IMGN779, a Novel CD33-targeting antibody–drug conjugate with DNA-alkylating activity, exhibits potent antitumor activity in models of AML

Yelena Kovtun, Paul Noordhuis, Kathleen R. Whiteman, Krystal Watkins, Gregory E. Jones, Lauren Harvey, Katharine C. Lai, Scott Portwood, Sharlene Adams, Callum M. Sloss, Gerrit Jan Schuurhuis, Gert Ossenkoppele, Eunice S. Wang, Jan Pinkas

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The myeloid differentiation antigen CD33 has long been exploited as a target for antibody-based therapeutic approaches in acute myeloid leukemia (AML). Validation of this strategy was provided with the approval of the CD33-targeting antibody–drug conjugate (ADC) gemtuzumab ozogamicin in 2000; the clinical utility of this agent, however, has been hampered by safety concerns. Thus, the full potential of CD33-directed therapy in AML remains to be realized, and considerable interest exists in the design and development of more effective ADCs that confer high therapeutic indices and favorable tolerability profiles. Here, we describe the preclinical characterization of a novel CD33-targeting ADC, IMGN779, which utilizes a unique DNA-alkylating payload to achieve potent antitumor effects with good tolerability. The payload, DGN462, is prototypical of a novel class of purpose-created indolinobenzodiazeprine pseudodimers, termed IGNs. With low picomolar potency, IMGN779 reduced viability in a panel of AML cell lines in vitro. Mechanistically, the cytotoxic activity of IMGN779 involved DNA damage, cell-cycle arrest, and apoptosis consistent with the mode of action of DGN462. Moreover, IMGN779 was highly active against patient-derived AML cells, including those with adverse molecular abnormalities, and sensitivity correlated to CD33 expression levels. In vivo, IMGN779 displayed robust antitumor efficacy in multiple AML xenograft and disseminated disease models, as evidenced by durable tumor regressions and prolonged survival. Taken together, these findings identify IMGN779 as a promising new candidate for evaluation as a novel therapeutic in AML.
Original languageEnglish
Pages (from-to)1271-1279
JournalMolecular Cancer Therapeutics
Volume17
Issue number6
DOIs
Publication statusPublished - 2018

Cite this

Kovtun, Yelena ; Noordhuis, Paul ; Whiteman, Kathleen R. ; Watkins, Krystal ; Jones, Gregory E. ; Harvey, Lauren ; Lai, Katharine C. ; Portwood, Scott ; Adams, Sharlene ; Sloss, Callum M. ; Schuurhuis, Gerrit Jan ; Ossenkoppele, Gert ; Wang, Eunice S. ; Pinkas, Jan. / IMGN779, a Novel CD33-targeting antibody–drug conjugate with DNA-alkylating activity, exhibits potent antitumor activity in models of AML. In: Molecular Cancer Therapeutics. 2018 ; Vol. 17, No. 6. pp. 1271-1279.
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title = "IMGN779, a Novel CD33-targeting antibody–drug conjugate with DNA-alkylating activity, exhibits potent antitumor activity in models of AML",
abstract = "The myeloid differentiation antigen CD33 has long been exploited as a target for antibody-based therapeutic approaches in acute myeloid leukemia (AML). Validation of this strategy was provided with the approval of the CD33-targeting antibody–drug conjugate (ADC) gemtuzumab ozogamicin in 2000; the clinical utility of this agent, however, has been hampered by safety concerns. Thus, the full potential of CD33-directed therapy in AML remains to be realized, and considerable interest exists in the design and development of more effective ADCs that confer high therapeutic indices and favorable tolerability profiles. Here, we describe the preclinical characterization of a novel CD33-targeting ADC, IMGN779, which utilizes a unique DNA-alkylating payload to achieve potent antitumor effects with good tolerability. The payload, DGN462, is prototypical of a novel class of purpose-created indolinobenzodiazeprine pseudodimers, termed IGNs. With low picomolar potency, IMGN779 reduced viability in a panel of AML cell lines in vitro. Mechanistically, the cytotoxic activity of IMGN779 involved DNA damage, cell-cycle arrest, and apoptosis consistent with the mode of action of DGN462. Moreover, IMGN779 was highly active against patient-derived AML cells, including those with adverse molecular abnormalities, and sensitivity correlated to CD33 expression levels. In vivo, IMGN779 displayed robust antitumor efficacy in multiple AML xenograft and disseminated disease models, as evidenced by durable tumor regressions and prolonged survival. Taken together, these findings identify IMGN779 as a promising new candidate for evaluation as a novel therapeutic in AML.",
author = "Yelena Kovtun and Paul Noordhuis and Whiteman, {Kathleen R.} and Krystal Watkins and Jones, {Gregory E.} and Lauren Harvey and Lai, {Katharine C.} and Scott Portwood and Sharlene Adams and Sloss, {Callum M.} and Schuurhuis, {Gerrit Jan} and Gert Ossenkoppele and Wang, {Eunice S.} and Jan Pinkas",
year = "2018",
doi = "10.1158/1535-7163.MCT-17-1077",
language = "English",
volume = "17",
pages = "1271--1279",
journal = "Molecular Cancer Therapeutics",
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Kovtun, Y, Noordhuis, P, Whiteman, KR, Watkins, K, Jones, GE, Harvey, L, Lai, KC, Portwood, S, Adams, S, Sloss, CM, Schuurhuis, GJ, Ossenkoppele, G, Wang, ES & Pinkas, J 2018, 'IMGN779, a Novel CD33-targeting antibody–drug conjugate with DNA-alkylating activity, exhibits potent antitumor activity in models of AML' Molecular Cancer Therapeutics, vol. 17, no. 6, pp. 1271-1279. https://doi.org/10.1158/1535-7163.MCT-17-1077

IMGN779, a Novel CD33-targeting antibody–drug conjugate with DNA-alkylating activity, exhibits potent antitumor activity in models of AML. / Kovtun, Yelena; Noordhuis, Paul; Whiteman, Kathleen R.; Watkins, Krystal; Jones, Gregory E.; Harvey, Lauren; Lai, Katharine C.; Portwood, Scott; Adams, Sharlene; Sloss, Callum M.; Schuurhuis, Gerrit Jan; Ossenkoppele, Gert; Wang, Eunice S.; Pinkas, Jan.

In: Molecular Cancer Therapeutics, Vol. 17, No. 6, 2018, p. 1271-1279.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - IMGN779, a Novel CD33-targeting antibody–drug conjugate with DNA-alkylating activity, exhibits potent antitumor activity in models of AML

AU - Kovtun, Yelena

AU - Noordhuis, Paul

AU - Whiteman, Kathleen R.

AU - Watkins, Krystal

AU - Jones, Gregory E.

AU - Harvey, Lauren

AU - Lai, Katharine C.

AU - Portwood, Scott

AU - Adams, Sharlene

AU - Sloss, Callum M.

AU - Schuurhuis, Gerrit Jan

AU - Ossenkoppele, Gert

AU - Wang, Eunice S.

AU - Pinkas, Jan

PY - 2018

Y1 - 2018

N2 - The myeloid differentiation antigen CD33 has long been exploited as a target for antibody-based therapeutic approaches in acute myeloid leukemia (AML). Validation of this strategy was provided with the approval of the CD33-targeting antibody–drug conjugate (ADC) gemtuzumab ozogamicin in 2000; the clinical utility of this agent, however, has been hampered by safety concerns. Thus, the full potential of CD33-directed therapy in AML remains to be realized, and considerable interest exists in the design and development of more effective ADCs that confer high therapeutic indices and favorable tolerability profiles. Here, we describe the preclinical characterization of a novel CD33-targeting ADC, IMGN779, which utilizes a unique DNA-alkylating payload to achieve potent antitumor effects with good tolerability. The payload, DGN462, is prototypical of a novel class of purpose-created indolinobenzodiazeprine pseudodimers, termed IGNs. With low picomolar potency, IMGN779 reduced viability in a panel of AML cell lines in vitro. Mechanistically, the cytotoxic activity of IMGN779 involved DNA damage, cell-cycle arrest, and apoptosis consistent with the mode of action of DGN462. Moreover, IMGN779 was highly active against patient-derived AML cells, including those with adverse molecular abnormalities, and sensitivity correlated to CD33 expression levels. In vivo, IMGN779 displayed robust antitumor efficacy in multiple AML xenograft and disseminated disease models, as evidenced by durable tumor regressions and prolonged survival. Taken together, these findings identify IMGN779 as a promising new candidate for evaluation as a novel therapeutic in AML.

AB - The myeloid differentiation antigen CD33 has long been exploited as a target for antibody-based therapeutic approaches in acute myeloid leukemia (AML). Validation of this strategy was provided with the approval of the CD33-targeting antibody–drug conjugate (ADC) gemtuzumab ozogamicin in 2000; the clinical utility of this agent, however, has been hampered by safety concerns. Thus, the full potential of CD33-directed therapy in AML remains to be realized, and considerable interest exists in the design and development of more effective ADCs that confer high therapeutic indices and favorable tolerability profiles. Here, we describe the preclinical characterization of a novel CD33-targeting ADC, IMGN779, which utilizes a unique DNA-alkylating payload to achieve potent antitumor effects with good tolerability. The payload, DGN462, is prototypical of a novel class of purpose-created indolinobenzodiazeprine pseudodimers, termed IGNs. With low picomolar potency, IMGN779 reduced viability in a panel of AML cell lines in vitro. Mechanistically, the cytotoxic activity of IMGN779 involved DNA damage, cell-cycle arrest, and apoptosis consistent with the mode of action of DGN462. Moreover, IMGN779 was highly active against patient-derived AML cells, including those with adverse molecular abnormalities, and sensitivity correlated to CD33 expression levels. In vivo, IMGN779 displayed robust antitumor efficacy in multiple AML xenograft and disseminated disease models, as evidenced by durable tumor regressions and prolonged survival. Taken together, these findings identify IMGN779 as a promising new candidate for evaluation as a novel therapeutic in AML.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/29588393

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