Development of Recombinant Immunotoxins for Hairy Cell Leukemia

Kreitman, Robert J.; Pastan, Ira

doi:10.3390/biom10081140

Cited by 19 publications

(13 citation statements)

References 125 publications

(242 reference statements)

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“…During the past decade, much progress has been made in the treatment of refractory/relapsed HCL using moxetumomab pasudotox (Moxe) 11,13,14 or BRAF inhibitors [15][16][17] . Moxe is a recombinant immunotoxin containing an antibody fragment (Fv) directed against the B-cell molecule CD22 conjugated to a truncated Pseudomonas exotoxin A 13,18 . Its structure and mechanism of action are depicted in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

How I treat refractory/relapsed hairy cell leukemia with BRAF inhibitors

Falini

Carolis

Tiacci

2022

Blood

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Hairy cell leukemia (HCL) responds very well to frontline chemotherapy with purine analogs (cladribine and pentostatine). However, about half of patients experience one or more relapses, which become progressively resistant to these myelotoxic and immunosuppressive agents. At progression, standard therapeutic options include a second course of purine analogs alone or in combination with rituximab, and, upon second relapse, therapy with the anti-CD22 immunotoxin moxetumomab pasudotox. Furthermore, blockade of the mutant BRAF-V600E kinase (the pathogenetic hallmark of HCL) through orally available specific inhibitors (vemurafenib or dabrafenib) effaces the peculiar morphologic, phenotypic and molecular identity of this disease as well as its typical anti-apoptotic behaviour, and is emerging as an attractive chemotherapy-free strategy in various clinical scenarios. These include patients with, or at risk of, severe infections and, in a highly effective combination with rituximab, patients with relapsed or refractory HCL. Other treatments explored in clinical trials are BTK inhibition with ibrutinib and co-inhibition of BRAF (through dabrafenib or vemurafenib) and its downstream target MEK (through trametinib or cobimetinib). Here, we focus on our experience with BRAF inhibitors in clinical trials and as off-label use in routine practice by presenting three challenging clinical cases to illustrate their management in the context of all available treatment options.

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Section: Introductionmentioning

confidence: 99%

How I treat refractory/relapsed hairy cell leukemia with BRAF inhibitors

Falini

Carolis

Tiacci

2022

Blood

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“…At least two of these ligand-toxin molecules, DAB389IL2 and DAB389IL3, have been approved with several other candidates in late-stage clinical evaluation. Recently, a PE-based immunotoxin, targeting CD22, was approved for treating patients with hairy cell leukemia [153,154]. Because many of these patients were immunosuppressed, multiple cycles of therapy could be given before anti-toxin antibodies were produced.…”

Section: Discussionmentioning

confidence: 99%

Targeting Receptors on Cancer Cells with Protein Toxins

Antignani¹,

Ho²,

Bilotta³

et al. 2020

Biomolecules

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Cancer cells frequently upregulate surface receptors that promote growth and survival. These receptors constitute valid targets for intervention. One strategy involves the delivery of toxic payloads with the goal of killing those cancer cells with high receptor levels. Delivery can be accomplished by attaching a toxic payload to either a receptor-binding antibody or a receptor-binding ligand. Generally, the cell-binding domain of the toxin is replaced with a ligand or antibody that dictates a new binding specificity. The advantage of this “immunotoxin” approach lies in the potency of these chimeric molecules for killing cancer cells. However, receptor expression on normal tissue represents a significant obstacle to therapeutic intervention.

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“…While DT B provides an excellent proof-of-concept system to target human tumor xenografts in mice, alternate approaches need to be developed for tumor-specific targeting in humans. For example, the recombinant immunotoxin moxetumomab pasudotox has been successfully developed to retarget Pseudomonas exotoxin A to bind CD22 on hairy cell leukemia cells to drive cellular apoptosis ( Kreitman and Pastan, 2020 ). In addition, several other toxin-based targeting and delivery strategies have been repurposed to selectively target specific tumor types.…”

Section: Hijacking Immune Targeting Toxins For Cancer Therapeuticsmentioning

confidence: 99%

Bacterial Toxin and Effector Regulation of Intestinal Immune Signaling

Woida

Satchell

2022

Front. Cell Dev. Biol.

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The host immune response is highly effective to detect and clear infecting bacterial pathogens. Given the elaborate surveillance systems of the host, it is evident that in order to productively infect a host, the bacteria often coordinate virulence factors to fine-tune the host response during infection. These coordinated events can include either suppressing or activating the signaling pathways that control the immune response and thereby promote bacterial colonization and infection. This review will cover the surveillance and signaling systems for detection of bacteria in the intestine and a sample of the toxins and effectors that have been characterized that cirumvent these signaling pathways. These factors that promote infection and disease progression have also been redirected as tools or therapeutics. Thus, these toxins are enemies deployed to enhance infection, but can also be redeployed as allies to enable research and protect against infection.

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Development of Recombinant Immunotoxins for Hairy Cell Leukemia

Cited by 19 publications

References 125 publications

How I treat refractory/relapsed hairy cell leukemia with BRAF inhibitors

How I treat refractory/relapsed hairy cell leukemia with BRAF inhibitors

Targeting Receptors on Cancer Cells with Protein Toxins

Bacterial Toxin and Effector Regulation of Intestinal Immune Signaling

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