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   A Humanized Anti-CD22-Onconase Antibody-Drug Conjugate Mediates Highly Potent Destruction of Targeted Tumor Cells  
   
نویسنده weber t. ,mavratzas a. ,kiesgen s. ,haase s. ,botticher b. ,exner e. ,mier w. ,grosse-hovest l. ,jager d. ,arndt m.a.e. ,krauss j.
منبع journal of immunology research - 2015 - دوره : 2015 - شماره : 0
چکیده    Antibody-drug conjugates (adcs) have evolved as a new class of potent cancer therapeutics. we here report on the development of adcs with specificity for the b-cell lineage specific (surface) antigen cd22 being expressed in the majority of hematological malignancies. as targeting moiety a previously generated humanized anti-cd22 single-chain variable fragment (scfv) derivative from the monoclonal antibody rfb4 was reengineered into a humanized igg1 antibody format (hurfb4). onconase (ranpirnase),a clinically active pancreatic-type ribonuclease,was employed as cytotoxic payload moiety. chemical conjugation via thiol-cleavable disulfide linkage retained full enzymatic activity and full binding affinity of the adc. development of sophisticated purification procedures using size exclusion and ion exchange chromatography allowed the separation of immunoconjugate species with stoichiometrically defined number of onconase cargos. a minimum of two onconase molecules per igg was required for achieving significant in vitro cytotoxicity towards lymphoma and leukemia cell lines. antibody-drug conjugates with an onconase to antibody ratio of 3: 1 exhibited an ic50 of 0.08 nm,corresponding to more than 18,400-fold increased cytotoxicity of the adc when compared with unconjugated onconase. these results justify further development of this adc as a promising first-in-class compound for the treatment of cd22-positive malignancies. © 2015 tobias weber et al.
آدرس department of medical oncology,national center for tumor diseases,heidelberg university hospital, Germany, department of medical oncology,national center for tumor diseases,heidelberg university hospital, Germany, department of medical oncology,national center for tumor diseases,heidelberg university hospital, Germany, department of medical oncology,national center for tumor diseases,heidelberg university hospital, Germany, department of medical oncology,national center for tumor diseases,heidelberg university hospital, Germany, department of medical oncology,national center for tumor diseases,heidelberg university hospital, Germany, department of nuclear medicine,heidelberg university hospital, Germany, department of immunology,university of tubingen, Germany, department of medical oncology,national center for tumor diseases,heidelberg university hospital, Germany, department of medical oncology,national center for tumor diseases,heidelberg university hospital,heidelberg,germany,immunotherapy program,national center for tumor diseases,german cancer research center, Germany, department of medical oncology,national center for tumor diseases,heidelberg university hospital, Germany
 
     
   
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