Antitumor Activities by a Humanized Cancer-Specific Anti-Podoplanin Monoclonal Antibody humPMab-117 Against Human Tumors.

in Cancer science by Tomohiro Tanaka, Hiroyuki Suzuki, Tomokazu Ohishi, Manabu Kawada, Mika K Kaneko, Yukinari Kato

TLDR

  • A humanized IgG monoclonal antibody (humPMab-117) was engineered to selectively target podoplanin-positive malignant tumors, showing strong antitumor efficacy in xenograft models and potential as a therapeutic strategy.

Abstract

Podoplanin (PDPN), also referred to as T1α/Aggrus, is a type I transmembrane sialoglycoprotein that plays a crucial role in invasiveness, stemness, and epithelial-to-mesenchymal transition, all of which contribute to the malignant progression of tumors. Therefore, a monoclonal antibody (mAb) against PDPN has been evaluated in preclinical models as a promising tumor therapy strategy. However, PDPN plays an essential role in normal development, such as in the development of the lungs. On-target toxicity by anti-PDPN mAbs to normal cells should be avoided to minimize adverse effects. A cancer-specific mAb against PDPN, PMab-117 (rat IgM, kappa), was previously established. This study engineered the humanized IgGversion (humPMab-117) to investigate antitumor activity. Flow cytometry analysis confirmed that humPMab-117 recognized PDPN-overexpressed glioma LN229 (LN229/PDPN) cells as well as PDPN-positive PC-10 (human lung squamous cell carcinoma) and LN319 (human glioblastoma) cells. In contrast, humPMab-117 did not react with normal epithelial cells from the lung bronchus, gingiva, mammary gland, corneal, and normal kidney podocytes, suggesting that humPMab-117 retains cancer-specific reactivity. Furthermore, humPMab-117 effectively induced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against LN229/PDPN, PC-10, and LN319 cells. In the xenograft tumor models, humPMab-117 demonstrated strong antitumor efficacy. These results suggest the potential of humPMab-117 as a therapeutic antibody for treating PDPN-positive malignant tumors.

Overview

  • The study aimed to develop a cancer-specific monoclonal antibody (mAb) against podoplanin (PDPN) to treat PDPN-positive malignant tumors, while avoiding on-target toxicity to normal cells.
  • The mAb, humPMab-117, was engineered to recognize PDPN-overexpressed glioma cells and human lung squamous cell carcinoma cells, but not normal epithelial cells.
  • The study investigated the antitumor activity and cytotoxic effects of humPMab-117 against PDPN-positive tumor cells and its potential as a therapeutic antibody.

Comparative Analysis & Findings

  • Flow cytometry analysis confirmed that humPMab-117 recognized PDPN-overexpressed glioma LX229 cells and PDPN-positive PC-10 and LN319 cells, but not normal epithelial cells.
  • HumPMab-117 induced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against LX229/PDPN, PC-10, and LN319 cells.
  • In xenograft tumor models, humPMab-117 demonstrated strong antitumor efficacy.

Implications and Future Directions

  • HumPMab-117 has potential as a therapeutic antibody for treating PDPN-positive malignant tumors, particularly gliomas and lung squamous cell carcinoma.
  • Future studies should investigate the optimal dosing, administration schedule, and combination therapy for humPMab-117 to achieve maximum antitumor efficacy.
  • The safety and efficacy of humPMab-117 in human clinical trials should be evaluated to determine its potential for clinical application.
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