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
Trademarks: -
Molecular Formula: -
CAS Registry Number: -
CAS Name: -
Molecular Weight: -
SMILES: -
InChI Key: -
InChI: -
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
