ArticleJournal of immunotoxicology
After TGN1412: recent developments in cytokine release assays.
Article in Journal of immunotoxicology. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 71 citations in OpenAlex.
- Immunomodulation profile of the biosimilar trastuzumab MYL-1401O in a bioequivalence phase I study.Scientific reports · 2024Trial
- Enhancement of CD117-Targeted Bispecific T-cell Engagement by CD33-Targeted Bispecific T-cell Costimulation in Acute Myeloid Leukemia.Cancer research communications · 2026Article
- Immunocytokines in cancer: a safety perspective.Frontiers in immunology · 2026Review
- Evaluation of a reference antibody panel for prediction of cytokine release in humanised mouse modelsFrontiers in immunology · 2026Article
- Potency-optimized CD28-activating bispecific antibody for the targeted treatment of Nectin-4 positive cancers.Journal for immunotherapy of cancer · 2025Article
- Preclinical Efficacy of VTX-0811: A Humanized First-in-Class PSGL-1 mAb Targeting TAMs to Suppress Tumor Growth.Cancers · 2024Article
- An In Vitro Human Skin Test for Predicting Skin Sensitization and Adverse Immune Reactions to Biologics.Toxics · 2024Article
- Article
- Single-cell deep phenotyping of cytokine release unmasks stimulation-specific biological signatures and distinct secretion dynamics.Cell reports methods · 2023Article
- Immuno-PET Monitoring of Lymphocytes Using the CD8-Specific Antibody REGN5054.Cancer immunology research · 2022Article
- The engineered CD80 variant fusion therapeutic davoceticept combines checkpoint antagonism with conditional CD28 costimulation for anti-tumor immunity.Nature communications · 2022Article
- A rapid, sensitive, and reproducible in vivo PBMC humanized murine model for determining therapeutic-related cytokine release syndrome.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Article
- Adverse immunostimulation caused by impurities: The dark side of biopharmaceuticals.British journal of clinical pharmacology · 2019Review
- Toll-Like Receptor-Mediated Recognition of Nucleic Acid Nanoparticles (NANPs) in Human Primary Blood Cells.Molecules (Basel, Switzerland) · 2019Article
- Impact of targeting transforming growth factor β-2 with antisense OT-101 on the cytokine and chemokine profile in patients with advanced pancreatic cancer.OncoTargets and therapy · 2018Article
- Recommendations for the Development and Validation of Neutralizing Antibody Assays in Support of Biosimilar Assessment.The AAPS journal · 2017Review
- Biomarkers for nonclinical infusion reactions in marketed biotherapeutics and considerations for study design.Current opinion in toxicology · 2017Review
- Applicability of predictive toxicology methods for monoclonal antibody therapeutics: status Quo and scope.Archives of toxicology · 2017Review
- Rapamycin-mediated mTOR inhibition uncouples HIV-1 latency reversal from cytokine-associated toxicity.The Journal of clinical investigation · 2017Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The failure of regulatory science to keep pace with and support the development of new biological medicines was very publically highlighted in March 2006 when the first-in-man Phase I clinical trial of the immunomodulatory CD28-specific monoclonal antibody (mAb) TGN1412 ended in disaster when all six volunteers suffered a life-threatening adverse reaction termed a 'Cytokine Storm'. The poor predictive value of standard pre-clinical safety tests and animal models applied to TGN1412 demonstrated the need for a new generation of immunotoxicity assays and animal models that are both sensitive and predictive of clinical outcome in man. The non-predictive result obtained from pre-clinical safety testing in cynomolgus macaques has now been attributed to a lack of CD28 expression on CD4+ effector memory T-cells that therefore cannot be stimulated by TGN1412. In contrast, high levels of CD28 are expressed on human CD4+ effector memory T-cells, the source of most TGN1412-stimulated pro-inflammatory cytokines. Standard in vitro safety tests with human cells were also non-predictive as they did not replicate in vivo presentation of TGN1412. It was subsequently shown that, if an immobilized therapeutic mAb-based assay or endothelial cell co-culture assay was used to evaluate TGN1412, then these would have predicted a pro-inflammatory response in man. New in vitro assays based on these approaches are now being applied to emerging therapeutics to hopefully prevent a repeat of the TGN1412 incident. It has emerged that the mechanism of pro-inflammatory cytokine release stimulated by TGN1412 is different to that of other therapeutic mAbs, such that standard pro-inflammatory markers such as TNFα and IL-8 are not discriminatory. Rather, IL-2 release and lymphoproliferation are optimal readouts of a TGN1412-like pro-inflammatory response.
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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.