Non-Hodgkin's lymphoma (NHL) is a prevalent cancer with an estimated 66,000 cases diagnosed in the United States in 2008, with the incidence doubling since 1980. Although treatments for NHLs greatly improved following the FDA approval of Rituxan, refractive malignancies still occur that are nonresponsive to current therapies in at least a third of all patients, indicating that improved treatment strategies are needed. One of the most reliable biomarkers and therapeutic targets for B cell NHL is CD20, which is a non- internalizing antigen that remains on the cell surface when bound to a complementary antibody. The crosslinking of CD20-bound antibodies with a secondary antibody results in apoptosis of these cells. The overall goal of this project is to generate new, drug-free macromolecular therapeutics for improved treatment of NHL. A new apoptosis induction system is proposed which is based on N-(2- hydroxypropyl)methacrylamide (HPMA) graft copolymer mediated formation of coiled-coil heterodimers at B- cell surface. 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. The system is composed of a pair of complementary coiled-coil peptides forming antiparallel heterodimers;Fab'fragment of the 1F5 anti-CD20 antibody;and HPMA copolymer. One peptide is conjugated to the Fab'fragment, the other is conjugated in multiple grafts to polyHPMA. A pair of oppositely charged pentaheptad peptides (CCE and CCK) that formed antiparallel coiled-coil heterodimers with a high degree of biorecognition was previously designed. It was hypothesized that the unique biorecognition of CCK and CCE peptides could be a basis for the design of a novel class of macromolecular therapeutics. Indeed, the exposure of CD20+ Raji B cells to Fab'-CCE resulted in the decoration of the cell surface with multiple copies of the CCE peptide via antigen-antibody fragment biorecognition. Further exposure of the CCE decorated cells to HPMA copolymer grafted with multiple copies of CCK resulted in the formation of CCE-CCK coiled-coil heterodimers on the cell surface. This second biorecognition event induced crosslinking of CD20 receptors and triggered apoptosis of Raji B cells. The system will be optimized based on the preliminary data. Shorter coiled-coil forming sequences containing L- and/or D-amino acid residues will be designed and evaluated. HPMA graft copolymer mediated coiled-coil formation at cell surface with concomitant receptor crosslinking and apoptosis induction will be assessed in vitro using five cell types and three apoptosis assays. Importantly, the efficacy and biocompatibility of drug-free macromolecular therapeutics will be evaluated in an animal model. Body distribution, impact of the dose and frequency of administration on the efficacy of treatment will be evaluated with the aim to select leading compound(s) and optimal treatment modalities. Finally, this new concept will be developed into a new therapeutic entity, drug-free macromolecular therapeutics.
The proposal presents a new paradigm for apoptosis induction based on coiled-coil recognition at the cell surface. This novel approach will be developed into a new class of drug-free macromolecular therapeutics suitable for the treatment of non-Hodgkin's lymphoma.
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