KaloBios Pharmaceuticals, Inc (PALO ALTO, California), a privately-held clinical development company focused on the development of therapeutic antibodies, announced that it has begun treating patients in a phase I clinical trial of its investigational rheumatoid arthritis (RA) therapeutic, KB002, an engineered chimeric human monoclonal antibody targeting the cytokine growth factor, granulocyte macrophage colony-stimulating factor (GM-CSF). GM-CSF is an important activator of macrophages, a major source of inflammatory cytokines and joint-degrading enzymes, and is thought to play a key role in the progression of RA. The trial is a randomized, double-blinded, placebo-controlled, single dose, dose escalating study that will enroll 32 patients with active disease at more than five medical centers throughout Australia (Adelaide, Brisbane, Melbourne, Sydney, and Townsville). Patients will be randomly assigned 3:1 to KB002 or placebo. The primary outcome of the trial is the safety and tolerability profile of KB002 in patients with RA at day 29. The secondary outcomes relate to the efficacy and pharmacokinetics of KB002 at day 29. KaloBios believes that clinical testing will show that KB002 can be used to treat RA patients who have become resistant to disease modifying anti-rheumatic drugs (DMARDs) and/or anti-TNF drugs.

KB002 is a low picomolar affinity, engineered human IgG1k antibody that neutralizes the activity of GM-CSF (ED50 of 15pM in an in vitro human cell proliferation assay). KaloBios' Humaneeringâ„¢ technology was used to convert a nonhuman antibody into an engineered human antibody having high affinity but close to human germline sequence.

GM-CSF is a hematopoietic growth factor that in vitro stimulates the survival, proliferation, differentiation, and function of myeloid cells especially monocyte/macrophages, neutrophils, and eosinophil granulocytes. Recently it has been shown that GM-CSF is not an essential hematopoietic growth factor because mice lacking the gene for GM-CSF have normal hematopoiesis. Although macrophages play a key role in tissue damage, repair, and protection against infection, the persistence of activated macrophages in disease lesions or damaged tissues may lead to the development of an uncontrolled autoimmune response. GM-CSF is a key activator of macrophages and there is a significant body of data that supports its pathological role in establishing and maintaining the autoimmune disease state: (1) GM-CSF gene knock-out mice are resistant to the induction of autoimmune diseases (eg, collagen-induced arthritis (CIA), experimental encephalomyelitis [EAE]), but show no major changes in hematopoiesis; (2) transgenic mice over-expressing GM-CSF in different tissues develop tissue-specific autoimmune reactions; (3) an antibody that neutralizes murine GM-CSF prevents and treats CIA and EAE in mice; (4) GM-CSF dosed to patients can reactivate their autoimmune disease; and (5) RA patients have elevated levels of GM-CSF in their diseased joints.

KB002 was discovered at the Ludwig Institute for Cancer Research (LICR) of Melbourne, Australia and was exclusively licensed to KaloBios in 2004. In animal studies, blocking the function of GM-CSF with a neutralizing antibody prevents the induction of arthritis, while treatment of ongoing disease with the antibody halts the progression of the disease. Because the function of GM-CSF is well conserved among mammals, it is believed that the information and first generation antibody developed by the LICR will lead to an effective drug in humans.

In 2005, KaloBios completed a series B financing round of $20 million. Lead investors MPM Capital and GBS Venture Partners Ltd were joined by Lotus BioScience Ventures Ltd and existing investors, Sofinnova Ventures, Inc; Alloy Ventures, Inc; 5AM Ventures; and Singapore BioInnovations Pte Ltd.

—A. Techman

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