Due to its ubiquitous expression in epithelial-based tumors and extensive characterization of its role in tumor growth, epidermal growth factor receptor (EGFR) has long been an attractive target for anti-cancer therapeutics. One intensely explored therapeutic strategy is the use of anti-EGFR monoclonal antibodies (mAbs). Two such constructs, both of which target the ligand-binding domain of the EGFR extracellular region, were recently approved by the FDA for cancer treatment, and numerous others are in clinical trials. Unfortunately, the efficacy of these drugs has been disappointingly low, necessitating the design of novel mAbs with complementary therapeutic mechanisms. In previous work, we demonstrated that treatment with combinations of non-competitive mAbs that target EGFR induce receptor clustering and downregulation by inhibiting endosomal recycling. We also established that mAb-induced downregulation does not activate EGFR or its downstream effectors and that it leads to synergistic reduction in migration and proliferation of cells that secrete autocrine ligand. We thus sought to encapsulate the benefits of receptor clustering into single multispecific molecules. To this end, we engineered two classes of antibody-based therapeutics: 1) Bispecific antibodies consisting of the mutant EGFR-targeted 806 scFv fused to the wild type EGFR-targeted 225 mAb; and 2) Antibody-fibronectin fusions consisting of EGFR-targeted fibronectin domains conjugated to the full 225 mAb. Both classes of compounds effectively cluster and downregulate receptor in a range of cancerous human cell lines. Furthermore, these compounds show promise in mouse xenograft models of cancer, indicating that they could form the basis for a new category of receptor tyrosine kinase-targeted drugs.
This preliminary program is subject to change.
![[ Visit Client Website ]](images/banner.gif)
Design and Pre-Clinical Evaluation of Novel Multispecific Antibody-Based Constructs Targeting Epidermal Growth Factor Receptor
Due to its ubiquitous expression in epithelial-based tumors and extensive characterization of its role in tumor growth, epidermal growth factor receptor (EGFR) has long been an attractive target for anti-cancer therapeutics. One intensely explored therapeutic strategy is the use of anti-EGFR monoclonal antibodies (mAbs). Two such constructs, both of which target the ligand-binding domain of the EGFR extracellular region, were recently approved by the FDA for cancer treatment, and numerous others are in clinical trials. Unfortunately, the efficacy of these drugs has been disappointingly low, necessitating the design of novel mAbs with complementary therapeutic mechanisms. In previous work, we demonstrated that treatment with combinations of non-competitive mAbs that target EGFR induce receptor clustering and downregulation by inhibiting endosomal recycling. We also established that mAb-induced downregulation does not activate EGFR or its downstream effectors and that it leads to synergistic reduction in migration and proliferation of cells that secrete autocrine ligand. We thus sought to encapsulate the benefits of receptor clustering into single multispecific molecules. To this end, we engineered two classes of antibody-based therapeutics: 1) Bispecific antibodies consisting of the mutant EGFR-targeted 806 scFv fused to the wild type EGFR-targeted 225 mAb; and 2) Antibody-fibronectin fusions consisting of EGFR-targeted fibronectin domains conjugated to the full 225 mAb. Both classes of compounds effectively cluster and downregulate receptor in a range of cancerous human cell lines. Furthermore, these compounds show promise in mouse xenograft models of cancer, indicating that they could form the basis for a new category of receptor tyrosine kinase-targeted drugs.