A Novel Bispecific Antibody Targeting EGFR and VEGFR2 Is Effective against Triple Negative Breast Cancer via Multiple Mechanisms of Action

• Published in: Cancers Vol. 13; no. 5; p. 1027
• Main Authors: Mohan, Nishant, Luo, Xiao, Shen, Yi, Olson, Zachary, Agrawal, Atul, Endo, Yukinori, Rotstein, David S, Pelosof, Lorraine C, Wu, Wen Jin
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.03.2021; MDPI
• Subjects: Angiogenesis; Animal models; Antibodies; Antigens; Antitumor agents; autocrine and paracrine; Autocrine signalling; Bispecific antibodies; bispecific antibody (BsAb); Breast cancer; Cancer therapies; Cell growth; EGFR; Endothelial cells; Epidermal growth factor; Epidermal growth factor receptors; FDA approval; Glycine; Immunoglobulin G; Metastasis; Monoclonal antibodies; Paracrine signalling; Proteins; Signal transduction; Targeted cancer therapy; triple-negative breast cancer (TNBC); Tumors; Vascular endothelial growth factor; VEGFR2; Xenografts; VEGFR2; autocrine and paracrine; triple-negative breast cancer (TNBC); bispecific antibody (BsAb); EGFR
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers13051027

Both EGFR and VEGFR2 frequently overexpress in TNBC and cooperate with each other in autocrine and paracrine manner to enhance tumor growth and angiogenesis. Therapeutic mAbs targeting EGFR (cetuximab) and VEGFR2 (ramucirumab) are approved by FDA for numerous cancer indications, but none of them are approved to treat breast cancers. TNBC cells secrete VEGF-A, which mediates angiogenesis on endothelial cells in a paracrine fashion, as well as promotes cancer cell growth in autocrine manner. To disrupt autocrine/paracrine loop in TNBC models in addition to mediating anti-EGFR tumor growth signaling and anti-VEGFR2 angiogenic pathway, we generated a BsAb co-targeting EGFR and VEGFR2 (designated as anti-EGFR/VEGFR2 BsAb), using publicly available sequences in which cetuximab IgG backbone is connected to the single chain variable fragment (scFv) of ramucirumab via a glycine linker. Physiochemical characterization data shows that anti-EGFR/VEGFR2 BsAb binds to both EGFR and VEGFR2 in a similar binding affinity comparable to parental antibodies. Anti-EGFR/VEGFR2 BsAb demonstrates in vitro and in vivo anti-tumor activity in TNBC models. Mechanistically, anti-EGFR/VEGFR2 BsAb not only directly inhibits both EGFR and VEGFR2 in TNBC cells but also disrupts autocrine mechanism in TNBC xenograft mouse model. Furthermore, anti-EGFR/VEGFR2 BsAb inhibits ligand-induced activation of VEGFR2 and blocks paracrine pathway mediated by VEGF secreted from TNBC cells in endothelial cells. Collectively, our novel findings demonstrate that anti-EGFR/VEGFR2 BsAb inhibits tumor growth via multiple mechanisms of action and warrants further investigation as a targeted antibody therapeutic for the treatment of TNBC.