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KB002 / KB003
Engineered antibodies targeting GM-CSF for the treatment of Autoimmune Diseases
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KB002/KB003 are engineered human IgG1k antibodies that KaloBios is developing for the treatment of autoimmune diseases, initially rheumatoid arthritis. Both antibodies are designed to neutralize GM-CSF (Granulocyte Macrophage Colony Stimulating Factor), a pro-inflammatory cytokine/growth factor that stimulates the survival, proliferation, differentiation and function of several types of white blood cells, including the monocytes/macrophages that play a key role in the tissue damage associated with many autoimmune diseases.
In 2004, KaloBios in-licensed KB002, a low picomolar affinity, first-in-class antibody, from the Ludwig Institute in Melbourne, Australia, where preclinical research suggested that its ability to inhibit GM-CSF could play a useful role in the treatment of autoimmune diseases, including rheumatoid arthritis. A Phase 1 study of KB002 in healthy volunteers was completed in the first half of 2007. A separate Phase 1/2 study is underway in rheumatoid arthritis patients, and KaloBios intends to begin studies in early 2008 for persistent asthma. KB003 is a Humaneered™ version of the KB002 antibody, and is currently in preclinical development and plans to initiate Phase 1 studies in the first quarter of 2008. KB002 is the prototype drug candidate for KB003, that is, the information learned from the clinical studies conducted with KB002 will be used to guide the development of KB003, and KB002 development will cease in 2008.
Role of GM-CSF in Autoimmune Disease
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GM-CSF plays a role in activating and maintaining the viability of macrophages, white blood cells that play a key role in both nonspecific defense (innate immunity) and cell-mediated immunity. These cells help rid the body of cellular debris and pathogens, and stimulate lymphocytes and other immune cells to respond to pathogens as part of the inflammatory immune response. In autoimmune diseases, where the body mounts an immune response against its own tissue, macrophages play an important role. In the autoimmune state, macrophages produce excess cytokines that prolong inflammation. Secondly, activated macrophages produce enzymes that directly cause tissue damage. Finally, macrophages |
| amplify the undesirable response by producing GM-CSF that activates additional macrophages. The role of GM-CSF in activating and maintaining the viability of macrophages thus provides a strong rationale for neutralizing this molecule as a treatment for inflammatory autoimmune diseases such as rheumatoid arthritis. |
The therapeutic potential of inhibiting GM-CSF in autoimmune disease is supported by a significant body of research data generated by researchers at the Ludwig Institute and elsewhere:
- 1.GM-CSF gene knock-out mice are resistant to the induction of autoimmune diseases e.g. collagen-induced arthritis (CIA), experimental encephalomyelitis (EAE) but show no major changes in hematopoiesis (Campbell et al J.Immunology 161:3639-3644, 1998, McQualter et al J. Exp. Med. 194:873-881,2001)
- 1.Transgenic mice over-expressing GM-CSF in different tissues develop tissue-specific autoimmune reactions (Biondo et al J. Immunology 166:2090-2099, 2001)
- 1.An antibody that neutralizes murine GM-CSF prevents and treats CIA and EAE in mice (Cook et al, Arthritis Research: 3(5); 293-298, 2001)
- GM-CSF dosed to patients can reactivate their autoimmune disease
- 1.Rheumatoid arthritis patients have elevated levels of GM-CSF in their diseased joints (Xu et al J. Clin. Invest.83: 876-882,1989)
KB002 in Rheumatoid Arthritis
Animal studies with KB002 have shown the ability of this antibody to slow joint erosion in mouse arthritis models more efficiently than a TNF antagonist and suggest that this antibody may have therapeutic potential for those patients who do not respond to that class of therapeutics. While anti-TNF blockers are established treatments for patients failing first-line, disease-modifying, anti-arthritis drugs (DMARDs), 40% of patients fail to respond to these agents or only respond until neutralizing antibodies develop as a consequence of repeated dosing. Furthermore, anti-TNF blockers deplete B cells, which sometimes lead to opportunistic infections and B cell leukemias. Anti-GM-CSF treatment is not B cell depleting.
KB002 - Current Status of Development
KaloBios completed a Phase 1 trial in healthy volunteers in the first half of 2007 and is currently conducting a Phase 1/2 human clinical study in rheumatoid arthritis patients with active disease, and plans to initiate a study in persistent asthma in early 2008.
KB003
KB003 is a Humaneered™ version of KB002, currently in preclinical development. KaloBios plans to initiate a Phase 1 healthy volunteer study in the first quarter of 2008. KaloBios believes that KB003 represents a potential best-in-class drug candidate with the same mode of action as KB002.
Contact
David W. Pritchard, CEO
KaloBios Pharmaceuticals, Inc.
3427 Hillview Avenue, Suite 200
Palo Alto, CA 94304
Main Tel: (650) 843-1897
Fax: (650 843-1896
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