Specific binding of TES-23 antibody to tumour vascular endothelium in mice, rats and human cancer tissue: A novel drug carrier for cancer targeting therapy

Abstract

SummaryThe tissue distribution of anti-tumour vascular endothelium monoclonal antibody (TES-23) produced by immunizing with plasma membrane vesicles from isolated rat tumour-derived endothelial cells (TECs) was assessed in various tumour-bearing animals. Radiolabelled TES-23 dramatically accumulated in KMT-17 fibrosarcoma, the source of isolated TECs after intravenous injection. In Meth-A fibrosarcoma, Colon-26 adenocarcinoma in BALB/c mice and HT-1080 human tumour tissue in nude mice, radioactivities of 125 I-labelled TES-23 were also up to 50 times higher than those of control antibody with little distribution to normal tissues. The selective recognition of TES-23 to TECs was competitively blocked by preadministration of unlabelled TES-23 in vivo. Furthermore, immunostaining of human tissue sections showed specific binding of TES-23 on endothelium in oesophagus cancers. These results indicate that tumour vascular endothelial cells express common antigen in different tumour types of various animal species. In order to clarify the efficacy of TES-23 as a drug carrier, an immunoconjugate, composed of TES-23 and neocarzinostatin, was tested for its anti-tumour effect in rats bearing KMT-17 fibrosarcomas. The immunoconjugate (TES-23-NCS) caused marked regression of the tumour, accompanied by haemorrhagic necrosis. Thus, from a clinical view, TES-23 would be a novel drug carrier because of its high specificity to tumour vascular endothelium and its application to many types of cancer. © 1999 Cancer Research Campaign Keywords: tumour vascular endothelium; immunoconjugate; targeting therapy; drug delivery system; monoclonal antibody 1155British Journal of Cancer (1999) 81(7), 1155-1161 © 1999 Cancer Research Campaign Article no. bjoc.1999 Received 30 June 1998 Revised 2 December 1998 Accepted 12 May 1999 Correspondence to: T Mayumi antibody (TES-23) that recognizes TECs by means of actively immunizing mice with membranes of TECs after passive immunization with endothelial cells derived from normal tissue (Ohizumi et al, 1997). This study was conducted to assess the distribution of the antigen recognized by TES-23 in many tumour types in mice, rats and humans, and suggests the usefulness of TES-23 for a targeting therapy against tumour vasculature. MATERIALS AND METHODS Isolation of tumour endothelial cellsTECs, or capillary endothelial cells in tumour tissue, were isolated from KMT-17 rat fibrosarcoma (kindly donated by Dr N Takeichi, Hokkaido University, Japan) by means of density-gradient centrifugation and attach-speed separation techniques as we previously reported (Utoguchi et al, 1995a). Briefly, minced and collagenasedigested KMT-17 tumour tissue was separated by Percoll (Amersham Pharmacia Biotech, Sweden) density-gradient centrifugation. The cells in the fraction enriched with endothelial cells were plated on tissue culture dishes in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal calf serum (FCS) and 50 µg ml -1 of endothelial cell growth supplement (ECGS, Sigma Chemical Co., St Lo...

Vascular disrupting agents

“…Human prostate (PC‐3) xenografts treated with this fusion protein demonstrated significant damage to the vascular endothelium, vessel thrombosis, extravasation of red blood cell components into the tumor interstitium, and marked tumor regression [Veenendaal et al, 2002]. Significant antitumor effects have also been described for the chemical conjugate of the plant toxin ricin A chain linked to monoclonal antibodies directed to mouse endoglin [Seon et al, 2001]; the cytotoxic molecule neocarzinostatin attached to TES‐23, a monoclonal antibody directed against a CD44‐related tumor endothelial cell marker [Tsunoda et al, 1999]; and an immunotoxin directed against the VEGF‐receptor complex [Thorpe et al, 2003].…”

Antibody-Based Targeting of Angiogenesis

“…It has been implicated in a variety of other responses, including leukocyte homing, activation, and invasion of malignant cells. Recent biodistribution and therapy studies, performed in mice and rats with an antibody against a CD44 splice variant, have characterized this antigen as an interesting vascular target expressed in different tumor types of various animal species (17).…”

Genetically engineered endostatin-lidamycin fusion proteins effectively inhibit tumor growth and metastasis

“…The clinical development ended in the U.S. in 2003 due to limited efficacy and problems with protein formulation and application [ 16 ]. Several studies reported the improved selectivity and efficacy of chimeric molecules comprised of toxins or other cytotoxic agents with targeting agents on tumor vasculature, such as vascular endothelial growth factor receptor-gelonin; Shiga-like toxin-vascular endothelial growth factor fusion protein and anti-TES-23 linked to neocarzinostatin [ 17 - 19 ]. So the combination of the targeted and cytotoxic effects by engineering two independent molecules sounds to be a promising way for drug design.…”