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"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.
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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
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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
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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
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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
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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
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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
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- 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
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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
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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.
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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.”
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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
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Self-citation
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Sorted by citations
Items 201–300 of 317
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Tribodies: Fab–scFv Fusion Proteins as a Platform to Create Multifunctional Pharmaceuticals
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“IBI37G5 induces a bell-shaped dose response in vitro In the Jurkat reporter assay, we observed that when the concentration of IBI37G5 (or GITRL trimer) exceeded that of peak activity, the NF-kB signal began to decrease rather than reaching a plateau, presenting a bell-shaped response that is reminiscent of some previo…”
BackgroundAhmed, S. S., Ahmed, M. M., Ishaq, A., Freer, M., Stebbings, R., & Dickinson, A. M. (2024) · Toxics · doi:10.3390/toxics12060401 · Cited by 6
“This is illustrated by the work of Stebbings et al. (2007) [20], where they compared several protocols to assess cytokine release, with the most successful being when TGN1412 was immobilized on endothelial cells and demonstrated that the simple interaction of TGN1412 with peripheral blood…”
MethodResultSelf-citationA pharmacologic perspective on newly emerging T ‐cell manipulation technologies
Smethurst, D. P. (2012) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2012.04475.x · Cited by 6
Les complications « toxiques » liées à l’utilisation des anticorps monoclonaux
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“25, décembre 2009 1133 SY NT HÈ SE RE VU ES soluble du TGN1412 en présence à la fois de lymphocytes et de cellules endothéliales humaines [16].”
BackgroundEvans, E. W. (2013) · Toxicologic Pathology · doi:10.1177/0192623313513075 · Cited by 6
Preclinical Studies of Pf-04849285, An Interferon-α8 Fusion Protein for the Treatment of HCV
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“In in vitro tests to predict cytokine release, PF-04849285 showed the induction of clinically acceptable levels of IL-6 and no significant cytokine release in a solid phase cytokine release assay [37].”
BackgroundCritical Aspects of Integrated Nonclinical Drug Development
Koch, E., & Plassmann, S. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-803620-4.00002-5 · Cited by 6
First-in-human trials with therapeutic proteins: regulatory rethink?
Schneider, C. K. (2008) · Expert Review of Clinical Pharmacology · doi:10.1586/17512433.1.3.327 · Cited by 6
Treating to re-establish tolerance in inflammatory arthritis – lessons from other diseases
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Novel hematopoietic progenitor kinase 1 inhibitor KHK-6 enhances T-cell activation
Ahn, M., Kim, E. H., Choi, Y., Chae, C. H., Kim, P., & Kim, S. H. (2024) · PLoS ONE · doi:10.1371/journal.pone.0305261 · Cited by 7
Translational immunotoxicology of immunomodulatory monoclonal antibodies
Brennan, F. R., & Kießling, A. (2016) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2016.08.002 · Cited by 5
Predicting Human Adverse Drug Reactions from Nonclinical Safety Studies
Valentin, J., Keisu, M., & Hammond, T. G. (2010) · Wiley eBooks · doi:10.1002/9780470571224.pse203 · Cited by 11
Correction: 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/annotation/4d1054ad-beef-4fb2-9e53-815a58863fe2 · Cited by 5
CD28 Family and Chronic Rejection: “To Belatacept...and Beyond!”
da Silva, M. V., Machado, J. R., Rocha, L. P., Castellano, L. R. C., dos Reis, M. A., & Corrêa, R. R. M. (2012) · Journal of Transplantation · doi:10.1155/2012/203780 · Cited by 4
“Conversely, a clinical trial adopting this strategy showed that the administration of anti-CD28 in six volunteers initiated a systemic inflammatory response [139], probably due to a huge secretion of proinflammatory cytokines by stimulated T-cells [140].”
BackgroundKizhedath, A., Wilkinson, S. C., & Glassey, J. (2018) · Antibodies · doi:10.3390/antib7030030 · Cited by 4
“Stebbings, R.; Findlay, L.; Edwards, C.; Eastwood, D.; Bird, C.; North, D.; Mistry, Y.; Dilger, P.; Liefooghe, E.; Cludts, I.; et al. “Cytokine storm” in the phase I trial of monoclonal antibody TGN1412: better understanding the causes to improve preclinical testing of immunotherapeutics.”
BackgroundAdvances in the development and use of human tissue-based techniques for drug toxicity testing
Clotworthy, M., & Archibald, K. (2013) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2013.802770 · Cited by 4
Highly sensitive in vitro cytokine release assay incorporating high-density preculture
Ito, S., Miwa, K., Hattori, C., Aida, T., Tsuchiya, Y., & Mori, K. (2021) · Journal of Immunotoxicology · doi:10.1080/1547691x.2021.1984617 · Cited by 4
“…peripheral blood mononuclear cells (PBMC) have become common in vitro assay systems to predict the risk of clinically relevant CRS because in vivo and in vitro animal studies failed to predict this risk (Stebbings et al. 2007; Eastwood et al. 2010; Hansel et al. 2010; Pallardy and Hunig 2010).”
BackgroundMadsen, N. H., Gad, M., & Larsen, J. (2022) · Journal of Immunological Methods · doi:10.1016/j.jim.2022.113231 · Cited by 4
Interactions of human IgGs with non-human systems
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Efficacy and safety of new medicines: a human focus
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Perspective of using in vitro models to understand immunotherapy-induced cytokine release syndrome
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Transfer from Research/Academia to Clinical/Regulated
Chowdhury, F., & Williams, A. P. (2016) · Bioanalysis · doi:10.4155/bio-2016-4994 · Cited by 3
Chakrabarti, S., & Jaiswal, S. R. (2023) · Frontiers in Hematology · doi:10.3389/frhem.2023.1243247 · Cited by 3
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“This was an unexpected result since the CD28 receptor is homologous between macaques and humans and the unexpected toxicity in clinical trial volunteers prompted extensive subsequent investigation [38].”
ResultAssessing agonistic potential of a candidate therapeutic anti-IL21R antibody
Guo, Y., Hill, A. A. V., Ramsey, R., et al. (2010) · Journal of Translational Medicine · doi:10.1186/1479-5876-8-50 · Cited by 3
“[14] also induced robust secretion of cytokine storm-associated proteins (Figures 3 and 4 respectively).”
BackgroundMethodInfluentialBiotherapeutic first-in-human dose selection: making use of preclinical markers
Johnson, D. E. (2010) · Expert Review of Clinical Pharmacology · doi:10.1586/ecp.10.5 · Cited by 3
Stančič, B., Qvarfordt, B., Berglund, M. M., Brenden, N., Sydow‐Báckman, M., Fransson, M. E., Nordling, S., & Magnusson, P. U. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.107237 · Cited by 3
“…blood assays show greater sensitivity to alemtuzumab-induced cytokine release, which is supposed to be triggered by the Fc portion of the mAb, while PBMC-based assays are more sensitive in predicting the cytokine response to anti-CD28 stimuli (e.g. TGN1412), where CRS is target mediated [8,14].”
InfluentialPreclinical Safety Considerations for the Development of Antibody-Based Therapeutics
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“Furthermore, in retrospect, the lack of a proliferative response of NHP-derived T cells to TGN1412 relative to human T cells should have been a concern and points toward the NHP not being a relevant species (Stebbings et al. 2007).”
BackgroundDifferentiation between Desired Immunomodulation and Potential Immunotoxicity
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“Endothelial cells were derived from a pooled stock of HUVEC jr2 cells [23].”
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“Importantly, Fc-silent noncrosslinking reagents do not elicit cytokine release, unlike the earlier Fc-containing anti-CD28 TGN1412 (18, 19).”
BackgroundOptimising the Development of Antibodies as Treatment for Cancer
Carden, C. P., Arkenau, H., & Bono, J. S. D. (2010) · Springer eBooks · doi:10.1007/978-1-4419-7358-0_19 · Cited by 3
“Extreme cytokine reactions have been seen in the TGN1424 case, as discussed below [57].”
BackgroundImmunotoxicology: A Brief History
Hastings, K. L. (2018) · Methods in molecular biology · doi:10.1007/978-1-4939-8549-4_1 · Cited by 2
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Self-citationStirred Tank Reactors for Cell Culture Technology
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Current Needs for New Therapeutic Agents and Discovery Strategies—A Systems Pharmacology Approach
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“The assay was based on features identified to improve assay sensitivity [27–29] for the human CD28 superagonist, TGN1412.”
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Antibody-Like Molecules Designed for Superior Targeting and Pharmacokinetics
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Early De-risking Strategy for Novel Biotherapeutics
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Immunotoxicology of Biopharmaceutics
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“Although this is obviously not required in the context of a potential biosimilar, we performed a cytokine release assay (CRA) to explore the potential modulation induced ex vivo by trastuzumab complexes on FcγRIII positive cells and its correlation with clinical observations 15–20 .”
Howick, J., Lantos, J. D., Treweek, S. P., Svobodová, M., Jacob, N., Edwards, A., Bostock, J., Bower, P., Gillies, K., & Hood, K. (2025) · Trials · doi:10.1186/s13063-025-08824-8 · Cited by 1
“Sometimes, serious unexpected harms are also discovered [26].”
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ICH S8: History and Perspectives
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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
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