Efficacy of an Fc-modified anti-CD123 antibody (CSL362) combined with chemotherapy in xenograft models of acute myelogenous leukemia in immunodeficient mice

Erwin M Lee, Dean Yee, Samantha J Busfield, Julie F McManus, Nicholas James Cummings, Gino Vairo, Andrew Wei, Hayley S Ramshaw, Jason A Powell, Angel F Lopez, Ian D Lewis, Martin N McCall, Richard B Lock

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The prognosis of older patients with acute myelogenous leukemia is generally poor. The interleukin-3 receptor a- 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.
Original languageEnglish
Pages (from-to)914 - 926
Number of pages13
JournalHaematologica: the hematology journal
Volume100
Issue number7
DOIs
Publication statusPublished - 2015

Cite this

Lee, Erwin M ; Yee, Dean ; Busfield, Samantha J ; McManus, Julie F ; Cummings, Nicholas James ; Vairo, Gino ; Wei, Andrew ; Ramshaw, Hayley S ; Powell, Jason A ; Lopez, Angel F ; Lewis, Ian D ; McCall, Martin N ; Lock, Richard B. / Efficacy of an Fc-modified anti-CD123 antibody (CSL362) combined with chemotherapy in xenograft models of acute myelogenous leukemia in immunodeficient mice. In: Haematologica: the hematology journal. 2015 ; Vol. 100, No. 7. pp. 914 - 926.
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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 a- 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.",
author = "Lee, {Erwin M} and Dean Yee and Busfield, {Samantha J} and McManus, {Julie F} and Cummings, {Nicholas James} and Gino Vairo and Andrew Wei and Ramshaw, {Hayley S} and Powell, {Jason A} and Lopez, {Angel F} and Lewis, {Ian D} and McCall, {Martin N} and Lock, {Richard B}",
year = "2015",
doi = "10.3324/haematol.2014.113092",
language = "English",
volume = "100",
pages = "914 -- 926",
journal = "Haematologica: the hematology journal",
issn = "0390-6078",
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Lee, EM, Yee, D, Busfield, SJ, McManus, JF, Cummings, NJ, Vairo, G, Wei, A, Ramshaw, HS, Powell, JA, Lopez, AF, Lewis, ID, McCall, MN & Lock, RB 2015, 'Efficacy of an Fc-modified anti-CD123 antibody (CSL362) combined with chemotherapy in xenograft models of acute myelogenous leukemia in immunodeficient mice' Haematologica: the hematology journal, vol. 100, no. 7, pp. 914 - 926. https://doi.org/10.3324/haematol.2014.113092

Efficacy of an Fc-modified anti-CD123 antibody (CSL362) combined with chemotherapy in xenograft models of acute myelogenous leukemia in immunodeficient mice. / Lee, Erwin M; Yee, Dean; Busfield, Samantha J; McManus, Julie F; Cummings, Nicholas James; Vairo, Gino; Wei, Andrew; Ramshaw, Hayley S; Powell, Jason A; Lopez, Angel F; Lewis, Ian D; McCall, Martin N; Lock, Richard B.

In: Haematologica: the hematology journal, Vol. 100, No. 7, 2015, p. 914 - 926.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Efficacy of an Fc-modified anti-CD123 antibody (CSL362) combined with chemotherapy in xenograft models of acute myelogenous leukemia in immunodeficient mice

AU - Lee, Erwin M

AU - Yee, Dean

AU - Busfield, Samantha J

AU - McManus, Julie F

AU - Cummings, Nicholas James

AU - Vairo, Gino

AU - Wei, Andrew

AU - Ramshaw, Hayley S

AU - Powell, Jason A

AU - Lopez, Angel F

AU - Lewis, Ian D

AU - McCall, Martin N

AU - Lock, Richard B

PY - 2015

Y1 - 2015

N2 - The prognosis of older patients with acute myelogenous leukemia is generally poor. The interleukin-3 receptor a- 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.

AB - The prognosis of older patients with acute myelogenous leukemia is generally poor. The interleukin-3 receptor a- 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.

UR - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486226/pdf/1000914.pdf

U2 - 10.3324/haematol.2014.113092

DO - 10.3324/haematol.2014.113092

M3 - Article

VL - 100

SP - 914

EP - 926

JO - Haematologica: the hematology journal

JF - Haematologica: the hematology journal

SN - 0390-6078

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