CD47-mediated PCD: a promising approach against refractory CLL
We have recently demonstrated that the targeting of CD47 with thrombospondin-1 (TSP-1) agonist peptides (e.g., PKHB1) induces PCD in CLL B-cells, including those from high-risk individuals with a dysfunctional TP53. We have also demonstrated that PKHB1 induces PCD specifically in the B malignant cells and that the treatment with the peptide eliminates the CLL cells in vivo in a xenografted NSG mice model (PLoS Medicine, 2015, 12: e1001796). In the forthcoming period, we will validate the potential use of CD47 agonists in CLL treatment by focusing on PKHB1-derivatives. Note that peptides are usually easier to produce and their effective cost is much lower when compared to therapeutic antibodies. Moreover, peptides have several advantages over small molecule drugs, e.g. they have higher affinity and specificity to interact with their target, while their toxicity remains low. To reach our objective, we will generate new CD47 peptide agonists with improved affinity to CD47 (collaboration with Pr. Karoyan UPMC). We plan to introduce non-natural amino-acids in the PKHB1 sequence and to generate a derivative homotrimer, which will mimic the natural interaction between TSP-1 and CD47. Then, we will validate the efficacy of the peptides on purified B-lymphocytes from a large panel of CLL cells, including those resistant to the current chemotherapeutics. We will monitor the induction of PCD in CLL cells and we will verifiy that the peptides are unable to induce cytotoxicity in other immune subsets. Finally, we test the hit peptides in the TCL-1 CLL mice model (Johnson et al. Blood 2006, 108:1334).