Abstract
Short peptide sequences from complementarity-determining regions (CDRs) of different immunoglobulins may exert anti-infective, immunomodulatory and antitumor activities regardless of the specificity of the original monoclonal antibody (mAb). In this sense, they resemble early molecules of innate immunity. C36L1 was identified as a bioactive light-chain CDR1 peptide by screening 19 conserved CDR sequences targeting murine B16F10-Nex2 melanoma. The 17-amino acid peptide is readily taken up by melanoma cells and acts on microtubules causing depolymerization, stress of the endoplasmic reticulum and intrinsic apoptosis. At low concentrations, C36L1 inhibited migration, invasion and proliferation of B16F10-Nex2 cells with cell cycle arrest at G2/M phase, by regulating the PI3K/Akt signaling axis involving Rho-GTPase and PTEN mediation. Peritumor injection of the peptide delayed growth of subcutaneously grafted melanoma cells. Intraperitoneal administration of C36L1 induced a significant immune-response dependent anti-tumor protection in a syngeneic metastatic melanoma model. Dendritic cells stimulated ex-vivo by the peptide and transferred to animals challenged with tumor cells were equally effective. The C36 VL CDR1 peptide is a promising microtubule-interacting drug that induces tumor cell death by apoptosis and inhibits metastases of highly aggressive melanoma cells.
Highlights
In mouse models or inhibit growth of tumors, inducing cytotoxicity by different mechanisms, including programmed cell death[10]
Synthetic peptide C36L1 based on the VL CDR1 of Fab C3619, significantly reduced lung colony formation of B16F10-Nex[2] melanoma cells in vivo and was cytotoxic to several human cancer cells in vitro, as well as murine melanoma[15]
We showed that the peptide conserved amino acid sequence is essential for the observed cytotoxic effects since the scrambled control peptide SC36 was inactive, as compared to an irrelevant complementarity determining regions of immunoglobulins (CDRs) peptide CE48-H2 (Fig. 1a)
Summary
In mouse models or inhibit growth of tumors, inducing cytotoxicity by different mechanisms, including programmed cell death (apoptosis)[10]. We have recently characterized an antitumor peptide (C7H2) that binds to β -actin and interferes in actin dynamics leading to cell apoptosis[12] This peptide is a VH CDR 2 from mAb C7, raised against Candida albicans antigens[1,3]. It exerted anti-tumor activities in vitro and in vivo against murine B16F10-Nex[2] melanoma and was cytotoxic to human cancer cell lineages. We investigated the mechanism of action of the antitumor VL CDR 1 of an anti-vaccinia C36 IgG, recognized as a novel microtubule de-stabilizing CDR peptide This CDR has a peptide sequence highly conserved in different immunoglobulin light kappa chains. Clone 36 (C36) was obtained from a combinatorial phage-display library of human Fab antibody fragments generated from IgG heavy- and light-chain genes cloned from the lymphocytes of a vaccinia virus immune donor[19]
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