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KB001
Humaneered™ high-affinity antibody fragment for the treatment of Pseudomonas aeruginosa infections
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KB001 is a Humaneered™, high-affinity antibody fragment that KaloBios is developing for the treatment of Pseudomonas aeruginosa infections. P. aeruginosa is an opportunistic pathogen that rarely causes disease in healthy people, but is a significant problem for critically ill or immunocompromised individuals. These include the approximately 70,000 worldwide patients with cystic fibrosis where P. aeruginosa is a major causative agent in the progressive loss of lung function resulting from recurrent and chronic respiratory tract infections with the bacterium. Others at risk from P. aeruginosa include patients on mechanical ventilators, neutropenic cancer patients, and burn patients. P. aeruginosa is notoriously resistant to antibiotics and new treatment approaches are greatly needed. KaloBios recently successfully completed a healthy volunteers study. The company plans to initiate Phase 1/2 studies in cystic fibrosis (“CF”) and intensive care patients on a ventilator in the first half of 2008.
Mechanism of Action
KB001 has a novel mechanism of action that directly targets the means by which P. aeruginosa is believed to cause disease. KaloBios has demonstrated that this Humaneered™ antibody fragment is effective against both antibiotic resistant and sensitive strains of the bacterium.
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P. aeruginosa injects its toxins into host cells through a syringe-like structure on its surface called the Type Three Secretion System (TTSS). The bacterium uses this structure to penetrate host cell membranes and inject toxins. The expression of TTSS correlates strongly with the bacterium’s pathogenicity. KB001 binds to a protein on the tip of the TTSS called PcrV, and in doing so, blocks the toxins secreted through the TTSS. Natural clearance mechanisms eliminate the bacteria if the TTSS is inhibited. PcrV is well conserved in all P. aeruginosa strains tested thus far. |
Preclinical Efficacy Demonstrated
KB001 is potent both therapeutically and prophylactically against P. aeruginosa in mouse disease models. The antibody is active as a Fab' fragment and stable for over 16 hours in sputum from CF patients. Interestingly, the antibody leads to the clearance of P. aeruginosa from the lungs of test animals.
The table below shows the percentage of mice showing no detectable bacteria remaining in the lungs 48 hours after intratracheal delivery of a 3-fold lethal dose of bacteria and varying doses of the Humaneered™ Fab' fragment. (Undetectable bacterial counts represent at least 1000-fold clearance of the bacterial inoculum.)
The figure below shows in a mouse pulmonary infection model that administration of a low dose of the Humaneered™ Fab' fragment (BA91) or KB001 PEGylated BA91 (10 µ/mouse) provides complete protection against a potentially lethal dose of P. aeruginosa strain PA103 administered intratracheally.
Current Status of Development
KaloBios recently completed a Phase 1 healthy human clinical trial of this molecule, and intends to start Phase 1/2 studies in CF patients and in intensive care patients on a ventilator in the first half of 2008.
Intellectual Property
The Medical College of Wisconsin in conjunction with the University of California at San Francisco developed the original mouse antibody and much of the understanding of its mechanism of action. KaloBios has secured a powerful and broad intellectual property portfolio, including issued patents from these universities protecting the target, as well as compositions and methods covering the use of antibodies to treat Pseudomonas infections in mammalian tissues.
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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