Accession Number:

ADA394358

Title:

Targeting of Adenovirus Vectors to Breast Cancer Mediated by Soluble Receptor-Ligand Fusion Proteins

Descriptive Note:

Annual rept. 15 May 2000-14 May 2001

Corporate Author:

ALABAMA UNIV IN BIRMINGHAM

Personal Author(s):

Report Date:

2001-06-01

Pagination or Media Count:

23.0

Abstract:

The use of adenovirus Ad vectors for cancer gene therapy applications is currently limited due to the broad viral tropism associated with the widespread expression of primary coxsackievirus and adenovirus receptor CAR in human tissues. To confer Ad targeting capability to relevant cell types we have proposed the use of soluble CAR ectodomain sCAR fused with ligand to block CAR-mediated tropism and simultaneously achieve infection through a novel receptor overexpressed on target cells. To target Ad vectors to breast cancer cell types we produced bispecific proteins containing sCAR and either alphav-integrin binding RGD-4C or NCR peptide motif possessing high potential for bacteriophage targeting to human breast cancer xenografts in mice. Specifically, we designed gene encoding sCAR, purification tag, phage T4 fibritin polypeptide, hinge region and site for cloning of ligand sequences. Incorporation of fibritin polypeptide provided trimerization of sCAR-fusion proteins that resulted in augmented affinity to Ad fiber knob domain and increased ability to block CAR-mediated Ad infection compared to monomeric sCAR protein. We also demonstrated that most of breast cancer cell lines tested display low CAR and high levels of alphav-integrins. Thus, utilization of constructed trimeric sCAR-ligand proteins for Ad targeting may augment Ad vectors potency for breast cancer treatment. 1

Subject Categories:

  • Biochemistry
  • Medicine and Medical Research
  • Microbiology

Distribution Statement:

APPROVED FOR PUBLIC RELEASE