Antibody darts on target for acute myelogenous leukemia

Barrett, A. John

doi:10.21037/atm.2017.01.54

Cited by 3 publications

(1 citation statement)

References 26 publications

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“…Cynomolgus monkeys were selected as a relevant species for these studies on the basis of their tissue distributions of NKp46 and CD123, which are similar to those in humans 43 , 44 , and because the CD123-NKCE molecule binds to cynomolgus antigens and Fc receptors with affinities similar to those of human (Extended Data Table 1 ). In addition, a regulatory cross-reactivity study 45 performed by immunohistochemistry with the CD123-NKCE molecule on panels of human and cynomolgus normal tissues, confirmed similar staining distribution in endothelial cells of vessels and in mononuclear cells in many organs on both species, with tissue localization similar to those previously reported for NKp46 and CD123 antigens 46 , 47 .…”

Section: Resultssupporting

confidence: 83%

Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123

et al. 2023

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CD123, the alpha chain of the IL-3 receptor, is an attractive target for acute myeloid leukemia (AML) treatment. However, cytotoxic antibodies or T cell engagers targeting CD123 had insufficient efficacy or safety in clinical trials. We show that expression of CD64, the high-affinity receptor for human IgG, on AML blasts confers resistance to anti-CD123 antibody-dependent cell cytotoxicity (ADCC) in vitro. We engineer a trifunctional natural killer cell engager (NKCE) that targets CD123 on AML blasts and NKp46 and CD16a on NK cells (CD123-NKCE). CD123-NKCE has potent antitumor activity against primary AML blasts regardless of CD64 expression and induces NK cell activation and cytokine secretion only in the presence of AML cells. Its antitumor activity in a mouse CD123+ tumor model exceeds that of the benchmark ADCC-enhanced antibody. In nonhuman primates, it had prolonged pharmacodynamic effects, depleting CD123+ cells for more than 10 days with no signs of toxicity and very low inflammatory cytokine induction over a large dose range. These results support clinical development of CD123-NKCE.

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Section: Resultssupporting

confidence: 83%

Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123

et al. 2023

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41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo

Baroni

Martinez

Agüera

et al. 2020

J Immunother Cancer

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BackgroundAcute myeloid leukemia (AML) is a hematopoietic malignancy which is biologically, phenotypically and genetically very heterogeneous. Outcome of patients with AML remains dismal, highlighting the need for improved, less toxic therapies. Chimeric antigen receptor T-cell (CART) immunotherapies for patients with refractory or relapse (R/R) AML are challenging because of the absence of a universal pan-AML target antigen and the shared expression of target antigens with normal hematopoietic stem/progenitor cells (HSPCs), which may lead to life-threating on-target/off-tumor cytotoxicity. CD33-redirected and CD123-redirected CARTs for AML are in advanced preclinical and clinical development, and they exhibit robust antileukemic activity. However, preclinical and clinical controversy exists on whether such CARTs are myeloablative.MethodsWe set out to comparatively characterize in vitro and in vivo the efficacy and safety of 41BB-based and CD28-based CARCD123. We analyzed 97 diagnostic and relapse AML primary samples to investigate whether CD123 is a suitable immunotherapeutic target, and we used several xenograft models and in vitro assays to assess the myeloablative potential of our second-generation CD123 CARTs.ResultsHere, we show that CD123 represents a bona fide target for AML and show that both 41BB-based and CD28-based CD123 CARTs are very efficient in eliminating both AML cell lines and primary cells in vitro and in vivo. However, both 41BB-based and CD28-based CD123 CARTs ablate normal human hematopoiesis and prevent the establishment of de novo hematopoietic reconstitution by targeting both immature and myeloid HSPCs.ConclusionsThis study calls for caution when clinically implementing CD123 CARTs, encouraging its preferential use as a bridge to allo-HSCT in patients with R/R AML.

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Detection of specific antibodies of classes G and M to bovine leukemia virus in the blood serum

Gulyukin

Капустина

Ezdakova

et al. 2019

Problems of Virology

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Введение. Лейкоз крупного рогатого скота (КРС)-широко распространённая во всём мире инфекция, возбудитель которой-вирус лейкоза крупного рогатого скота (ВЛКРС) по структурному строению и функциональным особенностям схож с вирусом Т-клеточного лейкоза человека (HTLV-1 и HTLV-2) и рассматривается как актуальная медико-социальная проблема. Изучение иммунного ответа у экспериментально инфицированных телят на ранней стадии развития болезни, синтеза специфических антител классов G (IgG) и M (IgM), диагностической информативности выявления IgM при лейкозе КРС актуально и определяет цель данного исследования. материал и методы. Образцы крови и сыворотки крови КРС: животных, экспериментально инфицированных ВЛКРС, больных лейкозом КРС; контрольные отрицательные; специфические к гетерологичным возбудителям болезней КРС. Непрямой и сэндвич-вариант твердофазного иммуноферментного анализа (ТФ ИФА); коммерческие наборы ТФ ИФА (IDEXX, США; ООО «Хема», ФКП Курская биофабрика фирма «БИОК», Россия) для выявления специфических IgG и IgM к ВЛКРС, в реакции иммунодиффузии в агаровом геле (РИД). результаты. Гуморальный иммунный ответ развивается вскоре после инфицирования-к 1-8-й неделе. IgM выявляются начиная с 3-х суток, а IgG-с 7-х суток после заражения. Обнаружено до 97% совпадений положительных результатов в РИД и непрямом варианте ТФ ИФА на основе моноклональных антител к IgM КРС. обсуждение. Динамика синтеза антител классов М и G к гликопротеину gp51 ВЛКРС имеет дозозависимый волнообразный характер, согласуется с уровнями повышения/снижения абсолютного и относительного количества лейкоцитов/лимфоцитов крови инфицированных телят. Выводы. Сывороточные специфические IgM обнаружены начиная с 3-х суток после инфицирования ВЛКРС. Раннее выявление IgM в сыворотке крови КРС может быть использовано как дополнительный тест для выявления больных животных.

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Antibody darts on target for acute myelogenous leukemia

Cited by 3 publications

References 26 publications

Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123

Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123

41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo

Detection of specific antibodies of classes G and M to bovine leukemia virus in the blood serum

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