Combining Anti-ERBB3 Antibodies Specific for Domain I and Domain III Enhances the Anti-Tumor Activity over the Individual Monoclonal Antibodies

Abstract

BackgroundInappropriate signaling through the epidermal growth factor receptor family (EGFR1/ERBB1, ERBB2/HER2, ERBB3/HER3, and ERBB4/HER4) of receptor tyrosine kinases leads to unregulated activation of multiple downstream signaling pathways that are linked to cancer formation and progression. In particular, ERBB3 plays a critical role in linking ERBB signaling to the phosphoinositide 3-kinase and Akt signaling pathway and increased levels of ERBB3-dependent signaling is also increasingly recognized as a mechanism for acquired resistance to ERBB-targeted therapies.MethodsWe had previously reported the isolation of a panel of anti-ERBB3 single-chain Fv antibodies through use of phage-display technology. In the current study scFv specific for domain I (F4) and domain III (A5) were converted into human IgG1 formats and analyzed for efficacy.ResultsTreatment of cells with an oligoclonal mixture of the A5/F4 IgGs appeared more effective at blocking both ligand-induced and ligand-independent signaling through ERBB3 than either single IgG alone. This correlated with improved ability to inhibit the cell growth both as a single agent and in combination with other ERBB-targeted therapies. Treatment of NCI-N87 tumor xenografts with the A5/F4 oligoclonal led to a statistically significant decrease in tumor growth rate that was further enhanced in combination with trastuzumab.ConclusionThese results suggest that an oligoclonal antibody mixture may be a more effective approach to downregulate ERBB3-dependent signaling.

Genetically Engineered Antibody Functionalized Platinum Nanoparticles Modified CVD‐Graphene Nanohybrid Transistor for the Detection of Breast Cancer Biomarker, HER3

“…We engineered the HER3 monoclonal antibody into an scFv antibody [ 45 ] with a pair of cysteine (thiol) residues inside the loop sequence bridging the V H and V L segments, allowing it to be immobilized on PtNPs embedded on graphene for the production of GFET-based biosensors. We engineered the HER3 monoclonal antibody into an scFv antibody [ 45 ] with a pair of cysteine (thiol) residues inside the loop sequence bridging the V H and V L segments, allowing it to be immobilized on PtNPs embedded on graphene for the production of GFET-based biosensors.…”

“…[ 45 ] An scFv version of the A5 antibody was expressed and purifi ed as previously described. [ 45 ] An scFv version of the A5 antibody was expressed and purifi ed as previously described.…”

Oligoclonal antibodies to target the ErbB family

“…This was observed with a mixture of two anti-ErbB3 mAbs that target domain I and domain III of the ErbB3 extracellular domain. 44 The oligoclonal combination was more effective at blocking both ligand-dependent and ligand-independent signaling through the ErbB3 receptor in vitro . This oligoclonal mixture of anti-ERbb3 antibodies also inhibited the growth inhibition of ErbB2-positive tumor xenografts.…”

Immunotherapy of cancer: from monoclonal to oligoclonal cocktails of anti‐cancer antibodies: IUPHAR Review 18

“…For example, lumretuzumab, a glycoengineered anti‐HER3 monoclonal antibody (Meulendijks et al , ), failed to show added benefit when combined with the EGFR inhibitor erlotinib in a phase I/II NSCLC trial. In addition, it is still unclear whether homo‐combinations of anti‐HER3 antibodies are endowed with synergistic anti‐tumour effects (D'Souza et al , ; Gaborit et al , ). Nevertheless, several non‐clinical studies have attributed an advantage to hetero‐combinations containing an anti‐HER3 component.…”