The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index; none of the 11 sources its claims cite is checked for support yet.
"Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics
Open accessAbstract
The CD28-specific mAb TGN1412 rapidly caused a life-threatening "cytokine storm" in all six healthy volunteers in the Phase I clinical trial of this superagonist, signaling a failure of preclinical safety testing. We report novel in vitro procedures in which TGN1412, immobilized in various ways, is presented to human white blood cells in a manner that stimulates the striking release of cytokines and profound lymphocyte proliferation that occurred in vivo in humans. The novel procedures would have predicted the toxicity of this superagonist and are now being applied to emerging immunotherapeutics and to other therapeutics that have the potential to act upon the immune system. Data from these novel procedures, along with data from in vitro and in vivo studies in nonhuman primates, suggest that the dose of TGN1412 given to human volunteers was close to the maximum immunostimulatory dose and that TGN1412 is not a superagonist in nonhuman primates.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
0 of 11 cited sources checked · 0 supported · 0 flagged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Even greater human lymphocyte proliferative responses were achieved with TGN1412 captured in aqueous phase by immobilized anti-human Fc Ab”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Lymphocyte proliferation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, human lymphocytes stimulated with aqueous TGN1412 captured by immobilized anti-Fc Ab stimulated greater IL-2 production than observed with immobilized TGN1412 alone (D).”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In marked contrast, TGN1412 air dried onto the walls of wells failed to stimulate significant production of TNF-␣, IL-6, and IL-8 from the diluted blood (20% v/v) of Cynomolgus macaques”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Results
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, with 0.4 g/well TGN1412, approximately equivalent to the human dose administered in the clinical trial, a strong proliferative response of human lymphocytes was observed.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Dose responses to TGN1412
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Measurement of proliferative responses of human lymphocytes to immobilized TGN1412 identified the optimal dose response as between 0.4 and 2 g/well (Fig. 7A).”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Dose responses to TGN1412
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Immobilized TGN1412 also stimulated IFN-␥ production by CD4 ϩ human lymphocytes.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Activation and intracellular cytokine staining
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In subsequent studies, we have confirmed that all of these IL-2 ϩ human lymphocytes are also positive for TNF-␣, following stimulation with immobilized TGN1412.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Activation and intracellular cytokine staining
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ELISA data for supernatants from 3-day cultures of human lymphocytes stimulated with immobilized TGN1412 confirmed high levels of IL-2 and lower levels of IFN-␥ in response to TGN1412 at low (0.4 to 2 g/well) but not high (20 and 200 g/well) concentrations of TGN1412.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Dose responses to TGN1412
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“With higher doses of 20 or 200 g/well, approximately equivalent to the doses (5 and 50 mg/kg) previously tested in Cynomolgus macaques, only weak proliferative response of human lymphocytes were observed.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Dose responses to TGN1412
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-2 alone did not stimulate proliferation of human or Cynomolgus macaque PBMC.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Lymphocyte proliferation
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 15
- Not yet classified. 15
- The quote only partly states this claim. 2
- Probably not a substantial claim. 2
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Stimulation of human lymphocytes with immobilized TGN1412 was accompanied by significant up-regulation of the activation marker CD25 (IL-2R␣) and proliferation.”
- Also stated in: § Effect of TGN1412 in Cynomolgus macaques · boosted
“A strong human lymphocyte proliferative response to immobilized TGN1412 was evident compared with immobilized isotype control Ab.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Activation and intracellular cytokine staining
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Effect of TGN1412 in Cynomolgus macaques · boosted
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“TGN1412 (1.0 and 10 g/well, but not 0.1 g/well) air dried onto the walls of wells in which PBMC were then cultured for 16 -24 h stimulated the release of TNF-␣, IL-6, and, especially, IL-8”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Results
Not yet classified.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although very low levels of intracellular IL-2 ϩ cells were detected in Cynomolgus macaque lymphocytes stimulated with immobilized TGN1412 (at 1 g/well) for 6 h, day 3 culture supernatants were negative for IL-2 measured by ELISA.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Dose responses to TGN1412
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No macaque lymphocyte proliferative response to immobilized TGN1412 alone was observed unless IL-2 was added to the wells.”
- Also stated in: § Discussion · plain
“in vitro Cynomolgus macaque lymphocytes did not proliferate when stimulated with immobilized TGN1412 unless IL-2 or rhesus CD3 Ab was added to cultures.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Effect of TGN1412 in Cynomolgus macaques
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Discussion · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Addition of IL-2 to human lymphocytes stimulated with immobilized TGN1412 did not increase the proliferative response”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Lymphocyte proliferation
Not yet classified.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“TGN1412 injected into Cynomolgus macaques at the doses (5 and 50 mg/kg) used in preclinical testing and also at 0.1 and 0.5 mg/kg was well tolerated in these nonhuman primates.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Discussion
Not yet classified.
In the paper
“Also, the TGN1412 passed the pharmacopoeial test for abnormal toxicity using mice and guinea pigs (6).”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > A
What the sources say
- Not checked yetcites [6] 2005
Not yet classified.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“With regard to the second finding, when immobilized by drying (with warm air) onto wells of 96-well plates, captured by immobilized anti-Fc Ab, or presented via a mechanism involving the participation of an endothelial cell monolayer, TGN1412 stimulated substantial release of cytokines, including TNF-␣, IL-2, IL-6, IL-8, and IFN-␥, and evoked a profound proliferation of human CD4 ϩ lymphocytes in”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Discussion
Not yet classified.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“although they did proliferate in response to immobilized TGN1412 when recombinant human IL-2 (4 IU/well) was added to the cultures (Fig. 5B)”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Lymphocyte proliferation
Not yet classified.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Pronounced proliferation of human lymphocytes incubated with immobilized TGN1412 was clearly evident compared with immobilized isotype-matched control Ab”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Lymphocyte proliferation
Not yet classified.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In subsequent studies, rhesus CD3 Ab in combination with immobilized TGN1412, but not alone, stimulated much stronger proliferative responses in Cynomolgus macaque lymphocytes, responses that were equivalent to the responses to mitogen.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Lymphocyte proliferation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This analysis, using a broad range of analytical techniques, showed that the TGN1412 complied with its specification and was of clinical grade.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > A
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Peak dose response for human lymphocytes was between 0.4 and 2 g/well (2-10 g/ml).”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Discussion
Not yet classified.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Myocarditis was observed in one animal in the control group and variable cardiac hypertrophy in some others, but no lesions that would correlate with the severe complications seen in the volunteers at the clinical trial were detected.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Effect of TGN1412 in Cynomolgus macaques
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A precursor frequency of 143 was obtained with isotype control Ab vs a precursor frequency of 349,586 per 10 6 human lymphocytes with TGN1412.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Effect of TGN1412 in Cynomolgus macaques
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“TGN1412 (0.1, 1.0, and 10 g/well) added in aqueous solution to a coculture of PBMC and human endothelial cells and cultured for 24 h stimulated the release of TNF-␣”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Despite its failure to respond to TGN1412, blood from Cynomolgus macaques responded to the positive controls of solutions of bacterial endotoxin (LPS, 1 endotoxin unit ϭ 1 IU ϭ 100 pg/ml) and PHA (90 g/ml).”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Results
Not yet classified.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Phenotypic analysis of proliferating lymphocytes identified CD4 ϩ T cells as the principle responding population (ϳ85% of proliferating cells)”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Lymphocyte proliferation
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“In the earlier in vitro studies, i.e., before the clinical trial, TGN1412 was simply added to white blood cells or cross-linked via its Fc region in aqueous solution, protocols that failed to stimulate release of cytokines and cell proliferation in the preclinical testing (10) and in the studies reported here.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Discussion
What the sources say
- Not checked yetcites [10] 2006
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, the responses of Cynomolgus macaque lymphocytes to immobilized TGN1412 plus IL-2 were only ϳ10% of the responses of human lymphocytes to immobilized TGN1412 alone or of Cynomolgus macaque lymphocytes stimulated with mitogen”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Lymphocyte proliferation
Not yet classified.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“When human whole blood at a final dilution of 20% (v/v) was substituted for PBMC, TGN1412 (1.0 and 10 g/well, but not 0.1 g/well) air dried onto the walls of wells in which 20% (v/v) human whole blood was then cultured for 24-h stimulated release of TNF-␣, IL-6, and IL-8”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Results
Not yet classified.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, macaque lymphocytes were activated by immobilized TGN1412 (as shown by the up-regulation of IL-2R expression and blast transformation), confirming binding to and interaction with macaque CD28.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Discussion
Not yet classified.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, the dose of TGN1412 given to volunteers in the clinical trial (0.1 mg/kg) would appear to have been close to the maximum immunostimulatory dose for lymphocyte proliferation.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Discussion
Not yet classified.
- Rests on an assumption: The in vitro concentration of TGN1412 can be converted to an equivalent in vivo dose in humans.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Essentially, TGN1412 is superagonistic in humans but not in Cynomolgus macaques.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, the profound difference in responses of human and macaque lymphocytes to immobilized TGN1412 appears to take place at the level of cell signaling pathways, because TGN1412 binds avidly to and activates CD28 ϩ lymphocytes from Cynomolgus macaques.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Consistent with our data, the superagonistic mouse anti-human CD28 mAb 5.11A1, from which TGN1412 was engineered, markedly stimulated human T cell proliferation in vitro, with a bell-shaped dose-response curve (11)”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Discussion
What the sources say
- Not checked yetcites [11] 2003
Not yet classified.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Obviously, this calculation relies upon an extrapolation from an in vivo dose to an in vitro concentration and, more fundamentally, from an in vivo study in humans to an in vitro study using isolated human white blood cells.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The results of the above experiments are representative of the results of other independent experiments conducted with cells or”
- Also stated in: § Results · plain
“blood from other donors but using different cell densities, incubation times, or other changes in experimental conditions.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Results
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe quote only partly states this claim.
- Also stated in: § Results · plain
In the paper
“As previously reported, human and Cynomolgus macaque CD28 extracellular domains are 100% identical, but this may not exclude functional differences (12).”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Discussion
What the sources say
- Not checked yetcites [12] 2006
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The CD28-specific mAb TGN1412 rapidly caused a life-threatening”
- Also stated in: § A · plain
“All six recipients of the Ab suffered life-threatening severe adverse events, secondary to a”
What the sources say
- Not checked yetcites [1] 2006
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § A · plain
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For human proliferative responses, n ϭ 8.For macaque proliferative responses, n ϭ 8.The data were obtained in two independent experiments.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Discussion
Not yet classified.
In the paper
“Moreover, macaque CD28 differs from human CD28 in three transmembrane residues and it has been suggested that this could alter associations with molecular partners (13).”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Discussion
What the sources say
- Not checked yetcites [13] 2006
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The data were obtained in three independent experiments, each comprising PBMC from different donors: four, four, and three donors, respectively.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Results
Strength:plain· not yet calibratedn = 3Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
The maximum dose of TGN1412 given to macaques was 50 mg/kg, which is 500 times the human dose.
“TGN1412 was injected into volunteers at 0.1 mg/kg and into monkeys at up to the much higher dose of 50 mg/kg, i.e., 500ϫ the human dose.”
The paper relies on this without support.
The in vitro presentation of TGN1412 to PBMC that elicits cytokine release and proliferation mimics the in vivo presentation that caused the clinical toxicity.
“they did not present the Ab to white blood cells in a manner that mimicked its presentation in vivo.”
The paper relies on this without support.
The in vitro concentration of TGN1412 can be converted to an equivalent in vivo dose in humans.
“this calculation relies upon an extrapolation from an in vivo dose to an in vitro concentration and, more fundamentally, from an in vivo study in humans to an in vitro study using isolated human white blood cells.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Subsequent analysis of the TGN1412 used at the trial showed that it was formulated correctly, complied with its product specification and was free from pro-inflammatory contaminants (Duff, 2006;Stebbings et al., 2007).”
From Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T‐cells (2010) · cites this paper as Stebbings et al., 2007
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Significantly, PBMCs from cynomolgus macaques were not stimulated in vitro by immobilized TGN1412 in agreement with the failure of in vivo administration at any dose tested to evoke any adverse response (Duff, 2006;Stebbings et al., 2007).”
From Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T‐cells (2010) · cites this paper as Stebbings et al., 2007
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“However, we previously reported that immobilized TGN1412 primed macaque CD4 + T-cells and that they underwent marked lymphoproliferation only when exogenous IL-2 was added (Stebbings et al., 2007).”
From Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T‐cells (2010) · cites this paper as Stebbings et al., 2007
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Standard in vitro safety tests with human cells were also non-predictive as they did not replicate in vivo presentation of TGN1412.”
From After TGN1412: Recent developments in cytokine release assays (2013) · cites this paper as Stebbings et al., 2007
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Initially a contaminant was suspected of causing the adverse drug responses, but subsequent analysis showed that the trial material was not contaminated and had been correctly formulated (Duff, 2006; Stebbings et al., 2007).”
From After TGN1412: Recent developments in cytokine release assays (2013) · cites this paper as Stebbings et al., 2007
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Moreover, the calculation of a safe starting dose in man based upon pre-clinical safety testing of TGN1412 in cynomolgus macaques was flawed.”
From After TGN1412: Recent developments in cytokine release assays (2013) · cites this paper as Stebbings et al., 2007
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In reality, this dose correlated with 45–80% receptor occupancy in man and a near maximum immunostimulatory dose in vitro (Stebbings et al., 2007; Waibler et al., 2008).”
From After TGN1412: Recent developments in cytokine release assays (2013) · cites this paper as Stebbings et al., 2007
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“It was established that TGN1412 stimulates CD4+ T-cells to undergo lymphoproliferation and release pro-inflammatory cytokines (Stebbings et al., 2007).”
From After TGN1412: Recent developments in cytokine release assays (2013) · cites this paper as Stebbings et al., 2007
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“When standard pre-clinical safety tests were independently repeated, using recovered clinical trial material, no pro-inflammatory cytokine release could be detected either in vitro with human white blood cells or when infused into cynomolgus macaques (Duff, 2006; Stebbings et al., 2007).”
From After TGN1412: Recent developments in cytokine release assays (2013) · cites this paper as Stebbings et al., 2007
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The possibility that this response was an artefact was ruled out by the observation that white blood cells from cynomolgus macaques were not stimulated by TGN1412 in a solid phase assay at any dose 4 . The pro-inflammatory response to TGN1412 was human specific.”
From Severity of the TGN 1412 trial disaster cytokine storm correlated with IL‐2 release (2013) · cites this paper as [4]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“When we investigated other therapeutic mAbs, known to be capable of causing adverse reactions, Mabthera and Campath-1H (Wing et al., 1995;Chung, 2008), using our new in vitro procedures, we did not detect lymphoproliferative responses or IL-2 release, the cardinal features of TGN1412 stimulation (Stebbings et al., 2007).”
From Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T‐cells (2010) · cites this paper as Stebbings et al., 2007
The cited source says what the claim attributes to it.
In the citing paper
“Following the TGN1412 incident, we developed new pre-clinical in vitro procedures using human PBMCs which can be applied to therapeutic mAbs during development, in order to prevent a repeat of the TGN1412 incident (Stebbings et al., 2007;Findlay et al., 2010).”
From Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T‐cells (2010) · cites this paper as Stebbings et al., 2007
The cited source says what the claim attributes to it.
In the citing paper
“Overall, these findings demonstrate that the in vitro safety procedures described by Stebbings et al. (2007) are applicable to other therapeutic mAbs, if IL-2 and IFN-g release are used as biomarkers for a TGN1412-type adverse response.”
From Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T‐cells (2010) · cites this paper as Stebbings et al. (2007)
The cited source says what the claim attributes to it.
In the citing paper
“Because macaque T-cells do not secrete IL-2 when stimulated with TGN1412 (Stebbings et al., 2007), it could be speculated that production of IL-2 by stimulated CD4 + effector memory T-cells is a missing factor required for in vitro lymphoproliferative responses by macaque CD4 + memory T-cells.”
From Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T‐cells (2010) · cites this paper as Stebbings et al., 2007
The cited source says what the claim attributes to it.
In the citing paper
“Central memory CD4 + T-cells are characterized by strong lymphoproliferative responses (Sallusto et al., 1999;2004), which TGN1412 stimulates from human, but not macaque PBMCs (Stebbings et al., 2007).”
From Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T‐cells (2010) · cites this paper as Stebbings et al., 2007
The cited source says what the claim attributes to it.
In the citing paper
“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.”
From After TGN1412: Recent developments in cytokine release assays (2013) · cites this paper as Stebbings et al., 2007
The cited source says what the claim attributes to it.
In the citing paper
“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.”
From After TGN1412: Recent developments in cytokine release assays (2013) · cites this paper as Stebbings et al., 2007
The cited source says what the claim attributes to it.
In the citing paper
“The result of this simple change in presentation was dramatic; massive lymphoproliferation and pro-inflammatory cytokine release that mirrored trial volunteer responses to TGN1412 (Stebbings et al., 2007; Figure 2).”
From After TGN1412: Recent developments in cytokine release assays (2013) · cites this paper as Stebbings et al., 2007
The cited source says what the claim attributes to it.
In the citing paper
“The result of this simple change in presentation was dramatic – massive pro-inflammatory cytokine release and lymphoproliferation that mirrored the responses to TGN1412 observed in trial volunteers 4 .”
From Severity of the TGN 1412 trial disaster cytokine storm correlated with IL‐2 release (2013) · cites this paper as [4]
The cited source says what the claim attributes to it.
In the citing paper
“pre-clinical safety tests, repeated with the same trial material, did not predict an adverse response in man 3 – 4 .”
From Severity of the TGN 1412 trial disaster cytokine storm correlated with IL‐2 release (2013) · cites this paper as [4]
The cited source says what the claim attributes to it.
In the citing paper
“Although the solid phase assay does not replicate in vivo presentation of TGN1412, which is not fully understood, it does induce substantial cytokine release equivalent to that reported in trial volunteers.”
From Severity of the TGN 1412 trial disaster cytokine storm correlated with IL‐2 release (2013) · cites this paper as [4]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Also, a similar cytokine release profile was obtained when TGN1412 (0.1, 1.0, and 10 μ g/well) was added in aqueous solution to a coculture of human PBMCs and endothelial cells.”
From The calm after the cytokine storm: lessons from the TGN1412 trial (2008) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“Interestingly, they could not duplicate these responses using PBMCs from cynomolgus monkeys, suggesting that TGN1412 does not behave the same in nonhuman primate species as in humans.”
From The calm after the cytokine storm: lessons from the TGN1412 trial (2008) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“They found that when TGN1412 (1.0 and 10.0 μ g/well) was air dried on wells and added to human PBMCs, it induced the release of large amounts of TNFα , IL-6, and IL-8.”
From The calm after the cytokine storm: lessons from the TGN1412 trial (2008) · cites this paper as [11]
In the citing paper
“In order for cytokine release to be induced, TGN1412 needs to be artificially immobilized on the plastic surface of the cell culture well [42]”
From The rise and fall of the CD 28 superagonist TGN 1412 and its return as TAB 08: a personal account (2016) · cites this paper as [42]
In the citing paper
“the plastic-immobilization protocol championed by Stebbings and colleagues allowed TGN1412 responses which mirrored the CRS of the phase I study quite well [42], indicating that there are cells present in PBMC capable of responding to TGN1412 with an in vitro cytokine storm, albeit under artificial conditions of antibody presentation.”
From The rise and fall of the CD 28 superagonist TGN 1412 and its return as TAB 08: a personal account (2016) · cites this paper as [42]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Figure 7B gives conflicting units for the peak dose range
MinorThe results give the peak IL-2 response as 0.4-2 g/well, but the Figure 7B caption labels that same range as g/ml. The caption also gives 2-10 g/ml as the corresponding concentration range.
“Peak dose response for human lymphocytes was between 0.4 and 2 g/ml (2-10 g/ml).”
“For IL-2 production measured by intracellular cytokine staining, the optimal dose response of human lymphocytes to immobilized TGN1412 was between 0.4 and 2 g/well (Fig. 7B).”
IL-2 result points to the wrong figure
MinorThe cited Figure 5C-D concerns macaque activation, not the human IL-2 comparison described in the sentence. Figure 6C-D depicts the stated comparison.
“Even higher levels of IL-2 ϩ human lymphocytes were obtained with TGN142 captured in aqueous solution by immobilized anti-human Fc Ab compared with controls (Fig. 5, C and D)”
“Figure: 6 FIGURE 6 . FIGURE 6. Intracellular cytokine staining of human lymphocytes for IL-2 following a 6-h stimulation with (A) negative control, (B) 1 g/well immobilized TGN1412, (C) a combination of 1 g/well aqueous TGN1412 and 1 g/well aqueous anti-human Fc Ab, (D) 1 g/well aqueous TGN1412 captured by 1 g/well immobilized anti-human Fc Ab.”
Citations
Cites
Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412
Suntharalingam, G., Perry, M. R., Ward, S., Brett, S. J., Castello-Cortes, A., Brunner, M. D., & Panoskaltsis, N. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa063842 · Cited by 2,164
Loss of Siglec expression on T lymphocytes during human evolution
Nguyen, D. H., Hurtado-Ziola, N., Gagneux, P., & Varki, A. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510484103 · Cited by 204
Lühder, F., Huang, Y., Dennehy, K. M., Guntermann, C., Müller, I., Winkler, E., Kerkau, T., Ikemizu, S., Davis, S. J., Hanke, T., et al. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20021024 · Cited by 193
Establishing risk of human experimentation with drugs: lessons from TGN1412
Kenter, M., & Cohen, A. (2006) · The Lancet · doi:10.1016/s0140-6736(06)69562-7 · Cited by 153
Givan, A. L., Fisher, J. L., Waugh, M., Ernstoff, M. S., & Wallace, P. K. (1999) · Journal of Immunological Methods · doi:10.1016/s0022-1759(99)00136-2 · Cited by 127
Beyersdorf, N., Hanke, T., Kerkau, T., & Hünig, T. (2005) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2005.042564 · Cited by 84
Hanke, T. (2006) · The Lancet · doi:10.1016/s0140-6736(06)69651-7 · Cited by 65
A rapid ‘one-plate’ in vitro test for pyrogens
Poole, S., Mistry, Y., Ball, C., Das, R. G., Opie, L. P., Tucker, G., & Patel, M. (2003) · Journal of Immunological Methods · doi:10.1016/s0022-1759(02)00519-7 · Cited by 47
Self-citation(2006) · PubMed · Cited by 44
Das, R. G., Brugger, P. C., Patel, M., et al. (2004) · Journal of Immunological Methods · doi:10.1016/j.jim.2004.03.002 · Cited by 37
Self-citation
Flagged first, then by citations
Research works printed but not linked: 14
- 2006, N. Engl. J. Med., 1018
- 2005, European Pharmacopoeia, 161
- 2003, J. Immunol. Methods, 209
- 2004, J. Immunol. Methods, 165
- 2005, European Pharmacopoeia, 152
- 2005, European Pharmacopoeia, 152
- 1999, J. Immunol. Methods, 99
- 2006, J. Rheumatol., 110
- 2005, Ann. Rheum. Dis., iv91
- 2006, Lancet, 1569
- 2003, J. Exp. Med., 949
- 2006, Lancet, 2205
- 2006, Lancet, 1387
- 2006, Proc. Natl. Acad. Sci. USA, 7765
Cited by
Sorted by citations
Items 101–200 of 317
Cryopreservation of human monocytes for pharmacopeial monocyte activation test
Koryakina, A., Frey, E., & Bruegger, P. (2014) · Journal of Immunological Methods · doi:10.1016/j.jim.2014.01.005 · Cited by 34
Kumar, S., Ghosh, S., Sharma, G., et al. (2021) · mAbs · doi:10.1080/19420862.2021.1954136 · Cited by 34
“To determine whether dostarlimab could stimulate T cells in the absence of T-cell receptor (TCR) activation, we tested dostarlimab in a cytokine release assay.(20) In this assay, stimulation of healthy donor PBMCs with anti-CD3 and anti-CD28-coated beads for 48 hours induced a dose-dependent increase in IFN-γ and IL-2…”
MethodDaneshian, M. (2011) · ALTEX · doi:10.14573/altex.2011.4.341 · Cited by 34
Bone marrow-liver-thymus (BLT) immune humanized mice as a model to predict cytokine release syndrome
Yan, H. H., Semple, K. M., Gonzaléz, C. M., & Howard, K. E. (2019) · Translational research · doi:10.1016/j.trsl.2019.04.007 · Cited by 33
Civoli, F., Kasinath, A., Cai, X.-Y., et al. (2019) · The AAPS Journal · doi:10.1208/s12248-019-0386-y · Cited by 32
Self-citationOpal, S. M., & Patrozou, E. (2008) · Critical Care Medicine · doi:10.1097/ccm.0b013e3181921497 · Cited by 32
“The dose administered to these normal volunteers could be expected to produce marked elevations in proinflammatory cytokines (51).”
BackgroundFindlay, L., Eastwood, D., Ball, C., Robinson, C. J., Bird, C., Wadhwa, M., Thorpe, S. J., Thorpe, R., Stebbings, R., & Poole, S. (2011) · Journal of Immunological Methods · doi:10.1016/j.jim.2011.06.022 · Cited by 31
Self-citationBracken, M. B. (2009) · Annals of Epidemiology · doi:10.1016/j.annepidem.2008.11.006 · Cited by 31
Dirks, J., Egli, A., Sester, U., et al. (2012) · Transplant Infectious Disease · doi:10.1111/tid.12025 · Cited by 30
“This knowledge may be of particular clinical relevance, as modulation of costimulatory receptors on T cells may bear the risk of uncontrolled T-cell activation and cytokine storm (10).”
BackgroundImmunogenicity of therapeutics: a matter of efficacy and safety
Nechansky, A., & Kircheis, R. (2010) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2010.514326 · Cited by 30
“The most infamous recent example of the inappropriate use of preclinical animal models lacking the equivalent specificity target molecule was the Phase I clinical trial for TeGenero’s TGN1412 [54], which caused catastrophic systemic organ failure in patients.”
BackgroundLi, Y. H., Carpenito, C., Wang, G., Surguladze, D., Forest, A., Malabunga, M., Murphy, M. Y., Zhang, Y., Sonyi, A., Chin, D., et al. (2018) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-018-0329-7 · Cited by 30
“Using a commercially available multiplex assay based on the Luminex platform (Luminex Corporation, Austin, TX), 21 cytokines including Fractalkine, GM-CSF, IFNγ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17A, IL-21, IL-23, ITAC, MIP-1α, MIP-1β, MIP-3α, and TNF-α were measured in cell cul…”
MethodFindlay, L., Sharp, G., Fox, B., Ball, C., Robinson, C. J., Bird, C., Stebbings, R., Eastwood, D., Wadhwa, M., Poole, S., et al. (2011) · Cytokine · doi:10.1016/j.cyto.2011.03.019 · Cited by 29
“, 4984 ± 940 pg/ml with primary HUVEC and 1 lg/well TGN1412 in 24 h co-cultures) tended to be higher than those induced by TGN1412 immobilised on plastic where, even using maximally optimised conditions, mean levels of around 1300 pg/ml for 10 lg/well were observed ([4,11] and unpublished observations).”
BackgroundInfluentialSelf-citationReed, D. M., Paschalaki, K. E., Starke, R. D., Mohamed, N. A., Sharp, G., Fox, B. J., Eastwood, D., Bristow, A., Ball, C., Vessillier, S., et al. (2015) · The FASEB Journal · doi:10.1096/fj.14-268144 · Cited by 29
“This was despite the drug passing all preclinical safety testing, including tests on human-isolated T lymphocytes (2).”
BackgroundInfluentialSelf-citationCassotta, M. (2019) · ALTEX · doi:10.14573/altex.1910011 · Cited by 31
“A poignant example of this issue was the immunotherapy trial of TGN1412 (targeting CD28 signaling), which caused an unpredicted cytokine storm in six volunteers (Stebbings et al., 2007; Hunig, 2012).”
BackgroundRecombinant antibodies for cancer therapy
Deonarain, M. P. (2008) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.8.8.1123 · Cited by 29
“Despite promising preclinical results, the Phase I clinical trials were disastrous with all six healthy volunteers suffering from life-threatening immune reactions causing a severe cytokine storm release from cells, thus disrupting this intricate balance [82] .”
BackgroundMethodArchibald, K., Coleman, R. A., & Foster, C. D. (2011) · The Lancet · doi:10.1016/s0140-6736(11)60802-7 · Cited by 28
Vandivort, T. C., Horton, D. B., & Johnson, S. B. (2020) · Journal of Clinical and Translational Science · doi:10.1017/cts.2020.493 · Cited by 28
“Subsequent analysis showed that TGN-1412 would have produced a substantial cytokine response in these experiments if it had been directly immobilized onto a cell culture plate, or presented utilizing coculture with an endothelial cell monolayer [29,37,38].”
MethodAutoimmune response to transthyretin in juvenile idiopathic arthritis
Clement, C. C., Moncrieffe, H., Lele, A., et al. (2016) · JCI Insight · doi:10.1172/jci.insight.85633 · Cited by 28
“The best clinical examples of protein aggregate-induced immunogenicity derive from the aggregation of therapeutic proteins (55), which, upon continuous injection, can induce an array of immune responses from the generation of autoantibody and delayed hypersensitivity to cytokine release syndrome and anaphylaxis (57).”
BackgroundQuality Control and Analytical Techniques for Biopharmaceuticals
Robinson, C. J., & Jones, C. (2010) · Bioanalysis · doi:10.4155/bio.10.161 · Cited by 28
Discordant biological and toxicological species responses to TLR3 activation
Mitchell, W. M., Nicodemus, C. F., Carter, W. A., Horvath, J. C., & Strayer, D. R. (2014) · The American Journal of Pathology · doi:10.1016/j.ajpath.2013.12.006 · Cited by 27
“Alternative methods of in vitro analysis, such as demonstrated by Stebbings et al, 36 need to be validated and adapted for regulatory evaluation for human safety.”
MethodAnimal extrapolation in preclinical studies: An analysis of the tragic case of TGN1412
Lemoine, M. (2016) · Studies in History and Philosophy of Science Part C Studies in History and Philosophy of Biological and Biomedical Sciences · doi:10.1016/j.shpsc.2016.12.004 · Cited by 27
Adaptive Evolution as a Predictor of Species-Specific Innate Immune Response
Webb, A. E., Gerek, Z. N., Morgan, C. C., Walsh, T., Loscher, C. E., Edwards, S. V., & O’Connell, M. J. (2015) · Molecular Biology and Evolution · doi:10.1093/molbev/msv051 · Cited by 27
“…is particularly problematic in clinical trials; for example, the anti-inflammatory drug TGN1412 reached clinical trial in 2006 following promising results from testing in crab-eating macaques, but in humans the drug elicited a cytokine storm and multiple organ failure (Stebbings et al. 2007).”
BackgroundInfluentialKizhedath, A., Wilkinson, S. C., & Glassey, J. (2016) · Archives of Toxicology · doi:10.1007/s00204-016-1876-7 · Cited by 29
“In standard cytokine release assays, the mAbs bind to receptors all over the cell which is not an accurate representation of the human systems where cytokine release is sometimes dependent on localized receptor interaction (Stebbings et al. 2007).”
BackgroundHussain, K., Hargreaves, C. E., Rowley, T. F., Sopp, J. M., Latham, K. V., Bhatta, P., Sherington, J., Cutler, R. M., Humphreys, D. P., Glennie, M. J., et al. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00390 · Cited by 27
“In recent years, the limited value of rodent models for predicting treatment responses in humans set inmotion intensive research to establish in vitro assays using human PBMCs; for example to predict the magnitude of cytokine release induced by therapeutic mAb (40).”
BackgroundAntibody engineering to develop new antirheumatic therapies
Isaacs, J. D. (2009) · Arthritis Research & Therapy · doi:10.1186/ar2594 · Cited by 27
“the cytokine storm that underpinned its toxicity [51].”
BackgroundICOS-LICOS interaction is critically involved in TGN1412-mediated T-cell activation
Weissmüller, S., Semmler, L. Y., Kalinke, U., Christians, S., Müller-Berghaus, J., & Waibler, Z. (2012) · Blood · doi:10.1182/blood-2011-12-401083 · Cited by 26
Choudhary, S., Dubey, A., Singh, A., Zamboni, P., Gupta, N., Singh, R., Tisato, V., Aggarwal, L. M., & Gemmati, D. (2025) · Exploration of BioMat-X · doi:10.37349/ebmx.2025.101351 · Cited by 32
Walker, M., Makropoulos, D., Achuthanandam, R., Arsdell, S. V., & Bugelski, P. J. (2011) · International Immunopharmacology · doi:10.1016/j.intimp.2011.06.001 · Cited by 26
“[16], developed an in vitro whole blood assay along with an assay using PBMC.”
BackgroundMethodResultInfluentialPoirier, N., Mary, C., Bas‐Bernardet, S. L., Daguin, V., Belarif, L., Chevalier, M., Hervouet, J., Minault, D., Ville, S., Charpy, V., et al. (2014) · mAbs · doi:10.4161/mabs.28375 · Cited by 26
“Concerning TGN1412, whereas binding affinity for CD28 was similar between cynomolgus macaques and humans,(21,32,33) PBMC from macaques were not stimulated in vitro by immobilized TGN1412, contrary to results with human cells.(24,34) It was first suggested that the differences could be due to the loss of Siglecs inhibi…”
ResultLapteva, M., del Río‐Sancho, S., Wu, E. Q., et al. (2019) · Scientific Reports · doi:10.1038/s41598-018-36966-0 · Cited by 26
Superagonistic CD28 Antibody Induces Donor-Specific Tolerance in Rat Renal Allografts
Azuma, H., Isaka, Y., Li, X., Hünig, T., Sakamoto, T., Nohmi, H., Takabatake, Y., Mizui, M., Kitazawa, Y., Ichimaru, N., et al. (2008) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2008.02358.x · Cited by 26
“This type of cytokine release had not been observed in preclinical studies of TGN 1412 (6,7), and it is currently unclear whether the severe effects of this type of cytokine release in vivo in humans are caused by direct ligation of CD28 on T cells or by interaction with cell types not included in the preclinical in v…”
BackgroundAnti-CD28 Antibody-Initiated Cytokine Storm in Canines
Rosinski, S. L., Storb, R. F., Strong, R. K., Sale, G. E., Stone, D. M., Gewe, M. M., Friend, D. J., Abrams, V. K., Randolph‐Habecker, J., & Graves, S. S. (2015) · Transplantation Direct · doi:10.1097/txd.0000000000000516 · Cited by 25
“Cultures of dog peripheral bloodmononuclear cells (PBMCs) were incubated on antibody-coated tissue culture plates based on described methods.(24,26,27,29,30) The following antibodies were assessed for stimulation: mouse anti-IgG1 isotype”
BackgroundMethodInfluentialMonoclonal antibody therapeutics: Leading companies to maximise sales and market share
Ziegelbauer, K. B., & Light, D. R. (2007) · Journal of Commercial Biotechnology · doi:10.1057/palgrave.jcb.3050081 · Cited by 25
Secreted and Transmembrane 1A Is a Novel Co-Stimulatory Ligand
Howie, D., Rueda, H. G., Brown, M. H., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0073610 · Cited by 25
“SECTM1A, 1A-ExIV, SECTM1B-Fc fusion proteins or Campath-1H as an Fc control with identical human IgG1 aglycosyl Fc region were immobilised by air-drying onto 96 well culture plates as described by Stebbings et al [30].”
MethodD’Cruz, O. J., Qazi, S., Hwang, L., Ng, K., & Trieu, V. N. (2018) · OncoTargets and Therapy · doi:10.2147/ott.s161905 · Cited by 25
How do we assure the quality of biological medicines?
Longstaff, C., Whitton, C. M., Stebbings, R., & Gray, E. (2008) · Drug Discovery Today · doi:10.1016/j.drudis.2008.09.010 · Cited by 25
Self-citationProgresses of T-cell-engaging bispecific antibodies in treatment of solid tumors
Liu, J., & Zhu, J. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.112609 · Cited by 23
Toxicology Paradise: Sorting Out Adverse and Non-adverse Findings in Animal Toxicity Studies
Baldrick, P., Cosenza, M. E., Alapatt, T., Bolon, B. N., Rhodes, M., & Waterson, I. (2020) · International Journal of Toxicology · doi:10.1177/1091581820935089 · Cited by 24
“One reason why it is thought that previous protocols failed to stimulate release of cytokines and lymphocyte proliferation was as a result of TGN1412 being cross-linked via its Fc region in aqueous solution.(14) Phenotypic analysis of proliferating lymphocytes identified CD4þ T-cells as the principle responding popula…”
BackgroundUnlocking the potential of agonist antibodies for treating cancer using antibody engineering
Jhajj, H. S., Lwo, T. S., Yao, E. L., & Tessier, P. M. (2022) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2022.09.012 · Cited by 23
Danilenko, D. M., & Wang, H. (2012) · Toxicologic Pathology · doi:10.1177/0192623311430237 · Cited by 24
Therapeutic Down-Modulators of Staphylococcal Superantigen-Induced Inflammation and Toxic Shock
Krakauer, T. (2010) · Toxins · doi:10.3390/toxins2081963 · Cited by 23
“However, even nonhuman primate models for human disease in drug efficacy Toxins 2010, 2 1972 testing is no guarantee of reproducibility of therapeutic effectiveness as demonstrated by the cytokine storm elicited in phase 1 trial of the monoclonal antibody to CD28 [109].”
InfluentialPreclinical screening for acute toxicity of therapeutic monoclonal antibodies in a hu‐SCID model
Brady, J. L., Harrison, L. C., Goodman, D. J., Cowan, P. J., Hawthorne, W. J., O’Connell, P. J., Sutherland, R. M., & Lew, A. M. (2014) · Clinical & Translational Immunology · doi:10.1038/cti.2014.28 · Cited by 23
Leach, M. W. (2013) · Toxicologic Pathology · doi:10.1177/0192623312451371 · Cited by 22
“The addition of this assay to nonclinical testing of biologics is the result of a clinical trial in which an agonistic anti-CD28 antibody (TGN1412) resulted in severe clinical reactions in all six volunteers that were dosed (Suntharalingam et al. 2006).”
Were monocytes responsible for initiating the cytokine storm in the TGN1412 clinical trial tragedy?
Sandilands, G. P., Wilson, M. R., Huser, C. A. M., Jolly, L., Sands, W. A., & McSharry, C. P. (2010) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2010.04264.x · Cited by 22
Evaluation of a TGN1412 analogue using in vitro assays and two immune humanized mouse models
Yan, H. H., Bhagwat, B., Sanden, D., Willingham, A. T., Tan, A., Knapton, A. D., Weaver, J. L., & Howard, K. E. (2019) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2019.03.020 · Cited by 22
Antibody C Region Influences TGN1412-like Functional Activity In Vitro
Ball, C., Fox, B. J., Hufton, S. E., Sharp, G., Poole, S., Stebbings, R., Eastwood, D., Findlay, L., Parren, P. W. H. I., Thorpe, R., et al. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1201795 · Cited by 22
“Previous in vitro studies have shown that in solution, TGN1412 has no detectable biological activity as measured by stimulation of cytokine release from PBMCs and requires some form of immobilization such as nonspecific adsorption to plastic surfaces or the presence of endothelial cells (HUVECs) (6, 12).”
BackgroundSelf-citationDevelopment of Antibody-Based Therapeutics
Tabrizi, M. A., Klakamp, S. L., & Bornstein, G. G. (2012) · Springer eBooks · doi:10.1007/978-1-4419-5955-3 · Cited by 23
Analysis of Pro-inflammatory Cytokine and Type II Interferon Induction by Nanoparticles
Potter, T. M., Neun, B. W., Rodriguez, J. C., et al. (2017) · Methods in molecular biology · doi:10.1007/978-1-4939-7352-1_15 · Cited by 21
Matas‐Céspedes, A., Brown, L., Mahbubani, K. T. A., Bareham, B. R., Higgins, J., Curran, M., de Haan, L., Lapointe, J., Stebbings, R., & Saeb‐Parsy, K. (2020) · Clinical & Translational Immunology · doi:10.1002/cti2.1202 · Cited by 21
Self-citationRunnels, H. A., Weber, G. L., Min, J., Kudlacz, E. M., Zobel, J., Donovan, C. B., Thiede, M. A., Zhang, J., Alpert, R., Salafia, M. A., et al. (2010) · Advances in Therapy · doi:10.1007/s12325-010-0010-0 · Cited by 21
Moore, G. L., Zeng, V. G., Diaz, J. E., Bonzon, C., Avery, K. N., Rashid, R., Qi, J., Nam, D. H., Jacinto, J. M., Dragovich, M. A., et al. (2024) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-24-0327 · Cited by 20
Vessillier, S., Fort, M. M., O’Donnell, L. M., Hinton, H. J., Nadwodny, K. L., Piccotti, J. R., Rigsby, P., Staflin, K., Stebbings, R., Mekala, D. J., et al. (2020) · Cytokine X · doi:10.1016/j.cytox.2020.100042 · Cited by 20
“It has been previously shown that the response to TGN1412 was dependent of FcγR cross-linking, which can be artificially simulated by SP presentation [5,25] or be induced by cell contact-dependent priming Table 5 Variance analysis of PBMC assay, SP presentation, combined 24 & 48 h time points (7 participants, 61 donor…”
BackgroundMethodSelf-citationA simple whole blood bioassay detects cytokine responses to anti-CD28SA and anti-CD52 antibodies
Bailey, L. K., Moreno, L., Manigold, T., Krasniqi, S., Kropshofer, H., Hinton, H. J., Singer, T., Suter‐Dick, L., Hansel, T. T., & Mitchell, J. A. (2012) · Journal of Pharmacological and Toxicological Methods · doi:10.1016/j.vascn.2012.12.003 · Cited by 18
“The mechanism by which immobilised or endothelial cell-presented TGN1412 and PBMCs interact or the specific cell types involved in TGN1412 responses has been addressed by others (Eastwood et al., 2010; Findlay et al., 2010, 2011; Hansel et al., 2010; Stebbings et al., 2007; Walker et al., 2011).”
BackgroundInfluentialICH S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals
Cavagnaro, J. A., & Sims, J. (2013) · AAPS advances in the pharmaceutical sciences series · doi:10.1007/978-1-4614-5950-7_10 · Cited by 18
David, C. A. W., Barrow, M., Murray, P. A., Rosseinsky, M. J., Owen, A., & Liptrott, N. J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165610 · Cited by 18
“The cytokine storm to this drug was not observed in the preclinical studies performed in rats and cynomolgus monkeys [4], but would have been detected using an in vitro cytokine release assay in primary human blood [8].”
MethodMatsumoto, M., Polli, J. R., Swaminathan, S. K., Datta, K., Kamperschroer, C., Fortin, M. C., Salian‐Mehta, S., Dave, R. A., Yang, Z., Arora, P., et al. (2024) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.3316 · Cited by 19
“16,17 With the soluble CR assay format, drug concentrations are readily available and the no-effect levels for CR can potentially be used to convert to a dose as part of consideration for the FIH starting dose selection, if appropriate based on MOA.”
Immune‐related adverse events of antibody‐based biological medicines in cancer therapy
Rajagopal, D., MacLeod, E., Corogeanu, D., & Vessillier, S. (2024) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.18470 · Cited by 20
“156,157 In addition, preclinical in vitro assays employing human cells stimulated with TGN1412 in aqueous phase did not replicate the in vivo presentation that involves coreceptor cross-linking at the immunological synapse.”
BackgroundSchmohl, M., Schneiderhan‐Marra, N., Baur, N., et al. (2012) · International Immunopharmacology · doi:10.1016/j.intimp.2012.10.010 · Cited by 17
Fletcher, E. A. K., Eltahir, M., Lindqvist, F., Rieth, J., Törnqvist, G., Leja-Jarblad, J., & Mangsbo, S. M. (2017) · International Immunopharmacology · doi:10.1016/j.intimp.2017.10.021 · Cited by 17
“Although, the mechanism of crosslinking TGN1412 in the loop system is unknown, IL-2 was released in the loop system more rapidly than in what was described in vitro plate assays with both diluted [35] and minimally diluted whole blood [36].”
BackgroundMedina, M. Á., Couturier, J. P., Feske, M. L., Mahne, A. E., Turner, M. A., Yu, X., Kozinetz, C. A., Orozco, A. F., Hutchison, A. T., Savidge, T., et al. (2012) · Journal of Leukocyte Biology · doi:10.1189/jlb.0511264 · Cited by 17
Rasool, G., Riaz, M., Abbas, M., Fatima, H., Qamar, M. M., Zafar, F., & Mahmood, Z. (2022) · International Journal of Immunopathology and Pharmacology · doi:10.1177/03946320221115316 · Cited by 16
An Examination of Chimpanzee Use in Human Cancer Research
Bailey, J. (2009) · Alternatives to Laboratory Animals · doi:10.1177/026119290903700410 · Cited by 16
“Though tested in rhesus and cynomolgus monkeys and not chimpanzees, TGN1412 induced a systemic inflammatory response in all six volunteers taking it in first-inhuman trials, despite being administered at a subclinical dose some 500 times lower than the dose found to be safe in animals (194).”
BackgroundChen, L., Qian, W., Pan, F., Li, D., Yu, W., Li, T., Yang, Y., Xu, Q., Ding, J., Dai, R., et al. (2023) · Immunotherapy · doi:10.2217/imt-2023-0256 · Cited by 16
Singh, M., Basu, S., Camell, C. D., Couturier, J. P., Nudelman, R. J., Medina, M. Á., Rodgers, J. R., & Lewis, D. E. (2008) · European Journal of Immunology · doi:10.1002/eji.200737929 · Cited by 15
Predicting cytokine storms: it's about density
Frigault, M. J., & June, C. H. (2011) · Blood · doi:10.1182/blood-2011-10-382598 · Cited by 14
Ethical considerations and challenges in first-in-human research
Koonrungsesomboon, N., Laothavorn, J., & Karbwang, J. (2016) · Translational research · doi:10.1016/j.trsl.2016.05.006 · Cited by 16
Impact of tissue penetration and albumin binding on design of T cell targeted bispecific agents
Kopp, A., Kwon, H., Johnston, C. M., Vance, S., Legg, J. W., Galson-Holt, L., & Thurber, G. M. (2024) · Neoplasia · doi:10.1016/j.neo.2023.100962 · Cited by 15
Zhou, Y. N., Gou, L., GUO, Z.-H., LIU, H.-R., WANG, J.-M., Zhou, S., Yang, J., & Li, X. (2015) · Molecular Medicine Reports · doi:10.3892/mmr.2015.3441 · Cited by 13
“The anti‐CD28 agonist antibody (TGN1412) has received attention due to its marked adverse reactions in Phase I clinical trials (27).”
BackgroundRoepcke, S., Plock, N., Yuan, J. J., Fedyk, E. R., Lahu, G., Zhao, L., & Smithson, G. M. (2018) · Pharmacology Research & Perspectives · doi:10.1002/prp2.402 · Cited by 13
“0003 mg/kg for the FIH trial.(6,24) Using data from preclinical studies,(22,23) we determined NK cell depletion as one of the most sensitive biological effects of TAK-079.”
MethodColeman, R. A. (2011) · ISRN Pharmaceutics · doi:10.5402/2011/806789 · Cited by 13
Fundamentals of Clinical Immunotoxicology
House, R. V. (2009) · Methods in molecular biology · doi:10.1007/978-1-60761-401-2_24 · Cited by 13
Gouty, D., Cai, C. C., Cai, X. Y., Kasinath, A., Kumar, V., Alvandkouhi, S., Yang, J., Pederson, S., Babbitt, B., Peritt, D., et al. (2017) · The AAPS Journal · doi:10.1208/s12248-017-0181-6 · Cited by 13
Human-like Response of Pig T Cells to Superagonistic Anti-CD28 Monoclonal Antibodies
Uehlein, S., Ding, X., Flößer, J., Schmidt, S., Steitz, J., Bille, M., Schnitter, F., Baltes, S., Saalmüller, A., Gerner, W., et al. (2021) · The Journal of Immunology · doi:10.4049/jimmunol.2100174 · Cited by 12
CD28 ligation increases macrophage suppression of T-cell proliferation
Silberman, D., Bucknum, A., Bartlett, T. M., Composto, G. M., Kozlowski, M., Walker, A., Werda, A., Cua, J., Sharpe, A. H., Somerville, J. E., et al. (2012) · Cellular and Molecular Immunology · doi:10.1038/cmi.2012.13 · Cited by 12
Papotto, P. H., Marengo, E. B., Sardinha, L. R., Carvalho, K. I., de Carvalho, A. E. Z., Castillo-Méndez, S. I., Jank, C. C., Vanhove, B., Goldberg, A. C., & Rizzo, L. V. (2017) · PLoS ONE · doi:10.1371/journal.pone.0171822 · Cited by 12
Majocchi, S., Lloveras, P., Nouveau, L., Legrand, M., Viandier, A., Malinge, P., Charreton, M., Raymond, C., Pace, E. A., Millard, B. L., et al. (2025) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-24-0298 · Cited by 12
“1B ), NI-3201 had no SA in the Stebbings assay (25), independent of the way the antibody was coated onto plates (Supplementary Fig.”
InfluentialNonclinical Tools to Assess Risk of Drug Hypersensitivity Reactions
Whritenour, J., Casinghino, S. R., Collinge, M., & Zhu, X. (2015) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010715-103354 · Cited by 10
Thaventhiran, T., Alhumeed, N., Yeang, H. X., Sethu, S., Downey, J. S., Alghanem, A. F., Olayanju, A., Smith, E., Cross, M. J., Webb, S. D., et al. (2014) · mAbs · doi:10.4161/mabs.29758 · Cited by 11
“TGN1412 is a CD28SA that caused an uncontrolled expansion of T cells with an accompanying cascade of proinflammatory cytokine release and infiltration of T cells into tissues, in all six healthy volunteers enrolled in a phase I clinical study.(3,4) Despite initial recovery, their conditions deteriorated and this may b…”
BackgroundSelf-citationRegulatory Forum Opinion Piece*
Lebrec, H. N. (2012) · Toxicologic Pathology · doi:10.1177/0192623312455526 · Cited by 11
“…TGN1412 in cynomolgus macaques did not predict the lifethreatening ‘‘cytokine storm’’ observed in all six healthy volunteers in the phase I clinical trial of this superagonist, partly because CD28 is not expressed on effector memory T cells in macaques (Stebbings et al. 2007; Eastwood et al. 2010).”
BackgroundAntibodies: monoclonal and polyclonal
Singh, A. K., Mishra, A., & Verma, A. (2020) · Animal Biotechnology · doi:10.1016/b978-0-12-811710-1.00015-x · Cited by 11
Breaking down the barriers to animal-free research
Hope, L., & Bailey, J. (2025) · Alternatives to Laboratory Animals · doi:10.1177/02611929251349465 · Cited by 12
“127,128 Furthermore, some animal studies cannot be replicated, and this can be due to incomplete experimental reporting, 129 lack of blinding, 130,131 low statistical power and in some cases inadequate statistical analyses.”
Fu, K., Cheng, Q., Liu, Z., Chen, Z., Wang, Y., Ruan, H., Zhou, L., Xiong, J., Xiao, R., Liu, S., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0104426 · Cited by 10
“have reported that PBMCs could efficiently predict the speciesspecific activity, immunogenicity or immunotoxicity of monoclonal antibodies (mAbs) and vaccines in preclinical safety testing [23,25].”
BackgroundScreening vaccine formulations for biological activity using fresh human whole blood
Brookes, R. H., Hakimi, J., Ha, Y., Aboutorabian, S., Ausar, S. F., Hasija, M., Smith, S. G., Todryk, S. M., Dockrell, H. M., & Rahman, N. (2014) · Human Vaccines & Immunotherapeutics · doi:10.4161/hv.27657 · Cited by 10
Singh, A., Chaudhary, S., Agarwal, A., et al. (2013) · Animal Biotechnology · doi:10.1016/b978-0-12-416002-6.00015-8 · Cited by 10
Human Fcγ receptors compete for TGN1412 binding that determines the antibody's effector function
Dudek, S., Weißmüller, S., Anzaghe, M., Miller, L., Sterr, S., Hoffmann, K., Hengel, H., & Waibler, Z. (2019) · European Journal of Immunology · doi:10.1002/eji.201847924 · Cited by 10
Xu, C., Meng, X., Chai, P., Liu, H., Duan, Z., Tsai, Y., & Wu, C. (2025) · Analytical Chemistry · doi:10.1021/acs.analchem.4c05681 · Cited by 9
Immune inhibitory receptor agonist therapeutics
Lovewell, R. R., Langermann, S., & Flies, D. B. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1566869 · Cited by 9
Ahmetaj‐Shala, B., Kawai, R., Marei, I., et al. (2019) · The FASEB Journal · doi:10.1096/fj.201901379rr · Cited by 9
Targeting CD28 to prevent transplant rejection
Yeung, M. Y., Najafian, N., & Sayegh, M. H. (2013) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2014.863875 · Cited by 9
“In hindsight, it is now clear that CD4 effector memory cells were predominantly responsible for the rapid release of cytokines [131,132].”
BackgroundRegulating interface science healthcare products: myths and uncertainties
Bravery, C. A. (2010) · Journal of The Royal Society Interface · doi:10.1098/rsif.2010.0442.focus · Cited by 9
Animal Research Is an Ethical Issue for Humans as Well as for Animals
Archibald, K. (2018) · Journal of Animal Ethics · doi:10.5406/janimalethics.8.1.0001 · Cited by 11
“…men” volunteers in 2006, after being declared completely safe at 500 times the dose in crab-eating ma- JAnE 8_1 text.indd 3 2/26/18 10:41 AM caques (stebbings et al., 2007). in January 2016, a man was killed in a Phase 1 clinical trial in france by a dose of a test drug 400 times smaller…”
BackgroundAdjuvants for Protein‐ and Carbohydrate‐Based Vaccines
Guy, B. (2008) · doi:10.1002/9780470473283.ch3 · Cited by 9
The application of human tissue for drug discovery and development
Clotworthy, M. (2012) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2012.689282 · Cited by 10
“For instance, cytokine release syndrome (such as resulted when Phase I volunteers were administered the experimental immunomodulator TGN 1412 in 2006) can now be modelled using assays on cells extracted from donated blood [20,21].”
MethodAnalysis of cytokine release assay data using machine learning approaches
Xiong, F., Janko, M., Walker, M., Makropoulos, D., Weinstock, D., Kam, M., & Hrebien, L. (2014) · International Immunopharmacology · doi:10.1016/j.intimp.2014.07.024 · Cited by 8
“These adverse events were not predicted by pre-clinical safety assessments using animal testing of the drugs [4].”
BackgroundCzerwiński, M., Kazmi, F., Parkinson, A., et al. (2014) · Drug Metabolism and Disposition · doi:10.1124/dmd.114.060186 · Cited by 8
“1-mg/kg dose of TGN1412 given to human volunteers (Stebbings et al., 2007).”
BackgroundMyers, L. P. (2018) · Methods in molecular biology · doi:10.1007/978-1-4939-8549-4_2 · Cited by 8
Elsayed, A., Pellegrino, C. E., Plüss, L., Peissert, F., Benz, R., Ulrich, F., Thorhallsdottir, G., Plaza, S. D., Villa, A., Mock, J., et al. (2023) · mAbs · doi:10.1080/19420862.2023.2220839 · Cited by 9
“A limitation of the in vitro superagonistic assay is that the mAbs had to be artificially coated on a solid support.(53) Alternatively, humanized NSG mice have been shown to be sensitive to predicting the toxicity of immunotherapeutic agents, including TGN1412, retrospectively.”
BackgroundTumor-targeting CTL expressing a single-chain Fv specific for VEGFR2
Kanagawa, N., Yanagawa, T., Mukai, Y., Yoshioka, Y., Okada, N., & Nakagawa, S. (2010) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2010.02.085 · Cited by 7
“Additionally, CD28-specific superagonistic mAb reportedly caused a life-threatening side effect, ‘‘cytokine storm”, in healthy volunteers in clinical trials [25,26].”
BackgroundIwata, Y., Harada, A., Hara, T., Kubo, C., Inoue, T., Tabo, M., Ploix, C. C., Manigold, T., Hinton, H. J., & Mishima, M. (2016) · The Journal of Toxicological Sciences · doi:10.2131/jts.41.523 · Cited by 7
“The assay format using immobilized mAb and PBMC provided much higher cytokine responses from antiCD28 mAb (Stebbings et al., 2007).”
MethodInfluentialStrohl, W. R. (2011) · Modecular medicine and medicinal · doi:10.1142/9781848166295_0005 · Cited by 13
Metadata
- Authors
- Stebbings, R., Findlay, L., Edwards, C., Eastwood, D., Bird, C., North, D., Mistry, Y., Dilger, P., Liefooghe, E., Cludts, I., Fox, B., Tarrant, G., Robinson, J., Meager, T., Dolman, C., Thorpe, S. J., Bristow, A., Wadhwa, M., Thorpe, R., & Poole, S.
- Affiliations
- National Institute for Biological Standards and Control (GB)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-09-01
- Volume
- 179
- Issue
- 5
- Pages
- 3325-3331
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1705666194
- Semantic Scholar
- eacb1c28d1345a05916a17b7d8cf11667ce5c89c
- Cited by
- 316
- References
- 13
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 17 · 2023: 11 · 2022: 8 · 2021: 6 · 2020: 17 · 2019: 14 · 2018: 14 · 2017: 14 · 2016: 17 · 2015: 18 · 2014: 24 · 2013: 24 · 2012: 30
- FWCI
- 8.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Royal Veterinary College
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- TGN1412, cytokine release syndrome, superagonists, preclinical safety, immunotherapeutics, lymphocyte proliferation, in vitro toxicity testing, non-human primates, dose-limiting toxicity
- MeSH terms
- Animals, Antibodies, Monoclonal, Drug Evaluation, Preclinical, Humans, Immunotherapy, Leukocytes, Mononuclear, Lymphocyte Activation, Macaca fascicularis, Cytokines, Clinical Trials, Phase I as Topic, Cell Proliferation, Antibodies, Monoclonal, Humanized
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-09-28, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-09-28 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
