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PRL3-zumab as an immunotherapy to inhibit tumors expressing PRL3 oncoprotein

Min Thura1, Abdul Qader Al-Aidaroos1, Abhishek Gupta1

  • 1Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, 138673, Singapore.

Nature Communications
|June 8, 2019
PubMed

Insights

A novel antibody drug, PRL3-zumab, targets the oncogenic phosphatase PRL3. This immunotherapy effectively inhibits cancer cells by engaging immune cells, offering a promising new approach for cancer treatment.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Antibody drugs offer targeted cancer therapy with fewer side effects.
  • The oncogenic phosphatase PRL3 is frequently expressed in various cancers.
  • PRL3's intracellular localization presents a challenge for antibody-based therapies.

Purpose of the Study:

  • To investigate the efficacy of the humanized antibody PRL3-zumab against PRL3-expressing cancers.
  • To elucidate the mechanism of action for PRL3-zumab in inhibiting cancer cells.
  • To determine the potential of targeting externalized PRL3 as an immunotherapy.

Main Methods:

  • In vivo and in vitro studies using PRL3-zumab.
  • Analysis of PRL3 antigen expression on cancer cells and exosomes.
  • Assessment of antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) pathways.
  • Evaluation of Fc region and Fcγ receptor engagement.

Main Results:

  • PRL3-zumab demonstrated specific inhibition of PRL3+ cancer cells in vivo, but not in vitro.
  • PRL3 antigens were found on the cell surface and outer exosomal membranes, indicating 'inside-out' externalization.
  • PRL3-zumab's mechanism involves intact Fc region and FcγII/III receptor engagement, recruiting immune cells like B cells, NK cells, and macrophages.
  • PRL3 is overexpressed in 80.6% of tested tumor samples across 11 cancer types, but not in normal tissues.

Conclusions:

  • Externalized PRL3 antigens can be targeted by PRL3-zumab.
  • The antibody utilizes immune effector mechanisms (ADCC/ADCP) for tumor elimination.
  • PRL3 represents a promising tumor-associated antigen for developing novel immunotherapies.

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