THR-317
(also known as TB-403; RO5323441; αPIGF) is a humanized recombinant
immunoglobulin (Ig) G1 monoclonal antibody directed to the
receptor-binding site of placental growth factor (PlGF). Inhibition of
angiogenesis as a therapeutic strategy in oncology has been validated by
treatments that block VEGF or its receptors, vascular endothelial growth factor
receptor (VEGFR-1, -2, -3). Several antiangiogenesis inhibitors targeting VEGF
or its receptors have been approved, such as the monoclonal antibody
bevacizumab and the tyrosine kinase inhibitors Sorafenib and Sunitinib [1, 2].
PlGF behaves
like VEGF in being an angiogenic factor and various preclinical studies have
demonstrated that targeting PlGF can result in significant inhibition of tumor
growth and metastasis.
In preclinical
studies, the antibody THR 317 exhibited high-affinity (nanomolar range) binding
to PlGF; in vitro inhibition of PlGF
binding to the receptor, vascular endothelial growth factor receptor 1
(VEGFR-1); and significant in vivo
antitumor activity.
Tumor Angiogenesis and Treatments:
Angiogenesis,
the formation of new blood vessels from pre-existing ones, plays a central role
in the process of tumor growth and metastasis. The proliferation of endothelium
and formation of new blood vessels further the size of solid tumors. It is
expected that blocking angiogenesis will be an efficient therapeutic approach
against many tumor types. The key signaling system that regulates proliferation
and migration of endothelial cells are vascular endothelium growth factor
(VEGF) and their receptors (VEGFR-1, -2 and -3). VEGFR-2, a receptor with
higher affinity and greater kinase activity, is more important in the direct
regulation of angiogenesis, mitogenic signaling, and permeability-enhancing
effects. VEGFRs are expressed at high levels in many types of human solid
tumors, including glioma, lung, breast, renal, ovarian and gastrointestinal
tract carcinomas. Inhibition of VEGFR has emerged as a potential therapy method
for cancers and it has been clinically validated with FDA-approvals of
bevacizumab, sorafenib, and suntinib [3].
PlGF is
a member of the VEGF family that is found only in very low levels under normal
physiological conditions, but is up-regulated in almost all major malignant
diseases. PlGF expression has shown to correlate with tumor stages and patient
survival in breast cancer, CRC and gastric cancer. Pre-clinical data support a
role for PlGF in tumor angiogenesis, and demonstrate that blocking PlGF can
inhibit tumor growth [1, 2].
PlGF is
a pleiotropic cytokine that not only stimulates angiogenesis by affecting
endothelial cell growth, migration, and survival, but also chemoattracts
angiocompetent macrophages and bone marrow progenitors and determines the
metastatic niche.
PlGF
has also been associated with relapse of human xenograft tumors after
radioimmunotherapy and relapse in cancer patients treated with VEGF inhibitors,
altogether suggesting that PlGF is important in the “angiogenic rescue program”
induced by a variety of anticancer therapeutic modalities [2].
Mechanism of Action in THR-317:
THR-317
is a humanized monoclonal antibody directed against placental growth factor
(PlGF).This monoclonal antibody binds with high affinity to the
receptor-binding site of PlGF and reduces tumor growth in xenograft
experiments. It is possible that, through inhibition of PlGF binding to its
receptor and subsequent downstream signaling, the antibody may exert a
pleiotropic mechanism of action that leads to antitumor activity and an
improved safety profile compared with those of other antiangiogenic treatments.
PlGF
blockade did not have a broad antiangiogenic efficacy; however, it might be
effective on-target in VEGFR1-expressing tumors. The inhibition of VEGF pathway
may induce the activity of tumor-associated-macrophages for angiogenesis
escape.
Dosages and Approvals:
THR-317
(Tradename: -) is being developed by ThromboGenics and BioInvent International
for treatment of Diabetic Macular Edema (DME).
It is under clinical trials [4, 5].
Reported Activities for THR-317:
THR-317
binds to both PlGF-1 and PlGF-2 in a dose dependent manner, and is not
cross-reactive with murine PlGF or human VEGF.
THR-317
inhibits the binding of human PlGF-1 or PlGF-2 to VEGFR-1 with IC50
values of 0.1 and 0.2 nM, respectively. THR-317 blocks PlGF-induced VEGFR-1
phosphorylation in Flt-1-transfected HEK293 cells. Antitumor activity has been
demonstrated in mutliple tumor models including ACHN and Caki-1 renal cell
carcinoma and Huh-7, hepatocellular carcinoma xenografts [1].
IC50 (Inhibition of binding of
human PIGF-1 to VEGFR-1) = 0.1 nM
IC50 (Inhibition of binding of
human PIGF-2 to VEGFR-1) = 0.2 nM
Summary
Common name: THF317; THF-317; THF
317; R-7334; RG 7334; RO-5323441; Anti-PlGF; αPIGF ; Anti-PlGF monoclonal
antibody; Anti-placental growth factor monoclonal antibody
Trademarks: -
Molecular Formula: -
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CAS Name: -
Molecular Weight: -
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InChI Key: -
InChI: -
Mechanism of Action: Angiogenesis Inhibitors;
Placenta Growth Factor (PIGF) Inhibitors; Monoclonal Antibodies (mAbs)
Activity: Anti-inflammatory Agents; Antineoplastics;
Eye Disorder Therapies; Angiogenesis Inhibitors
Status: Under Phase Trials
Chemical Class: Monoclonal
Antibodies (mAbs)
Originator: BioInvent International and ThromboGenics / BioInvent International;
Oncurious; Roche and ThromboGenics