Poly-␣ 2-8 sialic acid (PSA), attached to the neural cell adhesion molecule, is a permissive determinant for numerous morphogenetic and neural plasticity processes, making it a potential therapeutic target. Here, using a monoclonal antibody specific for PSA, we screened a phage-display library and identified two cyclic nine-amino acid peptides (p1, p2) that are PSA epitope analogues. We evaluated their bioactivity in vitro and in vivo. In culture, micromolar concentrations of the peptides promoted axon growth, defasciculation, and migration of neural progenitors. When injected into developing chicken retina, the peptides modified the trajectory of retinal ganglion cell axons. Moreover, they enhanced migration of grafted neuroblasts in mouse brain. These effects were selective and dependent upon the presence of PSA on transplanted cells. Our results demonstrate the feasibility and therapeutic potential of enhancing PSA biological activity.
Summary. We have taken advantage of the selection power of phage display technology to de®ne speci®c peptide mimotopes that recognize individual M-proteins, isolated from patients with multiple myeloma. Preferred amino acid motifs of phages binding to M-proteins were identi®ed in 6/9 patients investigated. Chemically synthesized peptides, corresponding to the phage-displayed peptide inserts, were used to verify the speci®city of binding in competition assays. The peptides were able to bind to the M-proteins, as well as the myeloma cells, with high sensitivity and speci®city. Employing simple immunological techniques, < 0´01 g/l of M-protein could be quanti®ed, suggesting a novel way for monitoring minimal residual disease in the production of guidelines for adjusting or reintroducing conventional chemotherapy. The peptide mimotopes de®ned by this technology may be useful as tumourspeci®c targeting agents and as a tool for purging cells in autologous bone marrow transplantation.Keywords: multiple myeloma, M-protein, phage display, peptides.Multiple myeloma accounts for > 10% of the haematological malignancies with an incidence peak at around 70 years of age and is characterized by neoplastic proliferation of a single plasma cell clone producing a monoclonal immunoglobulin, known as M-protein, paraprotein or M-component (Kyle, 1994). Therapy has been attempted for more than half a century with limited success, since approximately onethird of patients do not respond to chemotherapy and the remainder will eventually relapse if they do not succumb to other diseases (Singhal et al, 1997). The M-protein can be observed after serum electrophoresis as a localized band predominantly in the g area (Jeppsson et al, 1979), and semiquantitative estimation can be performed with densitometry (Kyle, 1994). These routine methods for monitoring the tumour load are rather crude, and immunochemical quanti®cation is often hampered by the background signal of normal immunoglobulin and the lack of a suitable reference (Kyle, 1994). Staining of bone marrow cells with class or subclass-speci®c antibodies detects both tumour cells and normal cells that produce the same immunoglobulin type. More sophisticated methods have been described for the detection and quanti®cation of circulating malignant cells (Bakkus et al, 1996;Bjo Èrkstrand et al, 1995;Brown et al, 1998;Corradini et al, 1995;Cremer et al, 1997;Dreyfus et al, 1995;Shimazaki et al, 1991;Yamada et al, 1989; van Zaanen et al, 1995).This report presents a simple way to quantify the M-protein. As immunoglobulins, M-proteins have the potential ability to bind antigens. We have taken advantage of the recently developed method of random peptide phage display libraries to identify peptides that are bound by the myeloma immunoglobulin of individual patients. Such peptides provide a novel and simple method for speci®c monitoring of the M-protein level and provide potential handles for targeting of the malignant clones. MATERIALS AND METHODS Patients.We investigated nine patients with mult...
Summary. With the aim of producing unique targets for malignant cells we have identified peptide ligands for the clonal surface immunoglobulin isolated from the B cells of a chronic lymphocytic leukaemia (CLL) patient. The peptides were identified from random-peptide phage-display libraries. The obtained ligands bound specifically to the surface of the target lymphocytes as well as to clonal immunoglobulin in lysate from the same cells. Peptide-based antigen mimotopes may have a future use in targeted therapy of CLL and other B-cell-derived malignancies displaying surface immunoglobulin.
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