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 .
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 .
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 .
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
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
Molecular Formula: -
CAS Registry Number: -
CAS Name: -
Molecular Weight: -
InChI Key: -
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
Synthesis Route for THR-317
To be updated shortly.
Sideeffects: The most frequently reported adverse events (AEs) were nasopharyngitis, headache, neck pain, and joint pain. There was no dose-related pattern of AEs identified .
Of particular interest were the common toxicities associated with VEGF-targeting agents such as hypertension, proteinuria, bowel perforation, hemorrhage, thrombosis, and wound dehiscence. There were no such AEs seen in this study after administration of THR-317.
Others: THR-317, a monoclonal antibody against PlGF, was investigated in clear cell renal cell carcinoma (ccRCC) xenografts since it has been proposed as a potential target in oncology. Human ccRCCs were implanted in athymic nude mice to evaluate the efficacy of THR-317 and to excise xenograft tumors for molecular experiments. THR-317 did not significantly inhibit tumor growth in treatment-naive or Sunitinib-resistant ccRCC xenografts. Gene expression profiling resulted in over-expression of the C1orf38 gene, which induced immunoreactivity in macrophages. Angiogenesis PCR arrays showed that VEGFR-1 was not expressed in ccRCC xenografts, highlighting THR-317 might be effective on-target in VEGFR1-expressing tumors .
1. Rizzo, C.; et. al. Abstract 1370: RO5323441, a humanized monoclonal antibody against the placenta growth factor, blocks PlGF-induced VEGFR-1 phosphorylation in vitro and tumor growth in vivo. AACR; Cancer Res 2010, 70(8 Suppl). (FMO only)
2. Martinsson-Niskanen, T.; et. al. Monoclonal antibody TB-403: a first-in-human, Phase I, double-blind, dose escalation study directed against placental growth factor in healthy male subjects. Clin Ther 2011, 33(9), 1142 - 1149. (FMO only)
3. Sharma, P. S.; et. al. VEGF/VEGFR pathway inhibitors as anti-angiogenic agents: present and future. Curr Cancer Drug Targets 2011, 11(5), 624 - 653. (FMO only) [A review by yours truly.]
4. ClinicalTrials.gov Phase I Study on Monoclonal Antibody TB-403 Directed Against PlGF in Patients With Solid Tumours. NCT00702494
5. ClinicalTrials.gov A Two-Part Study of TB-403 in Pediatric Subjects With Relapsed or Refractory Medulloblastoma. NCT02748135
6. Bessho, H.; et. al. Inhibition of placental growth factor in renal cell carcinoma. Anticancer Res 2015, 35(1), 531 - 541. (FMO only)