Critical Issues in the Development of Immunotoxins for Anticancer Therapy

Kim, Jisun; Jun, Sei-Yong; Kim, Yong‐Sung

doi:10.1016/j.xphs.2019.10.037

Cited by 69 publications

(60 citation statements)

References 151 publications

(207 reference statements)

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“…For instance, owing to its translocation domain the diphtheria toxin is able under condition of low acidity to insert its catalytic subunit into the endosome membrane and transfer it into the cytosol, whereas Pseudomonas exotoxin can be trans ferred via vesicular trafficking system through the Golgi apparatus into the ER and then into the cytosol by retro grade transport. ADP ribosylation subunits of such toxins exhibit extremely high cytotoxicity, which often rises a question as to whether they exhibit therapeutic range ade quate for clinical practice [220]. Nonetheless, the three immunotoxins have been already approved for clinical BIOCHEMISTRY (Moscow) Vol.…”

Section: The Use Of Egfr As a Delivery Systemmentioning

confidence: 99%

“…85 No. 9 2020 application in treatment of several hematological cancers: IL 2 fused to diphtheria toxin fragment (Ontak) for treat ment of T cell lymphoma; anti CD22 antibody linked to a Pseudomonas exotoxin (Lumoxiti) for treatment of hairy cell leukemia, and IL 3 coupled to a portion of diphtheria toxin (Elzonris) for treatment of blastic plas macytoid dendritic cell neoplasm [220].…”

Section: The Use Of Egfr As a Delivery Systemmentioning

confidence: 99%

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Epidermal Growth Factor Receptor: Key to Selective Intracellular Delivery

Rosenkranz

Slastnikova

2020

Biochemistry Moscow

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Epidermal growth factor receptor (EGFR) is an integral surface protein mediating cellular response to a number of growth factors. Its overexpression and increased activation due to mutations is one of the most common traits of many types of cancer. Development and clinical use of the agents, which block EGFR activation, became a prime example of the personalized targeted medicine. However, despite the obvious success in this area, cancer cure remains unattainable in most cases. Because of that, as well as the result of the search for possible ways to overcome the difficulties of treatment, a huge number of new treatment methods relying on the use of EGFR overexpression and its changes to destroy cancer cells. Modern data on the structure, functioning, and intracellular transport of EGFR, its natural ligands, as well as signaling cascades triggered by the EGFR activation, peculiarities of the EGFR expression and activation in oncological disorders, as well as applied therapeutic approaches aimed at blocking EGFR signaling pathway are summarized and analyzed in this review. Approaches to the targeted delivery of various chemotherapeutic agents, radionuclides, immunotoxins, photosensitizers, as well as the prospects for gene therapy aimed at cancer cells with EGFR overexpression are reviewed in detail. It should be noted that increasing attention is being paid nowadays to the development of multifunctional systems, either carrying several different active agents, or possessing several environment-dependent transport functions. Potentials of the systems based on receptor-mediated endocytosis of EGFR and their possible advantages and limitations are discussed.

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Section: The Use Of Egfr As a Delivery Systemmentioning

confidence: 99%

Section: The Use Of Egfr As a Delivery Systemmentioning

confidence: 99%

Epidermal Growth Factor Receptor: Key to Selective Intracellular Delivery

Rosenkranz

Slastnikova

2020

Biochemistry Moscow

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“…Toxins are highly cytotoxic moleculesinternalization of just one molecule into the cytosol is sufficient to induce cell death (98,99). The majority of toxins used in immunotoxin design are either plant-or bacterial based, such as the bacterial pseudomonas exotoxin, diphtheria toxin and Shigalike toxin, and the plant toxins ricin, gelonin and pokeweed antiviral protein, among many others (100). The majority of toxins belong to the group of ribosome-inactivating proteins, which induce ribotoxic stress, halt protein production and cause subsequent apoptosis (101).…”

Section: Immunotoxinsmentioning

confidence: 99%

“…However, toxins can be deimmunized by the removal of critical T cell and B cell epitopes via genetic engineering (104,105). For an in-depth insight into immunotoxin rationale, design, and advances, we refer to these reviews (100,106,107).…”

Section: Immunotoxinsmentioning

confidence: 99%

Targeted Therapy With Immunoconjugates for Multiple Myeloma

2020

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The introduction of proteasome inhibitors (PI) and immunomodulatory drugs (IMiD) has markedly increased the survival of multiple myeloma (MM) patients. Also, the unconjugated monoclonal antibodies (mAb) daratumumab (anti-CD38) and elotuzumab (anti-SLAMF7) have revolutionized MM treatment given their clinical efficacy and safety, illustrating the potential of targeted immunotherapy as a powerful treatment strategy for MM. Nonetheless, most patients eventually develop PI-, IMiD-, and mAb-refractory disease because of the selection of resistant MM clones, which associates with a poor prognosis. Accordingly, these patients remain in urgent need of new therapies with novel mechanisms of action. In this respect, mAbs or mAb fragments can also be utilized as carriers of potent effector moieties to specifically target surface antigens on cells of interest. Such immunoconjugates have the potential to exert anti-MM activity in heavily pretreated patients due to their distinct and pleiotropic mechanisms of action. In addition, the fusion of highly cytotoxic compounds to mAbs decreases the off-target toxicity, thereby improving the therapeutic window. According to the effector moiety, immunoconjugates are classified into antibody-drug conjugates, immunotoxins, immunocytokines, or radioimmunoconjugates. This review will focus on the mechanisms of action, safety and efficacy of several promising immunoconjugates that are under investigation in preclinical and/or clinical MM studies. We will also include a discussion on combination therapy with immunoconjugates, resistance mechanisms, and future developments.

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“…Currently, over 20 IT therapeutics are being tested in the clinical trials. As elegantly reviewed by Kim et al [ 20 ], common themes among the FDA-approved toxin-mediated therapeutics include the target recognition moiety that specifically targets hematological cancer cells, and the truncated bacterial toxins that allow reduced levels of immunogenicity and non-specific binding.…”

Section: Current Fda-approved Toxin-mediated Therapeuticsmentioning

confidence: 99%

Immunotoxin Screening System: A Rapid and Direct Approach to Obtain Functional Antibodies with Internalization Capacities

Hamamichi

Fukuhara

2020

Toxins

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Toxins, while harmful and potentially lethal, have been engineered to develop potent therapeutics including cytotoxins and immunotoxins (ITs), which are modalities with highly selective targeting capabilities. Currently, three cytotoxins and IT are FDA-approved for treatment of multiple forms of hematological cancer, and additional ITs are tested in the clinical trials or at the preclinical level. For next generation of ITs, as well as antibody-mediated drug delivery systems, specific targeting by monoclonal antibodies is critical to enhance efficacies and reduce side effects, and this methodological field remains open to discover potent therapeutic monoclonal antibodies. Here, we describe our application of engineered toxin termed a cell-based IT screening system. This unique screening strategy offers the following advantages: (1) identification of monoclonal antibodies that recognize cell-surface molecules, (2) selection of the antibodies that are internalized into the cells, (3) selection of the antibodies that induce cytotoxicity since they are linked with toxins, and (4) determination of state-specific activities of the antibodies by differential screening under multiple experimental conditions. Since the functional monoclonal antibodies with internalization capacities have been identified successfully, we have pursued their subsequent modifications beyond antibody drug conjugates, resulting in development of immunoliposomes. Collectively, this screening system by using engineered toxin is a versatile platform, which enables straight-forward and rapid selection for discovery of novel functional antibodies.

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Critical Issues in the Development of Immunotoxins for Anticancer Therapy

Cited by 69 publications

References 151 publications

Epidermal Growth Factor Receptor: Key to Selective Intracellular Delivery

Epidermal Growth Factor Receptor: Key to Selective Intracellular Delivery

Targeted Therapy With Immunoconjugates for Multiple Myeloma

Immunotoxin Screening System: A Rapid and Direct Approach to Obtain Functional Antibodies with Internalization Capacities

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