Abstract A85: Peptides specific for chronic lymphocytic leukemic cells: Characterization and use in targeted drug delivery.

Abstract

Abstract The ability to selectively target drugs to Chronic Lymphocytic Leukemia (CLL) cells may significantly improve the efficacy of current chemotherapy protocols for this disease. Our studies in model leukemic systems have already demonstrated that a strategy involving Peptide-Drug Conjugates (PDCs) may achieve this goal. In a previous preliminary study, we used a phage display peptide library to isolate a series of peptides that bind CLL cells. The current research has expanded on this work and began by absorbing a 7-mer linear and 7-mer cyclic phage display peptide libraries on a series of normal human or murine primary cells. Rigorous pre-absorption reduces the original vast phage library population (1011 clones) and enhances the ability to select peptides specific for the target CLL cells. The cells used included endothelial, heart, kidney, lung, liver, skin, fibroblasts and several subpopulations of blood cells. These absorptions resulted in a 7-log reduction in the size of the phage libraries. The stock libraries were also injected into mice. Recovery of blood circulating phage 24hrs later showed that in vivo absorption reduced the pool size of viable phage by approximately 8-logs. These "absorbed" libraries now form the basis for isolating CLL cell-bound and cell-internalizing phage. Target cells include murine cell lines derived from spontaneously-developed aggressive CLL (BCL-1 and A20) and human patient CLL cells. Analysis of peptide sequences of A-20 binding or internalizing phage clones revealed overlap in amino acid usage but not one consistent consensus sequence, suggesting that these peptides target different CLL-specific membrane components, some of which can induce phage internalization and should be applicable for PDCs. Using a similar approach, we are isolating peptides for BCL-1 cells as well as peptides to cells from an initial cohort of CLL patients. The bioinformatic and biochemical results for all these peptides will be presented. Peptides selected on the basis of uptake kinetics will be conjugated to cytotoxic drugs using our dendrimer technology. This technology has already allowed us to demonstrate improved efficacy of known CLL drugs. Progress on this stage of the project will also be presented. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A85. Citation Format: Michael A. Firer, Bat-Chen Lubin, Sharon Cohen, Galia Luboshits. Peptides specific for chronic lymphocytic leukemic cells: Characterization and use in targeted drug delivery. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A85.