Leukemia targeting ligands isolated from phage display peptide libraries

Jäger, Stefan; Jahnke, Annika; Wilmes, Thomas; Adebahr, S.; Vögtle, F.-Nora; deLima-Hahn, Elisethe; Pfeifer, Dietmar; Berg, Tobias; Lübbert, Michael; Trepel, Martin

doi:10.1038/sj.leu.2404548

Cited by 35 publications

(20 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[1][2][3][4][5] The selected peptide ligands are readily internalized by cells and may therefore be potentially useful in ligand-directed drug delivery. Recently, we described an arginine-rich motif that is internalized into leukemia and lymphoma cells through the macropinocytotic pathway; however, the precise cell surface receptor has yet to be identified.…”

Section: Introductionmentioning

confidence: 99%

Targeting neuropilin-1 in human leukemia and lymphoma

Karjalainen

Jaalouk

Bueso‐Ramos

et al. 2011

Blood

View full text Add to dashboard Cite

Targeted drug delivery offers an opportunity for the development of safer and more effective therapies for the treatment of cancer. In this study, we sought to identify short, cell-internalizing peptide ligands that could serve as directive agents for specific drug delivery in hematologic malignancies. By screening of human leukemia cells with a combinatorial phage display peptide library, we isolated a peptide motif, sequence Phe-Phe/TyrAny-Leu-Arg-Ser (F F / Y XLRS), which bound to different leukemia cell lines and to patient-derived bone marrow samples. The motif was internalized through a receptor-mediated pathway, and we next identified the corresponding receptor as the transmembrane glycoprotein neuropilin-1 (NRP-1). Moreover, we observed a potent anti-leukemia cell effect when the targeting motif was synthesized in tandem to the pro-apoptotic sequence D (KLAKLAK) 2 . Finally, our results confirmed increased expression of NRP-1 in representative human leukemia and lymphoma cell lines and in a panel of bone marrow specimens obtained from patients with acute lymphoblastic leukemia or acute myelogenous leukemia compared with normal bone marrow. These results indicate that NRP-1 could potentially be used as a target for liganddirected therapy in human leukemias and lymphomas and that the prototype CGFYWLRSC-GG-D (KLAKLAK) 2 is a promising drug candidate in this setting. (Blood. 2011;117(3):920-927) IntroductionThe development of targeted drug-delivery strategies for safer and more effective therapy in human hematologic malignancies has been a long-standing goal for clinical and basic investigators. We reasoned that profiling of human leukemia-and lymphoma-derived cell lines with combinatorial libraries might yield ligand peptide sequences that bind to specific internalizing receptors on cell surfaces and may potentially lead to the discovery of new or unrecognized therapeutic targets. Such targeting motifs could also serve as vehicles for the preferential delivery of cytotoxic agents to leukemia and lymphoma cells.Several cell surface-binding peptides recognizing receptors in the membranes of lymphoma and leukemia cell lines have been reported. [1][2][3][4][5] The selected peptide ligands are readily internalized by cells and may therefore be potentially useful in ligand-directed drug delivery. Recently, we described an arginine-rich motif that is internalized into leukemia and lymphoma cells through the macropinocytotic pathway; however, the precise cell surface receptor has yet to be identified. 6 In effect, there is currently a relative lack of well-defined ligand-receptor systems for targeting human leukemia or lymphoma cells. The identification and validation of ligandreceptor pairs for these hematologic cancer cells relative to normal leukocytes would potentially represent a differential strategy and perhaps even improve disease outcomes.In this study, we used a combinatorial phage display-based subtractive selection 7-9 to identify ligand motifs that bind to specific cell surface receptors on human leuk...

show abstract

Section: Introductionmentioning

confidence: 99%

Targeting neuropilin-1 in human leukemia and lymphoma

Karjalainen

Jaalouk

Bueso‐Ramos

et al. 2011

Blood

View full text Add to dashboard Cite

show abstract

“…Cell surface-binding peptide motifs have been reported in lymphoma and leukemia lines (8 -11). Unfortunately, so far their corresponding receptors are either unknown (9,10) or relatively nonspecific adhesion molecules such as certain integrins (8,11) to which ligand binding does not enable clear enough differentiation between normal leukocytes and tumor cells; as a result, potentially useful ligand-receptor systems have not as yet emerged in leukemias and lymphomas. Thus, rather than attempt to identify other ligand (peptide)-receptor (protein) systems in leukemia-or lymphoma-derived cells, we reasoned that targeting a physiological cell translocation mechanism may serve as an alternative approach to this challenge.…”

mentioning

confidence: 99%

Combinatorial Targeting of the Macropinocytotic Pathway in Leukemia and Lymphoma Cells

Nishimura

Takahashi

Kamikatahira

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

Ligand-directed delivery of agents to leukemia and lymphoma cells has the potential to yield new mechanistic disease insights and targeted therapies. Here we set out to target the macropinocytotic pathway with a combinatorial approach. From the screening of acute T-lymphoblastic leukemia Molt-4 cells with a random phage-display peptide library, we isolated a phage displaying the sequence CAYHRLRRC. This peptide contains a lymph node-homing motif (Cys-Ala-Tyr) and a cell-penetrating motif (Arg-Leu-Arg-Arg). Binding of this ligand-directed phage to a large panel of leukemia/lymphoma cells and to patient-derived samples was much higher than to non-leukemia control cells. CAYHRLRRC phage internalization into Molt-4 cells is both energy-and temperature-dependent. Flow cytometry with fluorescein-labeled peptide and endocytosis blocking with specific inhibitors revealed that CAYHRLRRC is indeed taken up through macropinocytosis in Molt-4 and K562 human leukemia cells. Unexpectedly, the cell surface receptor for the CAYHRL-RRC peptide is not a heparan sulfate proteoglycan as it would be predicted for other cell-penetrating peptides. Confirming this interpretation, a CAYHRLRRC-directed peptidomimetic-induced cell death in all the leukemia and lymphoma cells was evaluated, whereas a control transactivator of transcription protein (tat)-directed proapoptotic peptidomimetic was non-selective. In summary, the targeting peptide CAYHRLRRC is selectively internalized through macropinocytosis in leukemia and lymphoma cells and has potential as a drug lead for ligand-directed anti-leukemia therapies.Leukemias and lymphomas are hematological malignant diseases characterized by impaired differentiation, increased clonal cell proliferation, and hematopoiesis suppression; the standard treatment for these tumors today is still predominantly based on nonspecific cytotoxics that disrupt nucleic acid and protein synthesis, often with severe side effects and relatively poor outcomes (1-3). However, selective anti-leukemia drugs have recently been developed (4), thus conceptually validating the scientific hope for a revolutionary targeted pharmacology against this group of diseases.Over the past decade, we have selected phage-display random peptide libraries in vitro and in vivo to isolate and exploit tumor-specific and angiogenesis-related ligand-receptor systems toward targeted drug design and translation (5-7). Because cell trafficking and homing from the blood and/or lymphatic vessels to lymphoid and myeloid tissues to virtually all organs are essential leukocyte functions, we reasoned that targeting membranes would be a suitable approach to discover leukemia-specific ligands. Cell surface-binding peptide motifs have been reported in lymphoma and leukemia lines (8 -11). Unfortunately, so far their corresponding receptors are either unknown (9, 10) or relatively nonspecific adhesion molecules such as certain integrins (8, 11) to which ligand binding does not enable clear enough differentiation between normal leukocytes and tumor cells; ...

show abstract

“…There are many advantages to the use of small peptides including low cost, absence of significant immunogenicity, and ease of coupling to cytotoxic agents. The most important advantage of peptides is their versatility (Aggarwal et al, 2006;Jäger et al, 2007;Lee et al, 2007;Rasmussen et al, 2002). For example, tumor binding peptide sequences can be incorporated into the coat proteins of viruses (Grifman et al, 2001;White et al, 2004), and novel targeting tools, such as liposomes and nanoparticles, can be used together with the peptides (Hajitou et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, RNA aptamers have been developed for use as targeting and imaging tools (Hicke et al, 2001;. However, to expand the potential utility of TNC as a tumor microenvironment target, a versatile alternative molecule such as a small peptide should also be developed (Aggarwal et al, 2006;Jäger et al, 2007;Lee et al, 2007;Rasmussen et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Selection and Characterization of Tenascin C Targeting Peptide

Kim

Choi

et al. 2012

Molecules and Cells

View full text Add to dashboard Cite

Since tenascin C is a factor expressed highly in the tumorassociated matrix, it would be a desirable first step for targeting the tumor-specific microenvironment. In fact, a high level of tenascin C expression has been reported in most solid tumors, including lung cancer, colon cancer and glioblastoma. Therefore, the targeted binding of tenascin C in tumor stroma would inhibit tumor metastasis by modulating cancer cell growth and migration. We isolated a peptide that bound to tenascin C by phage display peptide library selection, and the selected peptide specifically recognized tenascin C protein in xenograft mouse tissue. We also observed exclusive staining of tenascin C by the selected peptide in tumor patient tissues. Moreover, the peptide reduced tenascin C-induced cell rounding and migration. We propose that the tenascin C targeting peptide may be useful as a specific anti-cancer diagnostic and therapeutic tool for most human solid tumors.

show abstract

Leukemia targeting ligands isolated from phage display peptide libraries

Cited by 35 publications

References 57 publications

Targeting neuropilin-1 in human leukemia and lymphoma

Targeting neuropilin-1 in human leukemia and lymphoma

Combinatorial Targeting of the Macropinocytotic Pathway in Leukemia and Lymphoma Cells

Selection and Characterization of Tenascin C Targeting Peptide

Contact Info

Product

Resources

About