title: Coiled-coil based drug-free macromolecular therapeutics: in vivo efficacy.
abstract: We evaluated a new concept in cancer therapy, coiled-coil mediated induction of apoptosis in Raji B cells, for treatment of human B-cell lymphoma in a preclinical animal model. The system is composed of a pair of complementary coiled-coil peptides, CCE and CCK, forming antiparallel heterodimers; Fab' fragment of the 1F5 anti-CD20 antibody; and N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. One peptide is conjugated to the Fab' fragment (Fab'-CCE), the other is conjugated in multiple grafts to polyHPMA (CCK-P; P is the HPMA copolymer backbone). Intravenous administration of Fab'-CCE conjugate, followed by the administration of CCK-P produced long-term survivors in SCID (C.B.-17) mice bearing human B-lymphoma xenografts. The rationale of the design is the absence of low molecular weight drugs and the fact that crosslinking of CD20 at B-cell surface results in apoptosis. This approach creates a new paradigm for manipulating molecular recognition principles in the design of improved cancer treatment.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Kuangshi
authors.initials: K
authors.lastname: Wu
authors.forename: Jiyuan
authors.initials: J
authors.lastname: Yang
authors.forename: Jihua
authors.initials: J
authors.lastname: Liu
authors.forename: Jindřich
authors.initials: J
authors.lastname: Kopeček
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D019281:Dimerization; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics*; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D046912:Multiprotein Complexes; D010446:Peptide Fragments