Antibodies blocking PlGF or VEGF interactions with the NRP1 receptor mediate antiproliferative effects

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Vascular endothelial growth factor A (VEGFA) inhibitors are promising cancer therapies, but tumor resistance limits efficacy.
• Resistance can arise from upregulation of placental growth factor 2 (PlGF-2), another ligand for VEGF receptor 1 (VEGFR1) and neuropilin receptor 1 (NRP1).
• Understanding VEGFA and PlGF-2 interactions with receptors and extracellular matrix is complex.

Purpose of the Study:

• To discover novel antibodies that precisely block PlGF-2 or VEGFA binding to NRP1, especially in the presence of heparin.
• To develop tools for probing PlGF and VEGFA biology and overcoming resistance mechanisms.
• To investigate the role of NRP1 in cancer cell proliferation and migration.

Main Methods:

• Development and characterization of new antibodies targeting VEGFA and PlGF-2 interactions with NRP1.
• Assessment of anti-VEGFA antibodies in a human umbilical vein endothelial cell (HUVEC) angiogenesis model.
• In vitro evaluation of antibody effects on Caki-I kidney carcinoma cell proliferation and migration.
• Analysis of antibody binding specificities, including dual reactivity.

Main Results:

• Anti-VEGFA antibodies blocking VEGFR1 and NRP1 interactions reduced HUVEC tube formation, supporting vascular normalization.
• Antibodies blocking PlGF-2 or VEGFA binding to NRP1 significantly reduced kidney carcinoma cell proliferation and migration.
• One antibody demonstrated dual reactivity to both VEGFA and PlGF-2, suggesting a novel therapeutic avenue.
• These findings highlight new mechanisms to disrupt PlGF activity and confirm NRP1's role in cell proliferation.

Conclusions:

• Novel antibodies provide precise blockade of VEGFA and PlGF-2 interactions with NRP1.
• These antibodies offer new strategies to overcome tumor resistance to anti-VEGF therapies.
• The study underscores the importance of NRP1 in cancer cell proliferation and suggests dual-targeting antibodies as a potential therapeutic approach.