Monday, October 24, 2016

Drugs in Clinical Pipeline: Cabiralizumab | Monoclonal Antibodies (mAbs) | Cancer Treatment | Anti-Inflammatory Agents | Anti-CSF1R Antibody


Cabiralizumab (also known as FPA008) is a humanized IgG4 monoclonal antibody that binds to human colony stimulating factor 1 receptor (CSF1R), and blocks the ability of IL34 and CSF1 to activate CSF1R expressed on macrophages. Cabiralizumab specifically targets macrophages and monocytes, immune cells that are activated or elevated in multiple disease settings [1, 2].
Upon administration, anti-CSF1R monoclonal antibody Cabiralizumab binds to CSF1R expressed on monocytes, macrophages, and osteoclasts; subsequently inhibits the binding of the CSF1R ligands colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34), to CSF1R. This prevents CSF1R activation and CSF1R-mediated signaling in these cells, thereby blocking the production of inflammatory mediators by macrophages and monocytes and reducing inflammation.
By blocking the recruitment to the tumor microenvironment and activity of CSF1R-dependent tumor-associated macrophages (TAMs), Cabiralizumab enhances T-cell infiltration and antitumor T-cell immune responses, which inhibits the proliferation of tumor cells.
Additionally, Cabiralizumab prevents the activation of osteoclasts and blocks bone destruction. TAMs play key roles in immune suppression and promoting inflammation, tumor cell proliferation and survival.
Cabiralizumab is being evaluated in Phase 1 trials involving patients with Rheumatoid Arthritis (RA), and in combination with other agents such as nivolumab in patients with selected advanced cancers.
The originator of Cabiralizumab, Five Prime is continuing to evaluate Cabiralizumab in a Phase 2 study in the orphan indication, pigmented villonodular synovitis (PVNS), as part of company’s independent development. PVNS is a locally aggressive tumor of the synovium where over-expression of CSF1 recruits macrophages to form the tumor mass in the joints. PVNS patients experience a high level of joint morbidity and have no approved treatment options

Colony Stimulating Factor 1 Receptor (CSF1R) as a Drug Target
Colony stimulating factor 1 receptor (CSF1R; also referred to as FMS, FIM2, C-FMS, and CD115) is a single-pass transmembrane receptor with an N-terminal extracellular domain (ECD) and a C-terminal intracellular domain with tyrosine kinase activity. Ligand binding of CSF1 or the interleukin 34 ligand (IL34) to CSF1R leads to receptor dimerization, upregulation of CSF1R protein tyrosine kinase activity, phosphorylation of CSF1R tyrosine residues, and downstream signaling events. Both CSF1 and IL34 stimulate monocyte survival, proliferation, and differentiation into macrophages.
Cancer Target: Many tumor cells have been found to secrete CSF1, which activates monocyte/macrophage cells through CSF1R. The level of CSF1 in tumors has been shown to correlate with the level of tumor-associated macrophages (TAMs) in the tumor. Higher levels of TAMs have been found to correlate with poorer patient prognoses. In addition, CSF1 has been found to promote tumor growth and progression to metastasis in, for example, human breast cancer xenografts in mice. Further, CSF1R appears to play a role in osteolytic bone destruction in bone metastasis, as a small molecule inhibitor of receptor tyrosine kinase activity suppresses that destruction [2, 3].
Inflammatory and Autoimmune Disease Target: CSF1 and its receptor have also been found to be involved in various inflammatory and autoimmune diseases. For example, synovial endothelial cells from joints afflicted with rheumatoid arthritis have been found to produce CSF1, suggesting a role for CSF1 and its receptor in the disease. Blocking CSF1R activity with an antibody results in positive clinical effects in mouse models of arthritis, including a reduction in the destruction of bone and cartilage and a reduction in macrophage numbers.
Mature differentiated myeloid lineage cells such as macrophages, microglial cells, and osteoclasts contribute to pathology of various diseases such as rheumatoid arthritis, multiple sclerosis and diseases of bone loss. Differentiated myeloid lineage cells are derived from peripheral blood monocyte intermediates. CSF1R stimulation contributes to development of monocytes from bone marrow precursors, to monocyte proliferation and survival, and to differentiation of peripheral blood monocytes into differentiated myeloid lineage cells such as macrophages, microglial cells, and osteoclasts. CSF1R stimulation thus contributes to proliferation, survival, activation, and maturation of differentiated myeloid lineage cells, and in the pathologic setting, CSF1R stimulation contributes to the ability of differentiated myeloid lineage cells to mediate disease pathology.
Hence, antagonists of CSF1R signaling would therefore be useful in the treatment of various CSF1R-related diseases, such as cancer, inflammatory conditions, and autoimmune diseases.

Mechanism of Action in Cabiralizumab
Cabiralizumab is a potent humanized monoclonal antibody that binds to human colony stimulating factor 1 receptor (CSF1R), and blocks the ability of IL34 and CSF1 to activate CSF1R expressed on macrophages. It has nanomolar potency against CSF1R. It also blocks ligand-induced proliferation and survival responses in primary human monocytes.

Dosages and Approvals:
Cabiralizumab (Tradename: -) is being developed by Five Prime, which continues to evaluate Cabiralizumab (FPA008) in a Phase 2 study in the orphan indication, Pigmented Villonodular Synovitis (PVNS), as part of its independent development. PVNS is a locally aggressive tumor of the synovium where over-expression of CSF1 recruits macrophages to form the tumor mass in the joints. PVNS patients experience a high level of joint morbidity and have no approved treatment options. Five Prime is also evaluating Cabiralizumab in patients with Rheumatoid Arthritis (RA).
In October 2015, Five Prime announced an exclusive worldwide license and collaboration agreement with Bristol-Myers Squibb (BMS), for the development and commercialization of Five Prime's CSF1R antibody program, including cabiralizumab (FPA008). In September 2016, Five Prime announced it initiated the Phase 1b portion of the clinical trial evaluating the immunotherapy combination of Cabiralizumab (FPA008) with Nivolumab, Bristol-Myers Squibb's PD-1 immune checkpoint inhibitor, in multiple tumor types. These tumor types include: non-small cell lung cancer, squamous cell carcinoma of the head and neck, pancreatic cancer, glioblastoma, renal cell carcinoma and ovarian cancer.

Reported Activities for Cabiralizumab:
Cabiralizumab inhibit ligand-induced CSF1R phosphorylation in less than 1000 ng/ml range. It effectively blocks the ability of IL34 and CSF1 to activate CSF1R expressed on macrophages.

Summary

Common name: FPA008; FPA 008; FPA-008; Cabiralizumab; Anti-CSF1R monoclonal antibody
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Mechanism of Action: Anti-CSF1R Monoclonal Antibody; Monoclonal Antibodies (mAbs)
Activity: Anti-inflammatory Agents; Antineoplastics; Cancer Drug
Status: Under Phase Trials
Chemical Class: Monoclonal Antibodies (mAbs)
Originator: Five Prime / Bristol-Myers Squibb
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