Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies
| Autor: | Latha Sridharan, Sue Stephens, Douglas Armellino, Nitin K. Damle, Justin Keith Moran, Hamann Philip Ross, Kiran Khandke, Chandrasekhar Udata, Andrew George Popplewell, Philip Frost, John F. DiJoseph, Maureen Dougher, Boris Gorovits, Arthur Kunz, Erwin R. Boghaert |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Immunoconjugates
Lymphoma B-Cell Time Factors Gemtuzumab ozogamicin Sialic Acid Binding Ig-like Lectin 2 Immunology Mice Nude Antineoplastic Agents Antibodies Monoclonal Humanized Biochemistry Inhibitory Concentration 50 Mice chemistry.chemical_compound Therapeutic index Antigens CD Cell Line Tumor Lectins Calicheamicin medicine Animals Humans Inotuzumab Ozogamicin Inotuzumab ozogamicin Mice Inbred BALB C business.industry Lymphoma Non-Hodgkin CD22 Antibodies Monoclonal Myeloid leukemia Cell Biology Hematology Immunoconjugate Antigens Differentiation B-Lymphocyte Models Chemical chemistry Immunoglobulin G Monoclonal Cancer research Female Immunotherapy business Cell Adhesion Molecules Neoplasm Transplantation Protein Binding medicine.drug |
| Zdroj: | Blood. 103:1807-1814 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Antibody-targeted chemotherapy with gemtuzumab ozogamicin (CMA-676, a CD33-targeted immunoconjugate of N-acetyl-γ-calicheamicin dimethyl hydrazide [CalichDMH], a potent DNA-binding cytotoxic antitumor antibiotic) is a clinically validated therapeutic option for patients with acute myeloid leukemia (AML). Here, we describe the preclinical profile of another immunoconjugate of CalichDMH, CMC-544, targeted to CD22 expressed by B-lymphoid malignancies. CMC-544 comprises a humanized IgG4 anti-CD22 monoclonal antibody (mAb), G5/44, covalently linked to CalichDMH via an acid-labile 4-(4′-acetylphenoxy) butanoic acid (AcBut) linker. Both CMC-544 and unconjugated G5/44 bound human CD22 with subnanomolar affinity. CMC-544, but not unconjugated G5/44, exerted potent cytotoxicity against CD22+ B-cell lymphoma (BCL) cell lines (inhibitory concentration of 50%: 6-600 pM CalichDMH). CMC-544 caused a potent inhibition of growth of small but established BCL xenografts leading to cures (therapeutic index > 10). CMC-544 prevented the establishment of BCL xenografts and also caused regression of large BCLs (> 1.5 g tumor mass). In contrast, unconjugated CalichDMH, unconjugated G5/44, and an isotype-matched control conjugate, CMA-676, were ineffective against these BCL xenografts. Thus, CD22-targeted delivery of CalichDMH is a potent and effective preclinical therapeutic strategy for BCLs. The strong antitumor profile of CMC-544 supports its clinical evaluation as a treatment option for B-lymphoid malignancies. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|