Increased cytotoxic activity of Pseudomonas exotoxin and two chimeric toxins ending in KDEL.

Seetharam, Saraswathy; Chaudhary, Vijay; FitzGerald, David J.; Pastan, Ira

doi:10.1016/s0021-9258(19)47383-3

Cited by 191 publications

(49 citation statements)

References 30 publications

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“…M oreover, the secretory p athw ay contains enzymes th a t rem ove C -term inal basic residues, and indeed the sequence K D E L K acts as an efficient e r retention signal in C O S cells. F u rth e r m utagenesis studies have confirm ed th a t the sequence requirem ents for PE toxicity and retention of e r proteins are indistinguishable (see, for exam ple, Seetharam et al 1991).…”

Section: Subversion Of the Kdel Systemmentioning

confidence: 97%

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The Florey Lecture, 1992. The secretion of proteins by cells

Pelham

1992

Proc. R. Soc. Lond. B

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In eukaryotic cells, protein secretion provides a complex organizational problem. Secretory proteins are first transported, in an unfolded state, across the membrane of the endoplasmic reticulum (ER), and are then carried in small vesicles to the Golgi apparatus and finally to the cell membrane. The ER contains soluble proteins which catalyse the folding of newly synthesized polypeptides. These proteins are sorted from secretory proteins in the Golgi complex: they carry a sorting signal (the tetrapeptide KDEL or a related sequence) that allows them to be selectively retrieved and returned to the ER. This retrieval process also appears to be used by some bacterial toxins to aid their invasion of the cell: these toxins contain KDEL-like sequences and may, in effect, follow the secretory pathway in reverse. The membrane-bound receptor responsible for sorting luminal ER proteins has been identified in yeast by genetic means, and related receptors are found in mammalian cells. Unexpectedly, this receptor has a second role: in yeast it is required to maintain the normal size and function of the Golgi apparatus. By helping to maintain the composition of both ER and Golgi compartments, the KDEL receptor has an important role in the organization of the secretory pathway.

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Section: Subversion Of the Kdel Systemmentioning

confidence: 97%

“…P re-treatm ent of cells with brefeldin protects them against the lethal effects of PE (and several other toxins), im plying a role for the Golgi complex in toxin entry (Yoshida et al 1991;H udson & Grillo 1991;Sandvig al. 1991;Seetharam et al 1991).…”

Section: Subversion Of the Kdel Systemmentioning

confidence: 99%

The Florey Lecture, 1992. The secretion of proteins by cells

Pelham

1992

Proc. R. Soc. Lond. B

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“…In wild type ETA, amino acids 609-613, which was still used in the thiol conjugated immunotoxin ( 197 ), are encoding for the endoplasmic reticulum (ER) retention sequence REDLK. This sequence was altered to its mammalian counterpart, KDEL, which increases cytotoxicity ( 200 , 201 ). The linker exhibited a furin cleavage site that allowed the release of the toxin in the endosome upon binding of the scFv to EpCAM and subsequent internalization ( Figure 3 ).…”

Section: Immunotoxinsmentioning

confidence: 99%

Treating Bladder Cancer: Engineering of Current and Next Generation Antibody-, Fusion Protein-, mRNA-, Cell- and Viral-Based Therapeutics

Bogen

Grzeschik²,

Jakobsen

et al. 2021

Front. Oncol.

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Bladder cancer is a frequent malignancy and has a clinical need for new therapeutic approaches. Antibody and protein technologies came a long way in recent years and new engineering approaches were applied to generate innovative therapeutic entities with novel mechanisms of action. Furthermore, mRNA-based pharmaceuticals recently reached the market and CAR-T cells and viral-based gene therapy remain a major focus of biomedical research. This review focuses on the engineering of biologics, particularly therapeutic antibodies and their application in preclinical development and clinical trials, as well as approved monoclonal antibodies for the treatment of bladder cancer. Besides, newly emerging entities in the realm of bladder cancer like mRNA, gene therapy or cell-based therapeutics are discussed and evaluated. As many discussed molecules exhibit unique mechanisms of action based on innovative protein engineering, they reflect the next generation of cancer drugs. This review will shed light on the engineering strategies applied to develop these next generation treatments and provides deeper insights into their preclinical profiles, clinical stages, and ongoing trials. Furthermore, the distribution and expression of the targeted antigens and the intended mechanisms of action are elucidated.

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“…REDLK is similar to the eukaryotic endoplasmic reticulum retention sequences (lysine-aspargine-glutamine-leucine (KDEL)) and functions in the same manner. 45,46 In the endoplasmic reticulum, translocation to the cytosol can occur.…”

Section: Preclinical Pharmacology Pementioning

confidence: 99%

Targeted toxins

Brok

Gast

Schellens

et al. 1999

J Oncol Pharm Pract

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Objective. Current modalities used in the treatment of cancer often cause unacceptable damage to normal tissue. Toxins targeted toward tumor cells by antibodies or growth factors have the potential to selectively kill tumor cells while leaving normal tissue intact. The purpose of this review is to provide background information on targeted toxins and current clinical studies for this new class of anti-cancer compounds.Data sources. A MEDLINE search was conducted using the term "immunotoxins." Relevant articles were also obtained by the systematic examination of article references.Data synthesis. The toxins Pseudomonas exotoxin, diphtheria toxin, and ricin toxin are often used as targeted toxins. Deletion or mutation of the binding domains of these toxins decreased binding of the toxins to normal tissues. Antibodies or growth factors can be used as targeting moiety, and the resulting

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Increased cytotoxic activity of Pseudomonas exotoxin and two chimeric toxins ending in KDEL.

Cited by 191 publications

References 30 publications

The Florey Lecture, 1992. The secretion of proteins by cells

The Florey Lecture, 1992. The secretion of proteins by cells

Treating Bladder Cancer: Engineering of Current and Next Generation Antibody-, Fusion Protein-, mRNA-, Cell- and Viral-Based Therapeutics

Targeted toxins

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