Characterization of novel neutralizing mouse monoclonal antibody JM1-24-3 developed against MUC18 in metastatic melanoma

Runhua Feng,Joe X Zhou,Jeffrey E Lee,Matthew M May,Xiang Xu,Mason Lu,Victor Prieto,Dawen Sui,Kejing Xu,Weiya Xia,Xiaolian Gao,Stephen C Blacklow,Vijaya Ramachandran,Qinhong Ma,Huey Liu,Ming Li,Shenying Fang,Yuling Wang

doi:10.1186/s13046-020-01722-8

Abstract

BackgroundMUC18 is a glycoprotein highly expressed on the surface of melanoma and other cancers which promotes tumor progression and metastasis. However, its mechanism of action and suitability as a therapeutic target are unknown.MethodsA monoclonal antibody (mAb) (JM1-24-3) was generated from metastatic melanoma tumor live cell immunization, and high-throughput screening identified MUC18 as the target.ResultsAnalysis of molecular interactions between MUC18 and JM1-24-3 revealed that the downstream signaling events depended on binding of the mAb to a conformational epitope on the extracellular domain of MUC18. JM1-24-3 inhibited melanoma cell proliferation, migration and invasion in vitro and reduced tumor growth and metastasis in vivo.ConclusionThese results confirm that MUC18 is mechanistically important in melanoma growth and metastasis, suggest that the MUC18 epitope identified is a promising therapeutic target, and that the JM1-24-3 mAb may serve as the basis for a potential therapeutic agent.

Highlights

MUC18 is a glycoprotein highly expressed on the surface of melanoma and other cancers which promotes tumor progression and metastasis
* Correspondence: mlu@medabome.com; jelee@mdanderson.org †Runhua Feng and Yuling Wang contributed to this work. 1Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Full list of author information is available at the end of the article monoclonal antibody directed against a melanoma cell-surface antigen, which we subsequently identified as the functional, glycosylated protein MUC18
We found that these signaling events depended on binding of the monoclonal antibody (mAb) to a conformational epitope on the extracellular domain of MUC18

Summary

Introduction

MUC18 is a glycoprotein highly expressed on the surface of melanoma and other cancers which promotes tumor progression and metastasis. MUC18, known as MCAM (melanoma cell adhesion molecule), CD146 (cluster of differentiation 146), or METCAM/MelCAM (metastatic melanoma CAM), is expressed on the surface of metastatic melanoma and other cancer cells [2]. Expression of MUC18 has been demonstrated to promote tumorigenesis and tumor progression, and therapeutic targeting of MUC18 can reduce bone metastasis in a prostate cancer model [3]. MUC18 on melanoma cells, initiating downstream signaling events that were associated with inhibition of melanoma cell proliferation, migration, and invasion in vitro, and reduction in tumor growth and metastasis in vivo. We found that these signaling events depended on binding of the mAb to a conformational epitope on the extracellular domain of MUC18

Methods

Results

Discussion

Conclusion