ability to migrate from the vasculature into the tissues, forming new metastasis. Finally, IL-1α links these tumor processes to metabolic dysregulation, by signaling an injury response through IL-1 receptors on POMC neurons that interdigitate the endothelial microvasculature of the hypothalamus.

IL-1α MEDIATES TUMOR GROWTH

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Figure Initial growth of tumor results in an irregular microvasculature leading to enhanced platelet interaction with vascular endothelial (VE) cells. IL-1α present on platelets and/or produced by tumor cell signals activate VE, resulting in upregulation of adhesion molecules (ICAM, VCAM, E-selectin) and secretion of chemotactic cytokines (IL-8, MCP-1), facilitating diapedesis and recruitment of leukocytes into the tumor microenvironment. 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 cells travel with lymphatic drainage or penetrate the basement membrane to reach the circulation. In the circulation "sticky" tumor cells can interact with and adhere to platelets to form tumor-platelet micro-emboli.

Relevance to Xilonix™ Therapy

Inhibiting IL-1α signaling in the tumor microenvironment can inhibit tumor growth by blocking IL-1α effects on tumor survival, neoangeogenesis and tissue matrix remodeling.

IL-1α ROLE IN HEMATOGENOUS SPREAD AND METASTASIS

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Figure Tumor-platelet aggregates or "micro-emboli" are formed by the adherence of tumor cells and platelets via membrane glycoprotein interactions. By adhering platelets on their surface, tumor cells hijack platelet ability to activate vascular endothelium. 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™ will inhibit IL-1α mediated platelet activation of vascular endothelium and reduce the potential for tumors to extravasate the blood vessel and penetrate into tissue. This will reduce the metastatic potential of tumors.

ROLE FOR IL-1α IN METABOLIC DYSREGULATION

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Figure Platelet-tumor micro-emboli interact with endothelial cells of microvasculature in the arcuate nucleus. IL-1α on the surface of micro-emboli can trigger IL-1 receptors on VE. However, fenestrations in the microvasculature of the hypothalamus are penetrated by neuronal cells that also express IL-1 receptor. These cells, such as the POMC neurons, can respond to IL-1 stimulation to mediate central nervous system control of appetite, metabolism and well-being. In times of acute stress (such as trauma or illness), these neurons are able to sense "danger" and drive physiological mechanisms that provide enhanced ability to respond to stress, including breakdown of muscle protein for the mobilization of amino acid substrates to provide for gluconeogenesis. When the "danger" signal is chronic, as it is in cancer, this process drives pathologic wasting, including loss of crucial cardiac and diaphragmatic muscle.

Relevance to Xilonix™ Therapy

Treatment with Xilonix™ is expected to reduce IL-1α mediated signaling at the level of the hypothalamus. This will enable the body to normalize metabolic activity and correct the underlying wasting phenotype associated with malignancy.