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

  • J Exp Clin Cancer Res. 2020 Dec 5;39(1):273. doi: 10.1186/s13046-020-01722-8.
Runhua Feng  1  2 ,  Yuling Wang  1 ,  Vijaya Ramachandran  1 ,  Qinhong Ma  3 ,  Matthew M May  1  4 ,  Ming Li  1  5 ,  Joe X Zhou  6 ,  Xiang Xu  7  8 ,  Kejing Xu  1 ,  Shenying Fang  1 ,  Weiya Xia  9 ,  Dawen Sui  10 ,  Huey Liu  11 ,  Xiaolian Gao  12 ,  Victor Prieto  13 ,  Stephen C Blacklow  7 ,  Mason Lu  14  15 ,  Jeffrey E Lee  16
Affiliations
  • 1. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 2. Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 3. MedAbome, Inc., Fremont, CA, 94538, USA.
  • 4. Department of Otolaryngology, Mayo School of Graduate Medical Education, Rochester, MN, 55905, USA.
  • 5. Department of Pathology, Anhui Province Hospital, Anhui Medical University, Hefei, Anhui, 230032, China.
  • 6. LC Sciences, LLC, Houston, TX, 77054, USA.
  • 7. Department of Biological Chemistry and Molecular Pharmacology, Harvard University School of Medicine, Boston, MA, 02115, USA.
  • 8. Department of Pathology, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
  • 9. Department of Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 10. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 11. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 12. Department of Biology and Biochemistry, The University of Houston, Houston, TX, 77204, USA.
  • 13. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 14. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. [email protected].
  • 15. MedAbome, Inc., Fremont, CA, 94538, USA. [email protected].
  • 16. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. [email protected].
PMID: 33278894 DOI: 10.1186/s13046-020-01722-8
Abstract

Background: MUC18 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.

Methods: A monoclonal antibody (mAb) (JM1-24-3) was generated from metastatic melanoma tumor live cell immunization, and high-throughput screening identified MUC18 as the target.

Results: Analysis 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.

Conclusion: These 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.

Keywords
CD146; MUC18; Metastatic melanoma; Targeted therapy; Therapeutic antibody.
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