title: Efficacy of an Fc-modified anti-CD123 antibody (CSL362) combined with chemotherapy in xenograft models of acute myelogenous leukemia in immunodeficient mice.
abstract: The prognosis of older patients with acute myelogenous leukemia is generally poor. The interleukin-3 receptor α-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.
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Erwin M
authors.initials: EM
authors.lastname: Lee
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Dean
authors.initials: D
authors.lastname: Yee
authors.affiliation: CSL Limited, Parkville, Australia.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Busfield
authors.affiliation: Department of Microbiology, The Alfred Hospital and Monash University, Melbourne, Australia.
authors.forename: Julie F
authors.initials: JF
authors.lastname: McManus
authors.affiliation: Department of Haematology, The Alfred Hospital and Monash University, Melbourne, Australia.
authors.forename: Nik
authors.initials: N
authors.lastname: Cummings
authors.affiliation: CSL Limited, Parkville, Australia.
authors.forename: Gino
authors.initials: G
authors.lastname: Vairo
authors.affiliation: Department of Haematology, The Alfred Hospital and Monash University, Melbourne, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wei
authors.affiliation: The Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
authors.forename: Hayley S
authors.initials: HS
authors.lastname: Ramshaw
authors.affiliation: The Centre for Cancer Biology, SA Pathology, Adelaide, Australia School of Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Powell
authors.affiliation: The Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
authors.forename: Angel F
authors.initials: AF
authors.lastname: Lopez
authors.affiliation: Division of Haematology and Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Lewis
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Martin N
authors.initials: MN
authors.lastname: McCall
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Sydney, Australia rlock@ccia.unsw.edu.au.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003561:Cytarabine / Q000494:pharmacology; D003630:Daunorubicin; D005260:Female; D015870:Gene Expression; D006801:Humans; D016867:Immunocompromised Host; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000276:immunology; D053650:Interleukin-3 Receptor alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016019:Survival Analysis; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C115022:IL3RA protein, human; D007141:Immunoglobulin Fc Fragments; D053650:Interleukin-3 Receptor alpha Subunit; D003561:Cytarabine; D003630:Daunorubicin