Engineered antibodies targeting GM-CSF for the treatment of Inflammatory Diseases
PRODUCT DESCRIPTION
KB002 and KB003 are engineered human IgG1 antibodies targeting Granulocyte Macrophage Colony Stimulating Factor (GM-CSF). KB002, the precursor to KB003, is a first-in-class chimeric anti-GM-CSF antibody being used for initial human proof-of-concept studies. KB003 is a best-in-class Humaneered™ anti-GM-CSF antibody designed to minimize immunogenicity for chronic use in broad populations. KB003 will be used for all future development.
GM-CSF: A TARGET FOR TREATING INFLAMMATORY DISEASE
GM-CSF is a cytokine that plays a central role in the inflammatory immune response cascade. GM-CSF causes proliferation, prolonged survival, and differentiation of monocytes, macrophages and granulocytes (eosiniphils, neutrophils, and basophils). Abnormal function of this cascade, and increased GM-CSF levels in particular, has been reported as associated with a number of inflammatory diseases. Preclinical studies have shown neutralization of GM-CSF or GM-CSF knock-outs to be effective in a variety of disease models, including rheumatoid arthritis, asthma, COPD, multiple sclerosis, psoriasis, and cancer bone destruction. This breadth of activity makes GM-CSF an attractive therapeutic target to widely treat inflammatory disease (reference list below).
SAFETY
Preclinical toxicology and healthy human volunteer studies for both KB002 and KB003 are complete. In addition, four Phase 2a studies with KB002 have been completed.
CLINICAL PROOF-OF-CONCEPT
FUTURE DEVELOPMENT
KaloBios plans to initiate several multi-dose Phase 2b clinical trials with KB003 across various indications, with the first starting in the first quarter of 2010. KaloBios is seeking a partner in 2010 for this development program.
SELECTED REFERENCES FOR KB002/KB003 (ANTI-GM-CSF)
Copies of these references are available upon request.
Humaneered™ Technology
G.A. Papalia, et al.: High-resolution characterization of antigen binding fragment/antigen interactions using Biacore T100: Analytical Biochemistry; 2006
Rheumatoid Arthritis
I.K. Campbell, M.J. Rich, R.J. Bischof, A.R. Dunn, D. Grail and J.A. Hamilton: Protection from collagen-induced arthritis in granulocyte-macrophage colony-stimulating factor-deficient mice: Journal of Immunology; 1998, 161:3639-3644
A.D. Cook, E.L. Braine, I.K. Campbell, M.J. Rich and J.A. Hamilton: Blockade of collagen-induced arthritis post-onset by antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF): requirement for GM-CSF in the effector phase of disease: Arthritis Research; 2001, 3:293-298
J.A. Hamilton: GM-CSF in inflammation and autoimmunity: Trends in Immunology; 2002, 23, 8:403
B.P.C. Hazenberg, M.A. Van Leeuwen, M. van Rijswijk, A.C. Stern, E. Vellenga: Correction of granulocytopenia in Felty’s syndrome by granulocyte-macrophage colony-stimulating factor, simultaneous induction of interleukin-6 release and flare-up of the arthritis: Blood; 1989, 74, 8:2769-2773
Asthma
M.P. Hallsworth, G.P.C. Soh, S.J. Lane, J.P. Arm, T.H. Lee: Selective enhancement of GM-CSF, TNF-a, IL-1ß and IL-8 production by monocytes and macrophages of asthmatic subjects: Eur. Respir. J.; 1994, 7:1096-1102
S. Mattoli, M. Marini and A. Fasoli: Expression of the Potent Inflammatory Cytokines, GM-CSF, IL6, and IL8, in Bronchial Epithelial Cells of Asthmatic Patients: Chest; 1992, 101:27-29
C.S. Park, Y.S. Choi, S.Y. Ki, S.H. Moon, S.W. Jeong, S.T. Uh, Y.H. Kim: Granulocyte macrophage colony-stimulating factor is the main cytokine enhancing survival of eosinophils in asthmatic airways: Eur. Respir. J.; 1998, 12: 872-878
Naomi Yamashita, Hiroyuki Tashimo, Hirobumi Ishida, Fujito Kaneko, junichi Nakano, Hiroshi Kato, Koichi Hirai, Tadashi Horiuchi, and Ken Ohta: Attenuation of airway hyperresponsiveness in a murine asthma model by neutralization of granulocyte–macrophage colony-stimulating factor (GM-CSF): Cellular Immunology; 2002, 219: 92–97
Other Indications
J.L. McQualter, R. Darwiche, C.Ewing, M.Onuki, T.W.Kay, J.A. Hamilton, H.H. Reid, C.C.A. Bernard: Granulocyte macrophage colony-stimulating factor: A new putative target in multiple sclerosis: J.Exp.Med.; 2001, 194:873-881
R. Puljic, E. Benediktus, C. Plater-Zyberk, P.A. Baeurle, S. Szelenyi, K. Brune, A. Pahl: Lipopolysaccharide-induced lung inflammation is inhibited by neutralization of GM-CSF: Eur. J.Pharm; 2007, 557:230-235
In Vivo
Thomas T. Chen and Ronald Levy: Induction of autoantibody responses to GM-CSF by hyperimmunization with an Id-GM-CSF fusion protein: Journal of Immunology; 1995, 154:3105-3117
Ian N. Oliver, Tim Hercus, Angel Lopez, Matthew Vadas, Andre A. Somogyi, Ian Doyle, David J.R Foster, Dorothy Keefe, Anne Taylor, Michael Brown, L. Bik To, Julie Cole, Trevor Rawling, Bronwyn Cambareri, Melinda Myers, Nancy Olszweski, Stan Bastiras, Carol Senn, Allan Hey, Meera Verma and Peter Wigley: A phase I study of the GM-CSF antagonist E21R: Cancer Chemother. Pharmacol.; 2002, 50:171-178
Edouard Stanley, Graham J. Lieschke, Dianne Grail, Donald Metcalf, George Hodgson, John A.M Gall, Darryl W. Maher, Jonathan Cebon, Vincent Sinickas and Ashley R. Dunn: Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology: Proc. Natl. Acad. Sci. USA; 1994, 91:5592-5596
Martin Eisenblätter, Christiane Stahl-Hennig, Seraphin Kuate, Nicole Stolte, Edith Jasny, Helmut Hahna, Melissa Pope, Klara Tenner-Racz, Paul Racz, Ralph M. Steinman, Klaus Überla, Ralf Ignatius: Induction of neutralising antibodies restricts the use of human granulocyte/macrophage colony stimulating factor or vaccine studies in rhesus macaques: Vaccine; 2004, 22: 3295–3302
Contact
Scott Saywell, Sr. Director Business Development
KaloBios Pharmaceuticals, Inc.
260 East Grand Avenue
South San Francisco, CA 94080
Tel: (650) 243-3171
