A Humanized Anti-CD22-Onconase Antibody-Drug Conjugate Mediates Highly Potent Destruction of Targeted Tumor Cells
| Autor: | Stefan Kiesgen, Michaela A. E. Arndt, Dirk Jäger, Tobias Weber, Walter Mier, Ludger Grosse-Hovest, Athanasios Mavratzas, Benedikt Bötticher, Stephanie Haase, Jürgen Krauss, Evelyn Exner |
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| Rok vydání: | 2015 |
| Předmět: |
lcsh:Immunologic diseases. Allergy
Antibody-drug conjugate Immunoconjugates Article Subject medicine.drug_class Sialic Acid Binding Ig-like Lectin 2 Immunology Antineoplastic Agents Antibodies Monoclonal Humanized Monoclonal antibody Immunoglobulin G Ribonucleases Antigen Cell Line Tumor medicine Humans Immunology and Allergy Cytotoxicity biology Chemistry CD22 General Medicine Cytotoxicity Tests Immunologic Molecular biology Immunoconjugate Ranpirnase Cancer research biology.protein Drug Screening Assays Antitumor lcsh:RC581-607 Research Article |
| Zdroj: | Journal of Immunology Research, Vol 2015 (2015) Journal of Immunology Research |
| ISSN: | 2314-7156 2314-8861 |
| DOI: | 10.1155/2015/561814 |
| Popis: | 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 significantin vitrocytotoxicity towards lymphoma and leukemia cell lines. Antibody-drug conjugates with an Onconase to antibody ratio of 3 : 1 exhibited an IC50of 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. |
| Databáze: | OpenAIRE |
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