A Recombinant Immunotoxin against the Tumor-Associated Antigen Mesothelin Reengineered for High Activity, Low Off-Target Toxicity, and Reduced Antigenicity

Weldon, John E.; Xiang, Laiman; Zhang, Jingli; Beers, Richard; Walker, Dawn A.; Onda, Masanori; Hassan, Raffit; Pastan, Ira

doi:10.1158/1535-7163.mct-12-0336

Cited by 85 publications

(100 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Weldon et al constructed an anti-CD22 immunotoxin (HA22-LR) against hematological malignancies (37) and an anti-mesothelin immunotoxin (SS1-LR-GSS) against solid tumors (38) with lysosome protease resistance. They demonstrated that deletion of domain II or insertion of specific mutations within domain III led to enhanced stability without loss of its activity (36)(37)(38). Moreover, they found that deletion of domain II, with exception of the furin-cleavable site (aa 274-284), resulted not only in higher stability but also in an approximately twofold higher cytotoxicity compared to the initial construct (37).…”

Section: Discussionmentioning

confidence: 99%

In Vitro Evaluation of Humanized/De-immunized Anti-PSMA Immunotoxins for the Treatment of Prostate Cancer

Michalska

Schultze-Seemann

Kuckuck

et al. 2018

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

In Vitro Evaluation of Humanized/De-immunized Anti-PSMA Immunotoxins for the Treatment of Prostate Cancer

Michalska

Schultze-Seemann

Kuckuck

et al. 2018

View full text Add to dashboard Cite

“…Most recently, we reported that deletion of the near entirety of PE domain II can prevent VLS while preserving on-target cytotoxicity. This deletion does not affect two of the three putative endothelial binding motifs previously identified [21]. Further studies will be required to determine the minimal sequence responsible for PE-induced VLS.…”

Section: Vascular Leak Syndromementioning

confidence: 91%

Advances in Anticancer Immunotoxin Therapy

2015

Self Cite

View full text Add to dashboard Cite

Immunotoxins are a novel class of antibody-conjugated therapeutics currently in clinical development for a variety of malignancies. They consist of an antibody-based targeting domain fused to a bacterial toxin payload for cell killing. Immunotoxins kill cells by inhibiting protein synthesis, a unique mechanism of action that is toxic to both dividing and nondividing cells. Recent advances in the design and administration of immunotoxins are overcoming historical challenges in the field, leading to renewed interest in these therapeutics.The Oncologist 2015;20:176-185Implications for Practice: Immunotoxins are a novel class of antibody-based therapeutics currently in clinical development. A review of the field will help physicians better inform patients about the potential benefits and toxicities of these experimental treatments.

show abstract

“…3B). To improve cytotoxic activity, we inserted a Gly-GlySer peptide linker after the furin cleavage site because we found that this insertion improved cytotoxic activity of RITs targeting mesothelin (20). Fig.…”

Section: Significancementioning

confidence: 99%

Recombinant immunotoxin for cancer treatment with low immunogenicity by identification and silencing of human T-cell epitopes

Mazor

Eberle

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

101

106

View full text Add to dashboard Cite

Nonhuman proteins have valuable therapeutic properties, but their efficacy is limited by neutralizing antibodies. Recombinant immunotoxins (RITs) are potent anticancer agents that have produced many complete remissions in leukemia, but immunogenicity limits the number of doses that can be given to patients with normal immune systems. Using human cells, we identified eight helper T-cell epitopes in PE38, a portion of the bacterial protein Pseudomonas exotoxin A which consists of the toxin moiety of the RIT, and used this information to make LMB-T18 in which three epitopes were deleted and five others diminished by point mutations in key residues. LMB-T18 has high cytotoxic and antitumor activity and is very resistant to thermal denaturation. The new immunotoxin has a 93% decrease in T-cell epitopes and should have improved efficacy in patients because more treatment cycles can be given. Furthermore, the deimmunized toxin can be used to make RITs targeting other antigens, and the approach we describe can be used to deimmunize other therapeutically useful nonhuman proteins.deimmunization | protein engineering I mmunotoxins are chimeric proteins that combine the "magic bullet" specificity of an antibody with the high potency of a toxin. The high specificity of recombinant immunotoxins (RITs) leads to a dramatic decrease in side effects compared with chemotherapy. Moxetumomab Pasudotox (MP) is an RIT that consists of PE38, a fragment of Pseudomonas exotoxin A, fused to an anti-CD22 Fv (1). In a phase I trial for refractory hairy-cell leukemia (HCL), MP had an 86% response rate (2), with 46% complete remissions, and is now in phase III clinical trials (3).Immunogenicity is a stumbling block in the clinical success of many therapeutic proteins (4). Formation of neutralizing antidrug antibodies (5) inactivates the therapeutic agent and can cause serious adverse effects. Although MP had low immunogenicity in the immune-suppressed patients of the HCL trial, some patients did eventually develop antibodies. Consequently, fewer doses could be given to these patients, leading to a reduced response rate. Additionally, RITs targeting solid tumors are less effective than MP because of their high immunogenicity in patients with normal immune systems (6, 7).The role of helper T cells in mounting an immune response is well-established (8, 9). It was previously shown that elimination of murine T-cell epitopes reduced neutralizing antibody formation in mice (10), leading us to the hypothesis that reduction of human T-cell epitopes in the bacterial moiety of RITs would diminish its immunogenicity in humans, allowing more treatment cycles and better antitumor responses, as previously attempted for other therapeutic proteins like erythropoietin (11).To circumvent the immunogenicity of PE38, we previously used peptide pools to map the approximate location of the T-cell epitopes and found an immunodominant and promiscuous epitope that stimulated T cells in 42% of all donors (12). Here, we have done high-resolution mapping of the epitopes ...

show abstract

A Recombinant Immunotoxin against the Tumor-Associated Antigen Mesothelin Reengineered for High Activity, Low Off-Target Toxicity, and Reduced Antigenicity

Cited by 85 publications

References 45 publications

In Vitro Evaluation of Humanized/De-immunized Anti-PSMA Immunotoxins for the Treatment of Prostate Cancer

In Vitro Evaluation of Humanized/De-immunized Anti-PSMA Immunotoxins for the Treatment of Prostate Cancer

Advances in Anticancer Immunotoxin Therapy

Recombinant immunotoxin for cancer treatment with low immunogenicity by identification and silencing of human T-cell epitopes

Contact Info

Product

Resources

About