Gemtuzumab ozogamicin for acute myeloid leukemia

Appelbaum, Frederick R.; Bernstein, Irwin D.

doi:10.1182/blood-2017-09-797712

Cited by 140 publications

(106 citation statements)

References 40 publications

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“…Indeed, the first ADC of a highly potent DNA interacting agent to be evaluated in the clinic was gemtuzumab ozogamicin, which incorporated calicheamicin, a compound that causes DNA double strand breaks. This ADC was approved by the FDA, but subsequently withdrawn from the market due to toxic side effects, notably veno-occlusive disease (16,17). This ADC was re-approved recently after a new, lower dose regimen in combination with chemotherapy displayed therapeutic benefit.…”

Section: Introductionmentioning

confidence: 99%

A DNA-Interacting Payload Designed to Eliminate Cross-Linking Improves the Therapeutic Index of Antibody–Drug Conjugates (ADCs)

Miller

Shizuka

Wilhelm

et al. 2018

Molecular Cancer Therapeutics

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Tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) is now a clinically validated approach for cancer treatment. In an attempt to improve the clinical success rate of ADCs, emphasis has been recently placed on the use of DNA-cross-linking pyrrolobenzodiazepine compounds as the payload. Despite promising early clinical results with this class of ADCs, doses achievable have been low due to systemic toxicity. Here we describe the development of a new class of potent DNA-interacting agents wherein changing the mechanism of action from a cross-linker to a DNA alkylator improves the tolerability of the ADC. ADCs containing the DNA alkylator displayed similar in vitro potency, but improved bystander killing and in vivo efficacy, compared to those of the cross-linker. Thus, the improved in vivo tolerability and anti-tumor activity achieved in rodent models with ADCs of the novel DNA alkylator could provide an efficacious, yet safer option for cancer treatment.on May 9, 2018.

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Section: Introductionmentioning

confidence: 99%

A DNA-Interacting Payload Designed to Eliminate Cross-Linking Improves the Therapeutic Index of Antibody–Drug Conjugates (ADCs)

Miller

Shizuka

Wilhelm

et al. 2018

Molecular Cancer Therapeutics

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“…[2] ADCs are particular interesting for the treatment of cancer, since they combine the high potencyo fc ytotoxic molecules with the tumor specificity of monoclonal antibodies.ADCs thus have the potential to significantly broaden the therapeutic window compared to standard chemotherapy. [5] Nevertheless,challenges remain, especially in improving the linkage between drug and antibody. [5] Nevertheless,challenges remain, especially in improving the linkage between drug and antibody.…”

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confidence: 99%

Ethynylphosphonamidates for the Rapid and Cysteine‐Selective Generation of Efficacious Antibody–Drug Conjugates

et al. 2019

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Requirements for novel bioconjugation reactions for the synthesis of antibody–drug conjugates (ADCs) are exceptionally high, since conjugation selectivity as well as the stability and hydrophobicity of linkers and payloads drastically influence the performance and safety profile of the final product. We report Cys‐selective ethynylphosphonamidates as new reagents for the rapid generation of efficacious ADCs from native non‐engineered monoclonal antibodies through a simple one‐pot reduction and alkylation. Ethynylphosphonamidates can be easily substituted with hydrophilic residues, giving rise to electrophilic labeling reagents with tunable solubility properties. We demonstrate that ethynylphosphonamidate‐linked ADCs have excellent properties for next‐generation antibody therapeutics in terms of serum stability and in vivo antitumor activity.

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“…However, in this study, patients received lower dose chemotherapy when GO was added to their treatment compared to patients who only received chemotherapy. Subsequent studies have shown the efficacy of adding GO to chemotherapy leading to its reapproval in 2017 [21,22].…”

Section: Article Highlightsmentioning

confidence: 99%

Targeted therapy in acute myeloid leukemia: current status and new insights from a proteomic perspective

Dijk

Bont

Kornblau

2020

Expert Review of Proteomics

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Introduction: The biological heterogeneity of acute myeloid leukemia (AML) complicates personalized medicine. Individual prognosis is typically based on the presence of chromosomal and genetic lesions. Nevertheless, these classifications often lack a priori information about response to therapy. Since the protein expression landscape reflects the functional activity state of cells, we hypothesize that analyzing this can be used for the identification of protein activity markers to provide better risk stratification as well as may provide targeted therapeutic guidance in AML. Areas covered: Herein, we review recently new adopted drugs in the treatment for AML and discuss how quantitative proteomic techniques may contribute to better therapeutic selection in AML. Expert commentary: The net functional state of the cell is defined by the activity of protein within all the pathways that are active in the cell. Recognition of the proteomic profile of the leukemic blast could, therefore, complement current classification systems by providing a better a priori description of what pathways are important within a cell as a guide to the selection of therapy for the patient.

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Gemtuzumab ozogamicin for acute myeloid leukemia

Cited by 140 publications

References 40 publications

A DNA-Interacting Payload Designed to Eliminate Cross-Linking Improves the Therapeutic Index of Antibody–Drug Conjugates (ADCs)

A DNA-Interacting Payload Designed to Eliminate Cross-Linking Improves the Therapeutic Index of Antibody–Drug Conjugates (ADCs)

Ethynylphosphonamidates for the Rapid and Cysteine‐Selective Generation of Efficacious Antibody–Drug Conjugates

Targeted therapy in acute myeloid leukemia: current status and new insights from a proteomic perspective

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