Related Experiment Video
Updated: Mar 26, 2026
Targeted Antibody Blocking by a Dual-Functional Conjugate of Antigenic Peptide and Fc-III Mimetics DCAF
Published on: September 17, 2019
Novel strategy for a bispecific antibody: induction of dual target internalization and degradation
J M Lee1, S H Lee2, J-W Hwang3
1Open Innovation Team, Samsung Bioepis Co., Ltd., Incheon, South Korea.
Abstract:
Activation of the extensive cross-talk among the receptor tyrosine kinases (RTKs), particularly ErbB family-Met cross-talk, has emerged as a likely source of drug resistance. Notwithstanding brilliant successes were attained while using small-molecule inhibitors or antibody therapeutics against specific RTKs in multiple cancers over recent decades, a high recurrence rate remains unsolved in patients treated with these targeted inhibitors. It is well aligned with multifaceted properties of cancer and cross-talk and convergence of signaling pathways of RTKs. Thereby many therapeutic interventions have been actively developed to overcome inherent or acquired resistance. To date, no bispecific antibody (BsAb) showed complete depletion of dual RTKs from the plasma membrane and efficient dual degradation. In this manuscript, we report the first findings of a target-specific dual internalization and degradation of membrane RTKs induced by designed BsAbs based on the internalizing monoclonal antibodies and the therapeutic values of these BsAbs. Leveraging the anti-Met mAb able to internalize and degrade by a unique mechanism, we generated the BsAbs for Met/epidermal growth factor receptor (EGFR) and Met/HER2 to induce an efficient EGFR or HER2 internalization and degradation in the presence of Met that is frequently overexpressed in the invasive tumors and involved in the resistance against EGFR- or HER2-targeted therapies. We found that Met/EGFR BsAb ME22S induces dissociation of the Met-EGFR complex from Hsp90, followed by significant degradation of Met and EGFR. By employing patient-derived tumor models we demonstrate therapeutic potential of the BsAb-mediated dual degradation in various cancers.
Insights
New bispecific antibodies (BsAbs) target dual receptor tyrosine kinases (RTKs), inducing internalization and degradation to overcome cancer drug resistance. These novel BsAbs show therapeutic potential in patient-derived tumor models.
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- Receptor tyrosine kinase (RTK) cross-talk, especially involving Met and ErbB family members, is a key mechanism of drug resistance in cancer.
- Despite advances in targeted therapies, high recurrence rates persist due to complex signaling pathways and acquired resistance.
- Existing therapies often fail to completely deplete dual RTKs from the cell surface or induce their degradation.
Purpose of the Study:
- To develop and evaluate novel bispecific antibodies (BsAbs) capable of inducing dual internalization and degradation of membrane RTKs.
- To investigate the therapeutic potential of these BsAbs in overcoming resistance mediated by Met/EGFR and Met/HER2 cross-talk.
- To demonstrate the efficacy of BsAb-mediated dual degradation in patient-derived tumor models.
Main Methods:
- Design of BsAbs based on internalizing monoclonal antibodies targeting Met, EGFR, and HER2.
- Generation of Met/EGFR and Met/HER2 BsAbs to induce simultaneous internalization and degradation of target RTKs.
- Assessment of BsAb-induced RTK degradation, complex dissociation from Hsp90, and therapeutic efficacy in preclinical cancer models.
Main Results:
- Developed BsAbs that induce target-specific dual internalization and degradation of membrane RTKs.
- Met/EGFR BsAb ME22S effectively dissociates the Met-EGFR complex from Hsp90, leading to significant degradation of both Met and EGFR.
- Demonstrated the therapeutic potential of BsAb-mediated dual degradation in patient-derived tumor models across various cancers.
Conclusions:
- Designed BsAbs offer a novel strategy for overcoming RTK-mediated drug resistance by inducing dual internalization and degradation.
- BsAb-mediated targeting of Met/EGFR and Met/HER2 pathways shows significant promise for cancer therapy.
- This approach represents a potential breakthrough in treating cancers with high recurrence rates due to RTK cross-talk.
Related Concept Videos
01:26Antibody Actions
Neutralization
Antibodies can bind to pathogens, preventing them from infecting host cells. This process...
01:15Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...