Biomaterial Database

A single chain immunotoxin, targeting the melanoma-associated chondroitin sulfate proteoglycan, is a potent inducer of apoptosis in cultured human melanoma cells. 2008

Michael Schwenkert, and Katrin Birkholz, and Michael Schwemmlein, and Christian Kellner, and Markus Kügler, and Matthias Peipp, and Dirk M Nettelbeck, and Beatrice Schuler-Thurner, and Niels Schaft, and Jan Dörrie, and Soldano Ferrone, and Eckhart Kämpgen, and Georg H Fey

University of Erlangen-Nuremberg, Erlangen, Germany.

A recombinant immunotoxin was constructed by fusing a single chain fragment variable antibody fragment, specific for the melanoma-associated chondroitin sulfate proteoglycan (MCSP), to a truncated variant of Pseudomonas exotoxin A (ETA'), carrying a C-terminal KDEL-peptide for improved retrograde intracellular transport. The resulting immunotoxin MCSP-ETA' was periplasmatically expressed in Escherichia coli and purified under native conditions by affinity chromatography resulting in a yield of approximately 30 mug/l bacterial culture. This immunotoxin induced antigen-specific apoptosis in the cultured human melanoma-derived cell lines A2058 and A375M, and treatment with a single dose of the agent eliminated up to 80% of these cells within 72 h. The dose needed for half-maximum killing (EC50) was approximately 1 nmol/l for both cell lines. MCSP-ETA' also displayed cytotoxic activity against cultured primary melanoma cells from patients with advanced disease (pathologic stages IIIC and IV), with net cell death reaching up to 70% within 96 h after treatment with a single dose of 14 nmol/l. MCSP-ETA' induced cell death synergistically with cyclosporin A, both in established human melanoma cell lines and cultured primary melanoma cells. The distinctive antigen-restricted induction of apoptosis and the synergy with cyclosporin A justify further evaluation of this novel agent with regard to its potential application for the treatment of malignant melanoma.

UI	MeSH Term	Description	Entries
D007166	Immunosuppressive Agents	Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-CELLS or by inhibiting the activation of HELPER CELLS. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of INTERLEUKINS and other CYTOKINES are emerging.	Immunosuppressant,Immunosuppressive Agent,Immunosuppressants,Agent, Immunosuppressive,Agents, Immunosuppressive
D007167	Immunotherapy	Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection.	Immunotherapies
D008545	Melanoma	A malignant neoplasm derived from cells that are capable of forming melanin, which may occur in the skin of any part of the body, in the eye, or, rarely, in the mucous membranes of the genitalia, anus, oral cavity, or other sites. It occurs mostly in adults and may originate de novo or from a pigmented nevus or malignant lentigo. Melanomas frequently metastasize widely, and the regional lymph nodes, liver, lungs, and brain are likely to be involved. The incidence of malignant skin melanomas is rising rapidly in all parts of the world. (Stedman, 25th ed; from Rook et al., Textbook of Dermatology, 4th ed, p2445)	Malignant Melanoma,Malignant Melanomas,Melanoma, Malignant,Melanomas,Melanomas, Malignant
D011508	Chondroitin Sulfate Proteoglycans	Proteoglycans consisting of proteins linked to one or more CHONDROITIN SULFATE-containing oligosaccharide chains.	Proteochondroitin Sulfates,Chondroitin Sulfate Proteoglycan,Proteochondroitin Sulfate,Proteoglycan, Chondroitin Sulfate,Proteoglycans, Chondroitin Sulfate,Sulfate Proteoglycan, Chondroitin,Sulfate Proteoglycans, Chondroitin
D011993	Recombinant Fusion Proteins	Recombinant proteins produced by the GENETIC TRANSLATION of fused genes formed by the combination of NUCLEIC ACID REGULATORY SEQUENCES of one or more genes with the protein coding sequences of one or more genes.	Fusion Proteins, Recombinant,Recombinant Chimeric Protein,Recombinant Fusion Protein,Recombinant Hybrid Protein,Chimeric Proteins, Recombinant,Hybrid Proteins, Recombinant,Recombinant Chimeric Proteins,Recombinant Hybrid Proteins,Chimeric Protein, Recombinant,Fusion Protein, Recombinant,Hybrid Protein, Recombinant,Protein, Recombinant Chimeric,Protein, Recombinant Fusion,Protein, Recombinant Hybrid,Proteins, Recombinant Chimeric,Proteins, Recombinant Fusion,Proteins, Recombinant Hybrid
D003602	Cytotoxicity, Immunologic	The phenomenon of target cell destruction by immunologically active effector cells. It may be brought about directly by sensitized T-lymphocytes or by lymphoid or myeloid "killer" cells, or it may be mediated by cytotoxic antibody, cytotoxic factor released by lymphoid cells, or complement.	Tumoricidal Activity, Immunologic,Immunologic Cytotoxicity,Immunologic Tumoricidal Activities,Immunologic Tumoricidal Activity,Tumoricidal Activities, Immunologic
D005098	Exotoxins	Toxins produced, especially by bacterial or fungal cells, and released into the culture medium or environment.	Exotoxin
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000097668	Pseudomonas aeruginosa Exotoxin A	An NAD-dependent ADP-ribosyltransferase that catalyzes the transfer of the ADP ribosyl moiety of oxidized NAD onto elongation factor 2 (EF-2) thus arresting protein synthesis. Commonly used as the toxin in immunotoxins.	Exotoxin A, Pseudomonas,Exotoxin A, Pseudomonas aeruginosa,Recombinant Truncated Pseudomonas Exotoxin A, Form PE38QQR,Recombinant Truncated Pseudomonas Exotoxin A, Form PE40,ToxA protein, Pseudomonas aeruginosa,ETA, Pseudomonas,PE38QQR,PE40 toxin
D000922	Immunotoxins	Semisynthetic conjugates of various toxic molecules, including RADIOACTIVE ISOTOPES and bacterial or plant toxins, with specific immune substances such as IMMUNOGLOBULINS; MONOCLONAL ANTIBODIES; and ANTIGENS. The antitumor or antiviral immune substance carries the toxin to the tumor or infected cell where the toxin exerts its poisonous effect.	Affinotoxin,Antibody-Toxin Conjugate,Antibody-Toxin Conjugates,Antibody-Toxin Hybrid,Antibody-Toxin Hybrids,Chimeric Toxins,Cytotoxin-Antibody Conjugate,Cytotoxin-Antibody Conjugates,Monoclonal Antibody-Toxin Conjugate,Targeted Toxin,Targeted Toxins,Toxin Carriers,Toxin Conjugates,Toxin-Antibody Conjugate,Toxin-Antibody Conjugates,Toxin-Antibody Hybrid,Toxin-Antibody Hybrids,Toxins, Chimeric,Toxins, Targeted,Affinotoxins,Chimeric Toxin,Immunotoxin,Monoclonal Antibody-Toxin Conjugates,Toxin Carrier,Toxin Conjugate,Antibody Toxin Conjugate,Antibody Toxin Conjugates,Antibody Toxin Hybrid,Antibody Toxin Hybrids,Antibody-Toxin Conjugate, Monoclonal,Antibody-Toxin Conjugates, Monoclonal,Carrier, Toxin,Carriers, Toxin,Conjugate, Antibody-Toxin,Conjugate, Cytotoxin-Antibody,Conjugate, Monoclonal Antibody-Toxin,Conjugate, Toxin,Conjugate, Toxin-Antibody,Conjugates, Antibody-Toxin,Conjugates, Cytotoxin-Antibody,Conjugates, Monoclonal Antibody-Toxin,Conjugates, Toxin,Conjugates, Toxin-Antibody,Cytotoxin Antibody Conjugate,Cytotoxin Antibody Conjugates,Hybrid, Antibody-Toxin,Hybrid, Toxin-Antibody,Hybrids, Antibody-Toxin,Hybrids, Toxin-Antibody,Monoclonal Antibody Toxin Conjugate,Monoclonal Antibody Toxin Conjugates,Toxin Antibody Conjugate,Toxin Antibody Conjugates,Toxin Antibody Hybrid,Toxin Antibody Hybrids,Toxin, Chimeric,Toxin, Targeted