Humaneered™ high-affinity antibody fragment for the treatment of Pseudomonas aeruginosa infections
PRODUCT DESCRIPTION
KB001 is a Humaneered™ high-affinity anti-PcrV PEGylated antibody Fab' fragment. The Humaneered™ antibody Fab' fragment is engineered to minimize immunogenicity for chronic use in broad populations.
PcrV PROTEIN: A TARGET SPECIFIC TO PSEUDOMONAS AERUGINOSA
Pseudomonas aeruginosa (Pa) is an opportunistic pathogen that is a significant problem for critically ill and immunocompromised individuals, including cystic fibrosis, mechanically ventilated, neutropenic, and burn patients. Pa avoids antibiotic treatment via cell membrane pumps, secretion of type I cephalosporinases, and evolution. Pa causes acute injury and mortality to target cells through the delivery of exotoxins by its Type Three Secretion System (TTSS) found on the surface of the bacteria. The bacterium uses the TTSS structure to penetrate host cell membranes and inject toxins, and the expression of TTSS correlates strongly with the bacterium�s pathogenicity. PcrV, an essential needle-tip protein of the TTSS, has a conserved protein sequence and its expression correlates with pathogenicity. There is no known mammalian protein homolog of the PcrV protein.
ANTI-PcrV: A NOVEL MOA THAT MAY SAFELY AVOID AND OVERCOME DRUG RESISTANCE
KB001 binds to PcrV, and when bound, it inhibits activity of the TTSS. Inhibition of PcrV reduces the pathogenicity of Pa and its toxicity to host immune and epithelial cells thereby enhancing natural antibody clearance mechanisms of Pa by the host. Furthermore, inhibition of Pa's virulence via a blocking antibody Fab' fragment is unlikely to be susceptible to the bacteria's natural defense mechanisms nor does it provide the selective pressure to the bacteria like antibiotic treatments thus minimizing the opportunity for the evolution of drug resistant strains. In addition, since PcrV is not found on human cells, the chance for unintended toxicity is minimized. Therefore, anti-PcrV serves as a potentially safe and effective treatment for Pa that may avoid drug resistance.
PRECLINICAL EFFICACY DEMONSTRATED
KB001 has demonstrated therapeutic and prophylactic efficacy against Pa in acute mouse disease models.
KB001 CLINICAL DEVELOPMENT
KaloBios has partnered with Sanofi Pasteur for this development program.
SELECTED REFERENCES FOR KB001 (ANTI-PCRV)
Copies of these references are available upon request.
Humaneered™ Anti-PcrV Antibodies
M. Baer, T. Sawa, P. Flynn, K. Luehrsen, D. Martinez, J.P. Wiener-Kronish, G. Yarranton, C. Bebbington: An engineered human antibody Fab fragment specific for Pseudomonas aeruginosa PcrV has potent anti-bacterial activity: Infection and Immunity (Dec 22nd 2008 epublished ahead of print publication)
G.A. Papalia, et al.: High-resolution characterization of antigen binding fragment/antigen interactions using Biacore T100: Analytical Biochemistry; 2006, 359:112-119.
C. Bebbington and G.Yarranton. Antibodies for the treatment of bacterial infections. Curr. Opinion. Biotechnol. (2009) 19: issue6
Cystic Fibrosis
C.L. Ordonez, N.R. Henig, N. Mayer-Hamblett, F.J. Accurso, J.L. Burns, J.F. Chmiel, C.L. Daines, R.L. Gibson, S. McNamara, G.Z. Retsch-Bogart, P.L. Zeitlin and M.L. Aitken: Inflammatory and microbiologic markers in induced sputum after intravenous antibiotics in cystic fibrosis: Am. J. Respir. Crit. Care Med.; 2003, 168:1471-1475
F. von Gotz, S. Haussler, D. Jordan, S. Saravanamuthu, D. Wehmhuner, A. Strubmann, J. Lauber, I. Attree, J. Buer, B. Tummler, I. Steinmetz: Expression analysis of a highly adherent and cytotoxic small colony variant of Pseudomonas aeruginosa isolated from a lung of a patient with cystic fibrosis: J. Bact.; 2004, 186:3837-3847
Yoshifumi Imamura, Katsunori Yanagihara, Yuichi Fukuda, Yukihiro Kaneko, Masafumi Seki, Koichi Izumikawa, Yoshitsugu Miyazaki, Yoichi Hirakata, Teiji Sawa, JP Wiener-Kronish an Shigeru Kohno: Effect of anti-PcrV antibody in murine chronic airway Pseudomonas aeruginosa infection model: Eur. Resp. Soc.; 200
Pneumonia / Lung Infection Animal Studies
Arup Roy-Burman, R.H. Savel, Sara Racine, B.L. Swanson, N.S. Revadigar, J. Fujimoto, T. Sawa, D.W. Frank, J.P. Wiener-Kronish: Type III protein secretion is associated with death in lower respiratory and systemic Pseudomonas aeruginosa infections: J. Inf. Dis.; 2001,183:1767-1774
K. Faure, J. Fujimoto, D.W Shimubukuro, T. Ajayi, N. Shime, K. Moriyama, E.G. Spack, J.Wiener-Kronish and T. Sawa: Effects of a monoclonal anti-PcrV antibody on Pseudomonas aeruginosa-induced acute lung injury in a rat model: J. Immune Based Therapies and Vaccines; 2003, 1:1-9
Dara W. Frank, A. Vallis, J. Wiener-Kronish, A. Roy-Burman, E.G. Spack, B.P. Mullaney, J.D. Marks, R. Fritz, T. Sawa: Generation and characterization of a protective monoclonal antibody to Pseudomonas aeruginosa PcrV: J. Inf. Dis.; 2002, 186:64-73
S. Muller, M.F. Feldman, G.R. Coornelis: The type III secretion system of gram-negative bacteria; a potential therapeutic target: Expert Opin. Ther. Targets; 2001, 5:327-339
N. Shime, T. Sawa, J. Fujimoto, K. Faure, L.R. Allmond, T. Karaca, B.L. Swanson, E.G. Spack, J. Wiener-Kronish: Therapeutic administration of anti-PcrV F(ab�)2 in sepsis associated with Pseudomonas aeruginosa: J. Immun.; 2001, 167:5880-5886
