Efficacy of an Fc-modified anti-CD123 antibody (CSL362) combined with chemotherapy in xenograft models of acute myelogenous leukemia in immunodeficient mice
| Autor: | Dean Yee, Hayley S. Ramshaw, Erwin M. Lee, Richard B. Lock, Jason A. Powell, Andrew H. Wei, Nicholas James Cummings, Ian D. Lewis, Julie McManus, Martin N. McCall, Angel F. Lopez, Samantha J. Busfield, Gino Vairo |
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| Přispěvatelé: | Lee, Erwin M, Yee, Dean, Busfield, Samantha J, McManus, Julie F, Cummings, Nik, Vairo, Gino, Wei, Andrew, Ramshaw, Hayley S, Powell, Jason A, Lopez, Angel F, Lewis, Ian D, McCall, Martin N, Lock, Richard B |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Adoptive cell transfer
Myeloid Daunorubicin Transplantation Heterologous Interleukin-3 Receptor alpha Subunit Gene Expression Antineoplastic Agents Pharmacology Biology Antibodies Monoclonal Humanized Xenograft Models Myelogenous Immunocompromised Host Mice medicine Animals Humans Chemotherapy Immunodeficient mice Acute leukemia Cytarabine Antibodies Monoclonal Acute Myelogenous Leukemia Hematology Articles medicine.disease Adoptive Transfer Survival Analysis Xenograft Model Antitumor Assays Immunoglobulin Fc Fragments Killer Cells Natural Leukemia Leukemia Myeloid Acute medicine.anatomical_structure Fc-Modified Anti-CD123 Antibody Female Bone marrow CSL362 medicine.drug |
| Popis: | The prognosis of older patients with acute myelogenous leukemia is generally poor. The interleukin-3 receptor alpha-chain (CD123) is highly expressed on the surface of acute leukemia cells compared with normal hematopoietic stem cells. CSL362 is a fully humanized, CD123-neutralizing monoclonal antibody containing a modified Fc structure, which enhances human natural killer cell antibody-dependent cell-mediated cytotoxicity. Six continuous acute myelogenous leukemia xenografts established from patient explants and characterized by cell and molecular criteria, produced progressively lethal disease 42-202 days after transplantation. CSL362 alone reduced engraftment of one of four and three of four acute myelogenous leukemia xenografts in the bone marrow and peripheral organs, respectively. A cytarabine and daunorubicin regimen was optimized using this model to identify potentially synergistic interactions with CSL362. Cytarabine/daunorubicin improved the survival of mice engrafted with four of four acute myelogenous leukemia xenografts by 31-41 days. Moreover, CSL362 extended the survival of cytarabine/daunorubicin-treated mice for two of two acute myelogenous leukemia xenografts, while augmentation of natural killer cell-deficient NSG mice with adoptively transferred human natural killer cells improved survival against a single xenograft. Interestingly, this enhanced CSL362 efficacy was lost in the absence of chemotherapy. This study shows that acute myelogenous leukemia xenografts provide a platform for the evaluation of new therapeutics, simulating complex in vivo interactions, and that the in vivo efficacy of CSL362 supports continued clinical development of this drug. Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
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