Breast cancer remains the second leading cause of
cancer death among women in the United States.
Breast cancer prognosis is particularly poor in case of
tumors overexpressing the
oncoprotein HER2/neu. A new nanobioconjugate of the
Polycefin(TM) family of anti-
cancer drugs based on biodegradable and non-toxic
polymalic acid (PMLA) was engineered for a multi-pronged attack on HER2/neu-positive
breast cancer cells. An antibody-
cytokine fusion
protein consisting of the immunostimulatory
cytokine interleukin-2 (IL-2) genetically fused to an antibody specific for human HER2/neu [anti-HER2/neu
IgG3-(IL-2)] was covalently attached to the PMLA backbone to target HER2/neu expressing
tumors and ensure the delivery of
IL-2 to the tumor microenvironment.
Antisense oligonucleotides (AON) were conjugated to the nanodrug to inhibit the expression of vascular
tumor protein laminin-411 in order to block
tumor angiogenesis. It is shown that the nanobioconjugate was capable of specifically binding human HER2/neu and retained the
biological activity of
IL-2. We also showed the uptake of the nanobioconjugate into HER2/neu-positive
breast cancer cells and enhanced
tumor targeting in vivo. The nanobioconjugate exhibited marked anti-
tumor activity manifested by significantly longer animal survival and significantly increased anti-HER2/neu immune response in immunocompetent mice bearing D2F2/E2 murine mammary
tumors that express human HER2/neu. The combination of laminin-411 AON and antibody-
cytokine fusion
protein on a single polymeric platform results in a new nanobioconjugate that can act against
cancer cells through inhibition of
tumor growth and angiogenesis and the orchestration of an immune response against the
tumor. The present
Polycefin(TM) variant may be a promising agent for treating HER2/neu expressing
tumors and demonstrates the versatility of the
Polycefin(TM) nanobioconjugate platform.