225Ac‐labeled CD33‐targeting antibody reverses resistance to Bcl‐2 inhibitor venetoclax in acute myeloid leukemia models

Garg, Ravendra; Allen, Kevin; Dawicki, Wojciech; Geoghegan, Eileen M.; Ludwig, Dale L.; Dadachova, Ekaterina

doi:10.1002/cam4.3665

Cited by 35 publications

(21 citation statements)

References 37 publications

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“…From these first results, investigations were pursued in a phase II trial in patients with untreated AML and treated with two administrations of 55 or 74 kBq/kg [ 65 ]. Other phase I dose-escalation were also performed from fractionated doses of 225 Ac-lintuzumab in combination with low-dose cytarabine (a chemotherapy agent for inhibition of cells proliferation by interaction with DNA) [ 66 ] or associated with venetoclax, a BCL-2 inhibitor inducing cells apoptosis [ 67 ] (NCT03867682).…”

Section: Actinium-225mentioning

confidence: 99%

Overview of the Most Promising Radionuclides for Targeted Alpha Therapy: The “Hopeful Eight”

et al. 2021

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Among all existing radionuclides, only a few are of interest for therapeutic applications and more specifically for targeted alpha therapy (TAT). From this selection, actinium-225, astatine-211, bismuth-212, bismuth-213, lead-212, radium-223, terbium-149 and thorium-227 are considered as the most suitable. Despite common general features, they all have their own physical characteristics that make them singular and so promising for TAT. These radionuclides were largely studied over the last two decades, leading to a better knowledge of their production process and chemical behavior, allowing for an increasing number of biological evaluations. The aim of this review is to summarize the main properties of these eight chosen radionuclides. An overview from their availability to the resulting clinical studies, by way of chemical design and preclinical studies is discussed.

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Section: Actinium-225mentioning

confidence: 99%

Overview of the Most Promising Radionuclides for Targeted Alpha Therapy: The “Hopeful Eight”

et al. 2021

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“…Moreover, 225Ac–lintuzumab has been shown to reverse resistance to venetoclax in AML models. A phase I/II study of venetoclax and lintuzumab–225Ac in R/R AML patients is currently ongoing (NCT03867682) [ 118 ].…”

Section: Harnessing Immunitymentioning

confidence: 99%

New Perspectives in Treating Acute Myeloid Leukemia: Driving towards a Patient-Tailored Strategy

Andreozzi

Massaro

Wittnebel

et al. 2022

IJMS

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For decades, intensive chemotherapy (IC) has been considered the best therapeutic option for treating acute myeloid leukemia (AML), with no curative option available for patients who are not eligible for IC or who have had failed IC. Over the last few years, several new drugs have enriched the therapeutic arsenal of AML treatment for both fit and unfit patients, raising new opportunities but also new challenges. These include the already approved venetoclax, the IDH1/2 inhibitors enasidenib and ivosidenib, gemtuzumab ozogamicin, the liposomal daunorubicin/cytarabine formulation CPX-351, and oral azacitidine. Venetoclax, an anti BCL2-inhibitor, in combination with hypomethylating agents (HMAs), has markedly improved the management of unfit and elderly patients from the perspective of improved quality of life and better survival. Venetoclax is currently under investigation in combination with other old and new drugs in early phase trials. Recently developed drugs with different mechanisms of action and new technologies that have already been investigated in other settings (BiTE and CAR-T cells) are currently being explored in AML, and ongoing trials should determine promising agents, more synergic combinations, and better treatment strategies. Access to new drugs and inclusion in clinical trials should be strongly encouraged to provide scientific evidence and to define the future standard of treatment in AML.

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“…Therefore, targeted immunotherapy based on antibody-drug conjugates targeting AML has been limited to CD33-targeting gemtuzumab ozogamicin (Mylotarg TM ) [56,57]. More recently, to overcome resistant AML tumors, 225 Ac-conjugated anti-CD33 (Actinium-225-lintuzumab) has been used in tandem with B cell lymphoma 2 selective inhibitor venetoclax to reduce antiapoptotic myeloid cell leukemia 1 overexpression [58].…”

Section: Siglec-3 (Cd33)mentioning

confidence: 99%

Siglecs as Therapeutic Targets in Cancer

Lim

Sari-Ak

Bagga

2021

Biology

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Hypersialylation is a common post-translational modification of protein and lipids found on cancer cell surfaces, which participate in cell-cell interactions and in the regulation of immune responses. Sialic acids are a family of nine-carbon α-keto acids found at the outermost ends of glycans attached to cell surfaces. Given their locations on cell surfaces, tumor cells aberrantly overexpress sialic acids, which are recognized by Siglec receptors found on immune cells to mediate broad immunomodulatory signaling. Enhanced sialylation exposed on cancer cell surfaces is exemplified as “self-associated molecular pattern” (SAMP), which tricks Siglec receptors found on leukocytes to greatly down-regulate immune responsiveness, leading to tumor growth. In this review, we focused on all 15 human Siglecs (including Siglec XII), many of which still remain understudied. We also highlighted strategies that disrupt the course of Siglec-sialic acid interactions, such as antibody-based therapies and sialic acid mimetics leading to tumor cell depletion. Herein, we introduced the central roles of Siglecs in mediating pro-tumor immunity and discussed strategies that target these receptors, which could benefit improved cancer immunotherapy.

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225Ac‐labeled CD33‐targeting antibody reverses resistance to Bcl‐2 inhibitor venetoclax in acute myeloid leukemia models

Cited by 35 publications

References 37 publications

Overview of the Most Promising Radionuclides for Targeted Alpha Therapy: The “Hopeful Eight”

Overview of the Most Promising Radionuclides for Targeted Alpha Therapy: The “Hopeful Eight”

New Perspectives in Treating Acute Myeloid Leukemia: Driving towards a Patient-Tailored Strategy

Siglecs as Therapeutic Targets in Cancer

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