The glycotope-specific RAV12 monoclonal antibody induces oncosis in vitro and has antitumor activity against gastrointestinal adenocarcinoma tumor xenografts in vivo

Mol Cancer Ther. 2007 Mar;6(3):856-65. doi: 10.1158/1535-7163.MCT-06-0581.

Abstract

RAV12 is a chimeric antibody that recognizes an N-linked carbohydrate antigen (RAAG12) strongly expressed on multiple solid organ cancers. More than 90% of tumors of colorectal, gastric, and pancreatic origin express RAAG12, and a majority of these tumors exhibit uniform RAAG12 expression. RAV12 exhibits potent cytotoxic activity in vitro against COLO 205 colon tumor cells via an oncotic cell death mechanism. RAV12-treated COLO 205 cells undergo morphologic changes consistent with oncosis, including cytoskeletal rearrangement, rapid plasma membrane swelling, and cell lysis. RAV12 inhibited the growth of RAAG12-expressing gastrointestinal tumor xenografts in athymic mice. In the case of SNU-16 tumor cells, twice weekly treatment of established s.c. tumors with 10 mg/kg RAV12 caused a approximately 70% suppression of tumor growth at the end of the study. This preclinical data has led to the initiation of a phase I/IIA clinical study of RAV12 in patients with metastatic or recurrent adenocarcinoma.

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / immunology
  • Adenocarcinoma / pathology
  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • Antigens, Tumor-Associated, Carbohydrate / immunology*
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • DNA-Binding Proteins / immunology
  • DNA-Binding Proteins / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes / immunology
  • Female
  • Fetus
  • Gastrointestinal Neoplasms / drug therapy*
  • Gastrointestinal Neoplasms / immunology
  • Gastrointestinal Neoplasms / pathology
  • Glycosylation
  • Humans
  • Immunization
  • Kidney / metabolism
  • Kidney / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Polymerase Chain Reaction
  • Repressor Proteins / immunology
  • Repressor Proteins / metabolism
  • Tissue Array Analysis
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays
  • Zinc Fingers

Substances

  • Antibodies, Monoclonal
  • Antigens, Tumor-Associated, Carbohydrate
  • DNA-Binding Proteins
  • Epitopes
  • Repressor Proteins
  • ZNF354C protein, human
  • Zfp354c protein, mouse