title: Polymalic acid nanobioconjugate for simultaneous immunostimulation and inhibition of tumor growth in HER2/neu-positive breast cancer.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Ding
authors.forename: Gustavo
authors.initials: G
authors.lastname: Helguera
authors.forename: José A
authors.initials: JA
authors.lastname: Rodríguez
authors.forename: Janet
authors.initials: J
authors.lastname: Markman
authors.forename: Rosendo
authors.initials: R
authors.lastname: Luria-Pérez
authors.forename: Pallavi
authors.initials: P
authors.lastname: Gangalum
authors.forename: Jose
authors.initials: J
authors.lastname: Portilla-Arias
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.forename: Tracy R
authors.initials: TR
authors.lastname: Daniels-Wells
authors.forename: Keith
authors.initials: K
authors.lastname: Black
authors.forename: Eggehard
authors.initials: E
authors.lastname: Holler
authors.forename: Manuel L
authors.initials: ML
authors.lastname: Penichet
authors.forename: Julia Y
authors.initials: JY
authors.lastname: Ljubimova
mesh_terms: D000818:Animals; D001940:Breast / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007114:Immunization; D018796:Immunoconjugates / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000276:immunology / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008293:Malates / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D011108:Polymers / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D018796:Immunoconjugates; D007074:Immunoglobulin G; D007376:Interleukin-2; D008293:Malates; D011108:Polymers; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; C121060:poly(malic acid)
keywords: Antibody-IL-2 fusion protein; Breast cancer; HER2/neu; Laminin-411; Nanobioconjugate; Polymalic acid