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A Novel Class of Human ADAM8 Inhibitory Antibodies for Treatment of Triple-Negative Breast Cancer
Nora D Mineva1,2, Stefania Pianetti1,2, Sonia G Das1
1Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA.
Abstract:
New targeted treatments are urgently needed to improve triple-negative breast cancer (TNBC) patient survival. Previously, we identified the cell surface protein A Disintegrin And Metalloprotease 8 (ADAM8) as a driver of TNBC tumor growth and spread via its metalloproteinase and disintegrin (MP and DI) domains. In proof-of-concept studies, we demonstrated that a monoclonal antibody (mAb) that simultaneously inhibits both domains represents a promising therapeutic approach. Here, we screened a hybridoma library using a multistep selection strategy, including flow cytometry for Ab binding to native conformation protein and in vitro cell-based functional assays to isolate a novel panel of highly specific human ADAM8 dual MP and DI inhibitory mAbs, called ADPs. The screening of four top candidates for in vivo anti-cancer activity in an orthotopic MDA-MB-231 TNBC model of ADAM8-driven primary growth identified two lead mAbs, ADP2 and ADP13. Flow cytometry, hydrogen/deuterium exchange-mass spectrometry (HDX-MS) and alanine (ALA) scanning mutagenesis revealed that dual MP and DI inhibition was mediated via binding to the DI. Further testing in mice showed ADP2 and ADP13 reduce aggressive TNBC characteristics, including locoregional regrowth and metastasis, and improve survival, demonstrating strong therapeutic potential. The continued development of these mAbs into an ADAM8-targeted therapy could revolutionize TNBC treatment.
Insights
New antibody therapies targeting A Disintegrin And Metalloprotease 8 (ADAM8) show promise for triple-negative breast cancer (TNBC). These antibodies inhibit both metalloproteinase and disintegrin domains, reducing tumor growth and improving survival in preclinical models.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- Triple-negative breast cancer (TNBC) lacks targeted therapies, necessitating novel treatment strategies.
- A Disintegrin And Metalloprotease 8 (ADAM8) is identified as a key driver of TNBC progression.
- ADAM8 exerts its pro-tumorigenic effects through its metalloproteinase (MP) and disintegrin (DI) domains.
Purpose of the Study:
- To develop novel human monoclonal antibodies (mAbs) targeting both MP and DI domains of ADAM8.
- To evaluate the therapeutic potential of these ADAM8-specific mAbs in preclinical TNBC models.
Main Methods:
- Screening of a hybridoma library using flow cytometry and cell-based functional assays to isolate ADAM8-specific mAbs (ADPs).
- In vivo efficacy studies in an orthotopic MDA-MB-231 TNBC mouse model.
- Characterization of mAb binding and inhibition mechanisms using flow cytometry, HDX-MS, and alanine scanning mutagenesis.
Main Results:
- A novel panel of human ADAM8 dual MP and DI inhibitory mAbs, termed ADPs, was successfully isolated.
- Two lead candidates, ADP2 and ADP13, demonstrated significant anti-cancer activity in vivo.
- These mAbs were shown to bind the DI domain, mediating dual inhibition and reducing aggressive TNBC characteristics like metastasis and improving survival.
Conclusions:
- ADAM8-targeted therapy using dual-inhibitory mAbs (ADP2 and ADP13) holds significant therapeutic potential for TNBC.
- Further development of these mAbs could offer a revolutionary treatment approach for TNBC patients.
- Targeting ADAM8 represents a promising strategy to overcome current limitations in TNBC treatment.
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