ArticleMolecular cancer therapeutics2010
Bioengineering a unique deimmunized bispecific targeted toxin that simultaneously recognizes human CD22 and CD19 receptors in a mouse model of B-cell metastases.
Article in Molecular cancer therapeutics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
21 citing papers in PubMed, 35 citations in OpenAlex.
- Generation of a Novel SORT1×HER2 Bispecific Antibody-Drug Conjugate Targeting HER2-Low-Expression Tumor.International journal of molecular sciences · 2023Article
- Hosts for Hostile Protein Production: The Challenge of Recombinant Immunotoxin Expression.Biomedicines · 2019Review
- 3D Bioprinted In Vitro Metastatic Models via Reconstruction of Tumor Microenvironments.Advanced materials (Deerfield Beach, Fla.) · 2019Article
- Development of a Deimmunized Bispecific Immunotoxin dDT2219 against B-Cell Malignancies.Toxins · 2018Article
- Development of a strategy and computational application to select candidate protein analogues with reduced HLA binding and immunogenicity.Immunology · 2018Article
- Review
- Review
- Article
- Phenotypic Knockout of CXCR4 Expression by a Novel Intrakine Mutant hSDF-1α/54/KDEL Inhibits Breast Cancer Metastasis.Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research · 2015Article
- Systematic comparison of single-chain Fv antibody-fusion toxin constructs containing Pseudomonas Exotoxin A or saporin produced in different microbial expression systems.Microbial cell factories · 2015Article
- A bispecific EpCAM/CD133-targeted toxin is effective against carcinoma.Targeted oncology · 2014Article
- Targeted tumor therapy by epidermal growth factor appended toxin and purified saponin: an evaluation of toxicity and therapeutic potential in syngeneic tumor bearing mice.Molecular oncology · 2013Article
- Immunotoxin targeting CD133(+) breast carcinoma cells.Drug delivery and translational research · 2013Article
- Bispecific targeting of EGFR and uPAR in a mouse model of head and neck squamous cell carcinoma.Oral oncology · 2012Article
- Article
- CD40 ligand is necessary and sufficient to support primary diffuse large B-cell lymphoma cells in culture: a tool for in vitro preclinical studies with primary B-cell malignancies.Leukemia & lymphoma · 2012Article
- Targeting tumor-initiating cancer cells with dCD133KDEL shows impressive tumor reductions in a xenotransplant model of human head and neck cancer.Molecular cancer therapeutics · 2011Article
- Pentostatin plus cyclophosphamide safely and effectively prevents immunotoxin immunogenicity in murine hosts.Clinical cancer research : an official journal of the American Association for Cancer Research · 2011Article
- Review
- SLT-VEGF reduces lung metastases, decreases tumor recurrence, and improves survival in an orthotopic melanoma model.Toxins · 2010Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
A drug of high potency and reduced immunogenicity is needed to develop a targeted biological drug that when injected systemically can penetrate to malignant B cells. Therefore, a novel deimmunized bispecific ligand-directed toxin targeted by dual high-affinity single-chain Fvs (scFv) spliced to PE38 with a KDEL COOH-terminus was genetically engineered. The aims were to reduce toxin immunogenicity using mutagenesis, measure the ability of mutated drug to elicit antitoxin antibody responses, and show that mutated drug was effective against systemic B-cell lymphoma in vivo. Both human anti-CD22 scFv and anti-CD19 scFv were cloned onto the same single-chain molecule with truncated pseudomonas exotoxin (PE38) to create the drug. Site-specific mutagenesis was used to mutate amino acids in seven key epitopic toxin regions that dictate B-cell generation of neutralizing antitoxin antibodies. Bioassays were used to determine whether mutation reduced potency, and ELISAs were done to determine whether antitoxin antibodies were reduced. Finally, a powerful genetically altered luciferase xenograft model was used that could be imaged in real time to determine the effect on systemic malignant human B-cell lymphoma, Raji-luc. Patient B-lineage acute lymphoblastic leukemia, B-cell chronic lymphocytic leukemia, and B lymphoma were high in CD22 and CD19 expression. 2219KDEL7mut was significantly effective against systemic Raji-luc in mice and prevented metastatic spread. Mutagenesis reduced neutralizing antitoxin antibodies by approximately 80% with no apparent loss in in vitro or in vivo activity. Because 2219KDEL7mut immunogenicity was significantly reduced and the drug was highly effective in vivo, we can now give multiple drug treatments with targeted toxins in future clinical trials.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.