Site-Specific PEGylation of Anti-Mesothelin Recombinant Immunotoxins Increases Half-life and Antitumor Activity

Zheng, Zeliang; Okada, Ryuhei; Kobayashi, Hisataka; Nagaya, Tadanobu; Jiang, Wei; Zhou, Qi; Lee, Fred; Bera, Tapan K.; Gao, Yifei; Kuhlman, William; Tai, Chin‐Hsien; Pastan, Ira

doi:10.1158/1535-7163.mct-19-0890

Cited by 14 publications

(15 citation statements)

References 21 publications

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“…Taken together, enhancement of LMB-100 efficacy is dependent not only on the selected chemotherapeutics but also on the type of cancer itself. None of the above studies could clearly define the mechanisms behind the observed synergistic effects, though further mechanistic and pharmacokinetic studies are underway ( 136 , 137 ).…”

Section: Pseudomonas Exotoxin Amentioning

confidence: 99%

Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin

2021

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Cancer is one of the prominent causes of death worldwide. Despite the existence of various modalities for cancer treatment, many types of cancer remain uncured or develop resistance to therapeutic strategies. Furthermore, almost all chemotherapeutics cause a range of side effects because they affect normal cells in addition to malignant cells. Therefore, the development of novel therapeutic agents that are targeted specifically toward cancer cells is indispensable. Immunotoxins (ITs) are a class of tumor cell-targeted fusion proteins consisting of both a targeting moiety and a toxic moiety. The targeting moiety is usually an antibody/antibody fragment or a ligand of the immune system that can bind an antigen or receptor that is only expressed or overexpressed by cancer cells but not normal cells. The toxic moiety is usually a protein toxin (or derivative) of animal, plant, insect, or bacterial origin. To date, three ITs have gained Food and Drug Administration (FDA) approval for human use, including denileukin diftitox (FDA approval: 1999), tagraxofusp (FDA approval: 2018), and moxetumomab pasudotox (FDA approval: 2018). All of these ITs take advantage of bacterial protein toxins. The toxic moiety of the first two ITs is a truncated form of diphtheria toxin, and the third is a derivative of Pseudomonas exotoxin (PE). There is a growing list of ITs using PE, or its derivatives, being evaluated preclinically or clinically. Here, we will review these ITs to highlight the advances in PE-based anticancer strategies, as well as review the targeting moieties that are used to reduce the non-specific destruction of non-cancerous cells. Although we tried to be as comprehensive as possible, we have limited our review to those ITs that have proceeded to clinical trials and are still under active clinical evaluation.

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Section: Pseudomonas Exotoxin Amentioning

confidence: 99%

Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin

2021

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“…PEGylation is a practical and effective strategy to improve the half-life of protein drugs in vivo [ 34 , 35 ]. However, PEGylation may reduce the cytotoxicity of the conjugates while increasing the half-life, where the degree of influence may be closely related to the molecular weight of the poly(ethylene glycol) (PEG) chain [ 36 , 37 , 38 ]. In addition, the coupling mode of PEG chains and small drug molecules may affect affibody affinity with their targets and then in turn affect the biological activity of the conjugates [ 39 , 40 ].…”

Section: Introductionmentioning

confidence: 99%

PEG Linker Improves Antitumor Efficacy and Safety of Affibody-Based Drug Conjugates

et al. 2021

IJMS

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Antibody drug conjugates (ADCs) have become an important modality of clinical cancer treatment. However, traditional ADCs have some limitations, such as reduced permeability in solid tumors due to the high molecular weight of monoclonal antibodies, difficulty in preparation and heterogeneity of products due to the high drug/antibody ratio (4–8 small molecules per antibody). Miniaturized ADCs may be a potential solution, although their short circulation half-life may lead to new problems. In this study, we propose a novel design strategy for miniaturized ADCs in which drug molecules and small ligand proteins are site-specifically coupled via a bifunctional poly(ethylene glycol) (PEG) chain. The results showed that the inserted PEG chains significantly prolonged the circulation half-life but also obviously reduced the cytotoxicity of the conjugates. Compared with the conjugate ZHER2-SMCC-MMAE (HM), which has no PEG insertion, ZHER2-PEG4K-MMAE (HP4KM) and ZHER2-PEG10K-MMAE (HP10KM) with 4 or 10 kDa PEG insertions have 2.5- and 11.2-fold half-life extensions and 4.5- and 22-fold in vitro cytotoxicity reductions, respectively. The combined effect leads to HP10KM having the most ideal tumor therapeutic ability at the same dosages in the animal model, and its off-target toxicity was also reduced by more than 4 times compared with that of HM. These results may indicate that prolonging the half-life is very helpful in improving the therapeutic capacity of miniaturized ADCs. In the future, the design of better strategies that can prolong half-life without affecting cytotoxicity may be useful for further improving the therapeutic potential of these molecules.

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“…A molecular weight of <60 kDa can result in a fast renal clearance and a reduced serum half-life and consequently requires repeated or continuous systemic administration in the patient. The attachment of polyethylene glycol (PEGylation) is one method to increase the molecular weight and the plasma half-life of targeted toxins [70].…”

Section: Enhancing Tumor Penetration and Affinitymentioning

confidence: 99%

Targeted Toxins for the Treatment of Prostate Cancer

Wolf

2021

Biomedicines

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Prostate cancer is the second most common cancer and the fifth leading cause of cancer deaths worldwide. Despite improvements in diagnosis and treatment, new treatment options are urgently needed for advanced stages of the disease. Targeted toxins are chemical conjugates or fully recombinant proteins consisting of a binding domain directed against a target antigen on the surface of cancer cells and a toxin domain, which is transported into the cell for the induction of apoptosis. In the last decades, targeted toxins against prostate cancer have been developed. Several challenges, however, became apparent that prevented their direct clinical use. They comprise immunogenicity, low target antigen binding, endosomal entrapment, and lysosomal/proteasomal degradation of the targeted toxins. Moreover, their efficacy is impaired by prostate tumors, which are marked by a dense microenvironment, low target antigen expression, and apoptosis resistance. In this review, current findings in the development of targeted toxins against prostate cancer in view of effective targeting, reduction of immunogenicity, improvement of intracellular trafficking, and overcoming apoptosis resistance are discussed. There are promising approaches that should lead to the clinical use of targeted toxins as therapeutic alternatives for advanced prostate cancer in the future.

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Site-Specific PEGylation of Anti-Mesothelin Recombinant Immunotoxins Increases Half-life and Antitumor Activity

Cited by 14 publications

References 21 publications

Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin

Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin

PEG Linker Improves Antitumor Efficacy and Safety of Affibody-Based Drug Conjugates

Targeted Toxins for the Treatment of Prostate Cancer

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