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.
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47 Own result · 15 Own interpretation · 9 Not checked yet · 4 Own method
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“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
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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
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plain- Asserted: passes — The authors put it forward as true.
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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
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It 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.
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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
plain- Asserted: passes — The authors put it forward as true.
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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
plain- Asserted: passes — The authors put it forward as true.
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- 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.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plain- Asserted: passes — The authors put it forward as true.
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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
“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.
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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
plain- Asserted: passes — The authors put it forward as true.
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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
“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
plain- Asserted: passes — The authors put it forward as true.
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It 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
plaindirect- Asserted: passes — The authors put it forward as true.
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The 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.
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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
plain- Asserted: passes — The authors put it forward as true.
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It 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
plain- Asserted: passes — The authors put it forward as true.
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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
“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
plaindirect- Asserted: passes — The authors put it forward as true.
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It 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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It 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
plaindirect- Asserted: passes — The authors put it forward as true.
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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 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
plain- Asserted: passes — The authors put it forward as true.
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The 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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It 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
plaindirectn = 6- Asserted: passes — The authors put it forward as true.
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It 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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably 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
plainn = 3- Asserted: passes — The authors put it forward as true.
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Probably 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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Discussion
“Peak dose response for human lymphocytes was between 0.4 and 2 g/ml (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 > Dose responses to TGN1412
“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).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ "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
“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)”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Discussion
“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
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
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The safety and side effects of monoclonal antibodies
Hansel, T. T., Kropshofer, H., Singer, T., Mitchell, J. A., & George, A. J. T. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3003 · Cited by 1,185
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Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo
Labrijn, A. F., Buijsse, A. O., van den Bremer, E. T. J., Verwilligen, A., Bleeker, W. K., Thorpe, S. J., Killestein, J., Polman, C. H., Aalberse, R. C., Schuurman, J., et al. (2009) · Nature Biotechnology · doi:10.1038/nbt.1553 · Cited by 297
Self-citationEastwood, D., Findlay, L., Poole, S., Bird, C., Wadhwa, M., Moore, M., Burns, C., Thorpe, R., & Stebbings, R. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00922.x · Cited by 300
“Consistent with the release of IL-2, only in vitro stimulation with TGN1412 resulted in a lymphoproliferative response (data not shown), as previously described (Stebbings et al., 2007).”
BackgroundMethodResultInfluentialSelf-citationMarx, U. (2016) · ALTEX · doi:10.14573/altex.1603161 · Cited by 295
“…1965; Woollam, 1965; Bauer et al.,1998; Stephens and Fillmore, 2000 Somia and Verma, 2000; Edwards, 2004 Dieppe et al., 2004; Arbor, 2004 Clair, 2008; Stebbings et al., 2012 Jouan, 2016; Mileni et al., 2008 Adverse Outcome Pathway / Mode of Action It was administered as a sleeping pill and an…”
Safety and immunotoxicity assessment of immunomodulatory monoclonal antibodies
Brennan, F. R., Morton, L. D., Spindeldreher, S., Kiessling, A., Allenspach, R., Hey, A., Müller, P., Frings, W., & Sims, J. (2010) · mAbs · doi:10.4161/mabs.2.3.11782 · Cited by 250
“In subsequent experiments TGN1412 did stimulate pro-inflammatory cytokine release in either PBMC or 1:5 diluted whole blood test systems if the antibody was immobilized by air drying to plastic or anti-Fc antibody capture, or if the antibody was added in aqueous phase in the presence of endothelial cells.(52) Addition…”
BackgroundMethodPharmacokinetics and toxicology of therapeutic proteins: Advances and challenges
Vugmeyster, Y. (2012) · World Journal of Biological Chemistry · doi:10.4331/wjbc.v3.i4.73 · Cited by 252
Rhode, P. R., Egan, J. O., Xu, W. V., Hong, H., Webb, G. M., Chen, X., Liu, B., Zhu, X., Wen, J., You, L., et al. (2015) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-15-0093-t · Cited by 225
“However, recent evidence showed that these animal models alone may not be sufficient to predict the safety profiles of immunomodulatory molecules in humans (35, 44).”
BackgroundMethodOnly humans have human placentas: molecular differences between mice and humans
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“Neutralization efforts using monoclonal antibodies targeting TGF-b and TGF-bRII(15) have been reported, but systemic inhibition of a multifactorial molecule and potent immune response modifier such as TGF-b will likely have unpredictable adverse consequences.(17) The alternative strategy of targeting the inhibition of…”
BackgroundChallenges and approaches for the development of safer immunomodulatory biologics
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Marx, U., Walles, H., Hoffmann, S., Lindner, G., Horland, R., Sonntag, F., Klotzbach, U., Sakharov, D. A., Tonevitsky, A., & Lauster, R. (2012) · Alternatives to Laboratory Animals · doi:10.1177/026119291204000504 · Cited by 179
Inflammatory findings on species extrapolations: humans are definitely no 70-kg mice
Leist, M., & Härtung, T. (2013) · Archives of Toxicology · doi:10.1007/s00204-013-1038-0 · Cited by 165
“Prominent examples of case studies that suggest poor predictivity are the experience with thalidomide, or with the TG1412 drug candidate, which caused terrible effects in man that had not been predicted from the available animal data (Stebbings et al. 2007).”
BackgroundMonoclonal antibody-induced cytokine-release syndrome
Bugelski, P. J., Achuthanandam, R., Capocasale, R. J., Treacy, G., & Bouman‐Thio, E. (2009) · Expert Review of Clinical Immunology · doi:10.1586/eci.09.31 · Cited by 163
Römer, P. S., Berr, S., Avota, E., Na, S.-Y., Battaglia, M., ten Berge, I., Einsele, H., & Hünig, T. (2011) · Blood · doi:10.1182/blood-2010-12-319780 · Cited by 153
Hinner, M. J., Aiba, R. S. B., Jaquin, T. J., Berger, S., Dürr, M. C., Schlosser, C. S., Allersdorfer, A., Wiedenmann, A., Matschiner, G., Schüler, J. B., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-3654 · Cited by 158
“Cytokine release assay To investigate the risk of systemic cytokine release in patients induced by PRS-343, an in vitro cytokine release assay (31) was carried out with PBMCs from 12 healthy control donors.”
MethodVafa, O., Gilliland, G. L., Brezski, R. J., Strake, B., Wilkinson, T., Lacy, E. R., Scallon, B. J., Teplyakov, A., Malia, T., & Strohl, W. R. (2013) · Methods · doi:10.1016/j.ymeth.2013.06.035 · Cited by 158
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“S6) (30), we first used the FDA-recommended in vitro dry- and wet-coated human T cell proliferation assays (38) to determine whether either of our costimulatory bispecific antibodies could promote T cell activation and cytokine release in a manner equivalent to in-house generated CD28-SA (table S1).”
MethodResultInnovations, challenges, and minimal information for standardization of humanized mice
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“Dendritic cells (DCs) are main orchestrators of the adaptive immune system presenting processed peptide antigens to T cells through MHC classes I/II and expressing key costimulatory molecules such as CD40 ligand (CD40L) required for B-cell activation and class switching (Steinman, 2012).”
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“hyperactivated and secrete inflammatory cytokines (27).”
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“To determine whether REGN2810 by itself stimulates T cells in the absence of TCR activation, we employed a cytokine release assay (45).”
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“Nevertheless, recent investigations on the mechanisms of the TGN-1412mediated “cytokine storm” will enable to develop novel procedures to improve non-clinical safety testing of immunomodulatory therapeutics (Stebbings et al., 2007).”
BackgroundCytokine release assays: Current practices and future directions
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Self-citationHynds, R. E., & Giangreco, A. (2012) · Stem Cells · doi:10.1002/stem.1290 · Cited by 107
Muller, P., & Brennan, F. R. (2009) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2008.273 · Cited by 107
Ramani, T., Auletta, C. S., Weinstock, D., Mounho-Zamora, B., Ryan, P. C., Salcedo, T. W., & Bannish, G. (2015) · International Journal of Toxicology · doi:10.1177/1091581815584918 · Cited by 103
Tabares, P., Berr, S., Römer, P. S., Chuvpilo, S., Matskevich, A. A., Tyrsin, D., Fedotov, Y., Einsele, H., Tony, H., & Hünig, T. (2014) · European Journal of Immunology · doi:10.1002/eji.201343967 · Cited by 97
Immunological substance testing on human lymphatic micro-organoids in vitro
Giese, C., Lubitz, A., Demmler, C. D., Reuschel, J., Bergner, K., & Marx, U. (2010) · Journal of Biotechnology · doi:10.1016/j.jbiotec.2010.03.001 · Cited by 95
Differential Monocyte Actuation in a Three‐Organ Functional Innate Immune System‐on‐a‐Chip
Sasserath, T., Rumsey, J. W., McAleer, C. W., Bridges, L. R., Long, C. J., Elbrecht, D. H., Schuler, F., Roth, A. B., Bertinetti‐LaPatki, C., Shuler, M. L., et al. (2020) · Advanced Science · doi:10.1002/advs.202000323 · Cited by 95
Horvath, C. J., & Milton, M. N. (2009) · Toxicologic Pathology · doi:10.1177/0192623309332986 · Cited by 87
“Within ninety minutes, those who had received TGN1412 had a systemic inflammatory response that was characterized by a rapid induction of proinflammatory cytokines and accompanied by headache, myalgia, nausea, diarrhea, erythema, vasodilatation, and hypotension (Suntharalingam et al. 2006).”
BackgroundResultInfluentialRao, D. A., Eid, R. E., Qin, L., Yi, T., Kirkiles-Smith, N. C., Tellides, G., & Pober, J. S. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20081661 · Cited by 86
Agoram, B. M. (2008) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2008.03297.x · Cited by 85
Harper, J. V., Adams, K. J., Bossi, G., Wright, D. E., Stacey, A., Bedke, N., Martinez-Hague, R., Blat, D., Humbert, L., Buchanan, H., et al. (2018) · PLoS ONE · doi:10.1371/journal.pone.0205491 · Cited by 87
Unraveling the Effect of Immunogenicity on the PK/PD, Efficacy, and Safety of Therapeutic Proteins
Smith, A. M., Manoli, H., Jaw, S., Frutoz, K., Epstein, A. L., Khawli, L. A., & Theil, F. (2016) · Journal of Immunology Research · doi:10.1155/2016/2342187 · Cited by 81
“Immunogenicity-related adverse events (AEs) may be as benign as a mild itchy rash or as serious as infusion reactions, anaphylaxis, and cytokine release syndrome (CRS) [13, 14].”
Signaling Signatures and Functional Properties of Anti-Human CD28 Superagonistic Antibodies
Waibler, Z., Sender, L. Y., Merten, C., Hartig, R., Kliche, S., Gunzer, M., Reichardt, P., Kalinke, U., & Schraven, B. (2008) · PLoS ONE · doi:10.1371/journal.pone.0001708 · Cited by 79
“In line with previous data obtained using TGN1412 [32] Fig.”
ResultThe calm after the cytokine storm: lessons from the TGN1412 trial
St. Clair, E. W. (2008) · Journal of Clinical Investigation · doi:10.1172/jci35382 · Cited by 79
Poirier, N., Mary, C., Dilek, N., Hervouet, J., Minault, D., Blancho, G., & Vanhove, B. (2012) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2012.04164.x · Cited by 79
“We therefore conducted a series of experiments following the recommendations published by the National Institute for Biological Standards and Control from the UK (58,59) after the TeGenero affair.”
BackgroundMethodFindlay, L., Eastwood, D., Stebbings, R., Sharp, G., Mistry, Y., Ball, C., Hood, J., Thorpe, R., & Poole, S. (2010) · Journal of Immunological Methods · doi:10.1016/j.jim.2009.10.013 · Cited by 74
Self-citationAfter TGN1412: Recent developments in cytokine release assays
Stebbings, R., Eastwood, D., Poole, S., & Thorpe, R. (2013) · Journal of Immunotoxicology · doi:10.3109/1547691x.2012.711783 · Cited by 73
“Predictivity of newly-proposed cytokine release assays Initial in vitro studies of pro-inflammatory cytokine release from human lymphocytes stimulated with immobilized TGN1412 measured high levels of tumor necrosis factor (TNF)-α and interleukin (IL)-8 (Stebbings et al., 2007).”
BackgroundMethodInfluentialSelf-citationConsiderations for the development of therapeutic monoclonal antibodies
Swann, P. G., Tolnay, M., Muthukkumar, S., Shapiro, M. A., Rellahan, B. L., & Clouse, K. A. (2008) · Current Opinion in Immunology · doi:10.1016/j.coi.2008.05.013 · Cited by 74
CD28 co-stimulation: novel insights and applications in cancer immunotherapy
Lotze, M. T., Olejniczak, S. H., & Skokos, D. (2024) · Nature reviews. Immunology · doi:10.1038/s41577-024-01061-1 · Cited by 86
“These and other conclusions of the Expert Scientific Group formed the basis for revision of the guidelines for first-in-human trials with investigational medicinal products by the European Medicines Agency 201 .”
Veitonmäki, N., Hansson, M., Zhan, F., Sundberg, A., Löfstedt, T., Ljungars, A., Li, Z., Niskanen, T. M., Zeng, M., Yang, Y., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.02.026 · Cited by 73
“In order tomaximize the chances of identifying any PBMCagonistic properties of BI-505, we used two different antibodycoating protocols in which the antibody was hypercrosslinked as previously described (Stebbings et al., 2007).”
MethodSafety of biologics, lessons learnt from TGN1412
Stebbings, R., Poole, S., & Thorpe, R. (2009) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2009.10.002 · Cited by 70
Self-citationPoirier, N., Blancho, G., Hiance, M., Mary, C., Assche, T. V., Leempoels, J., Ramael, S., Wang, W., Thépenier, V., Braudeau, C., et al. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1601538 · Cited by 66
“Before the initiation of the current phase I study in healthy volunteers, the antagonistic properties of FR104 had been assessed thoroughly in vitro, as previously recommended (33, 34) as well as in vivo using humanized mice (20) and baboons (27).”
BackgroundVessillier, S., Eastwood, D., Fox, B. J., Sathish, J. G., Sethu, S., Dougall, T., Thorpe, S. J., Thorpe, R., & Stebbings, R. (2015) · Journal of Immunological Methods · doi:10.1016/j.jim.2015.04.020 · Cited by 69
Self-citationEarly Implementation of QbD in Biopharmaceutical Development: A Practical Example
Zurdo, J., Arnell, A., Obrezanova, O., Smith, N., de la Cuesta, R. G., Gallagher, T. R. A., Michael, R., Stallwood, Y., Ekblad, C., Abrahmsén, L., et al. (2015) · BioMed Research International · doi:10.1155/2015/605427 · Cited by 72
“any sample contamination or errors in the manufacturing, formulation, dilution or administration of TGN1412 that led to the CRS response [63, 82–86].”
BackgroundPolson, A. G., & Fuji, R. N. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.01916.x · Cited by 66
“This acute cytokine reaction did not occur in the non-human primate study (Suntharalingam et al., 2006; Stebbings et al., 2007).”
BackgroundMonoclonal Antibody First Dose Cytokine Release Syndromes–Mechanisms and Prediction
Wing, M. G. (2008) · Journal of Immunotoxicology · doi:10.1080/15476910801897433 · Cited by 64
“However unlike the clinical situation where massive cytokine release was detected, cytokines could not be detected in vitro unless the antibody was immobilised by “dry coating” the plates with the product (Stebbings et al., 2007).”
BackgroundSurrogate end points in the design of immunotherapy trials: emerging lessons from type 1 diabetes
Roep, B. O., & Peakman, M. (2010) · Nature reviews. Immunology · doi:10.1038/nri2705 · Cited by 63
Ye, C., Yang, H., Cheng, M., Shultz, L. D., Greiner, D. L., Brehm, M. A., & Keck, J. (2020) · The FASEB Journal · doi:10.1096/fj.202001203r · Cited by 60
Human immunity in vitro — Solving immunogenicity and more
Giese, C., & Marx, U. (2014) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2013.12.011 · Cited by 65
Literature review on in vitro and alternative Developmental Neurotoxicity (DNT) testing methods
Fritsche, E., Alm, H., Baumann, J., Geerts, L., Håkansson, H., Masjosthusmann, S., & Witters, H. E. (2015) · EFSA Supporting Publications · doi:10.2903/sp.efsa.2015.en-778 · Cited by 61
Jiménez, S. A., & Piera-Velázquez, S. (2013) · Autoimmunity Reviews · doi:10.1016/j.autrev.2013.04.004 · Cited by 61
Therapeutic T-cell manipulation in rheumatoid arthritis: past, present and future
Isaacs, J. D. (2008) · Rheumatology · doi:10.1093/rheumatology/ken163 · Cited by 61
“The life-threatening cytokine storm experienced by the human volunteers was difficult to replicate in vitro even after the event and has resulted in further safeguards during mAb development [62, 63 ].”
Development of CDX-1140, an agonist CD40 antibody for cancer immunotherapy
Vitale, L. A., Thomas, L. J., He, L.-Z., et al. (2018) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-018-2267-0 · Cited by 59
Gaspar, M., Pravin, J., Rodrigues, L., Uhlenbroich, S., Everett, K. L., Wollerton, F., Morrow, M., Tuna, M., & Brewis, N. (2020) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-19-0798 · Cited by 58
“© 2020 American Association for Cancer Research. cancerimmunolres.aacrjournals.org Downloaded from control antibodies used, a CD28 antibody shown to induce cytokine storm in the clinic (TGN1412; ref.”
MethodTherapeutic Monoclonal Antibodies
Yamada, T. (2011) · The Keio Journal of Medicine · doi:10.2302/kjm.60.37 · Cited by 63
CD28 Superagonists: What Makes the Difference in Humans?
Schraven, B. L., & Kalinke, U. (2008) · Immunity · doi:10.1016/j.immuni.2008.04.003 · Cited by 59
Severity of the TGN 1412 trial disaster cytokine storm correlated with IL‐2 release
Eastwood, D., Bird, C., Dilger, P., Hockley, J., Findlay, L., Poole, S., Thorpe, S. J., Wadhwa, M., Thorpe, R., & Stebbings, R. (2013) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12165 · Cited by 58
Self-citationUpregulation of FcγRIIb on monocytes is necessary to promote the superagonist activity of TGN1412
Hussain, K., Hargreaves, C. E., Roghanian, A., Oldham, R. J., Chan, H. T. C., Mockridge, C. I., Chowdhury, F., Frendéus, B., Harper, K., Strefford, J. C., et al. (2014) · Blood · doi:10.1182/blood-2014-08-593061 · Cited by 55
“The immobilization of TGN1412 onto plastic or the addition of antiimmunoglobulin G (IgG) antibody has been shown to induce cytokine release in PBMC assays.(6,7) Both approaches provide extensive cross-linking of the mAb on the T-cell surface.”
BackgroundMethodA Monovalent Anti-Human CD28 Domain Antibody Antagonist: Preclinical Efficacy and Safety
Suchard, S. J., Davis, P. M., Kansal, S., Stetsko, D. K., Brosius, R., Tamura, J. K., Schneeweis, L. A., Bryson, J. W., Salcedo, T. W., Wang, H., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1300470 · Cited by 55
“(29) to demonstrate agonist activity of TGN1412 in vitro.”
BackgroundSchabowsky, R.-H., Elpek, K. G., Madireddi, S., Sharma, R. K., Yolcu, E. S., Bandura‐Morgan, L., Miller, R. E., MacLeod, K. J., Mittler, R. S., & Shirwan, H. (2009) · Vaccine · doi:10.1016/j.vaccine.2009.09.127 · Cited by 54
In vivoeffects of targeting CD79b with antibodies and antibody-drug conjugates
Zheng, B., Fuji, R. N., Elkins, K., et al. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-0369 · Cited by 54
“In some cases, cynomolgus monkeys are not predictive of cytokine release in humans; however, this appears to be a property of the target and not a general property of cynomolgus monkeys (23).”
BackgroundBegum, J., Day, W. P., Henderson, C. E., Purewal, S., Cerveira, J., Summers, H. D., Rees, P. C. T., Davies, D. C., & Filby, A. J. (2013) · Cytometry Part A · doi:10.1002/cyto.a.22403 · Cited by 54
“For example, we are also looking at the performance of lipophilic dyes in cell lines (36) using our metrics as although they are used successfully to track division (6,10), peak resolution is inferior compared with”
MethodFilby, A., Begum, J., Jalal, M., & Day, W. (2015) · Methods · doi:10.1016/j.ymeth.2015.02.016 · Cited by 53
An FDA oncology analysis of immune activating products and first-in-human dose selection
Saber, H., Gudi, R., Manning, M. L., Wearne, E., & Leighton, J. K. (2016) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2016.10.002 · Cited by 53
In vitro models for immunogenicity prediction of therapeutic proteins
Groell, F., Jordan, O., & Borchard, G. (2018) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2018.06.008 · Cited by 53
Grimaldi, C. M., Finco, D., Fort, M. M., Gliddon, D., Harper, K., Helms, W. S., Mitchell, J. A., O’Lone, R. B., Parish, S. T., Piché, M.-S., et al. (2016) · Cytokine · doi:10.1016/j.cyto.2016.06.006 · Cited by 52
Self-citationBailey, J., & Balls, M. (2019) · BMC Medical Ethics · doi:10.1186/s12910-019-0352-3 · Cited by 51
The laboratory’s role in combating COVID-19
Fang, B., & Meng, Q. H. (2020) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408363.2020.1776675 · Cited by 50
Wolf, B., Morgan, H., Krieg, J., Gani, Z., Milicov, A., Warncke, M., Brennan, F. R., Jones, S., Sims, J., & Kießling, A. (2012) · Cytokine · doi:10.1016/j.cyto.2012.08.018 · Cited by 50
Landrigan, A., Wong, M. T., & Utz, P. J. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003414 · Cited by 50
“Additionally, costimulation with ODNs is an attractive alternative to CD28 costimulation with respect to patient therapy, as anti-CD28 Abs have demonstrated life-threatening clinical toxicity (66).”
BackgroundThe rise and fall of the CD 28 superagonist TGN 1412 and its return as TAB 08: a personal account
Hünig, T. (2016) · The FEBS Journal · doi:10.1111/febs.13754 · Cited by 47
Immunotherapeutic strategies in autoimmune uveitis
Papotto, P. H., Marengo, E. B., Sardinha, L. R., Goldberg, A. C., & Rizzo, L. V. (2014) · Autoimmunity Reviews · doi:10.1016/j.autrev.2014.05.003 · Cited by 46
A CD28 superagonistic antibody elicits 2 functionally distinct waves of T cell activation in rats
Müller, N., van den Brandt, J., Odoardi, F., Tischner, D., Herath, J., Flügel, A., & Reichardt, H. M. (2008) · Journal of Clinical Investigation · doi:10.1172/jci32698 · Cited by 46
Shi, R., Honczarenko, M., Zhang, S. X., Fleener, C., Mora, J. R., Lee, S. K., Wang, R., Liu, X., Shevell, D. E., Yang, Z., et al. (2016) · The Journal of Clinical Pharmacology · doi:10.1002/jcph.791 · Cited by 44
Summary of a workshop on preclinical and translational safety assessment of CD3 bispecifics
Kamperschroer, C., Shenton, J. M., Lebrec, H. N., Leighton, J. K., Moore, P. A., & Thomas, O. (2020) · Journal of Immunotoxicology · doi:10.1080/1547691x.2020.1729902 · Cited by 45
Mechanisms of Adverse Drug Reactions to Biologics
Clarke, J. B. (2009) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-00663-0_16 · Cited by 45
“However, the manner in which the TGN1412 antibody was presented to the PBMCs proved crucial because when the antibody was first air dried onto the plate, wet coated on top of anti-Fc antibodies, or coated on top of endothelial cells, all resulted in the release of cytokines into the medium and lymphocyte proliferation…”
BackgroundMethodDhir, V., Fort, M. M., Mahmood, A., Higbee, R. G., Warren, W., Narayanan, P. K., & Wittman, V. (2011) · Journal of Immunotoxicology · doi:10.3109/1547691x.2011.613419 · Cited by 44
“Interestingly, in the absence of endothelial cells and collagen matrix, “RL-100” culture, the SI and/or magnitude of response to TGN1412 was greatly reduced for all the cytokines (Table 1, Figure 1); this latter finding confirmed a need for F c R-mediate cross-linking to occur for efficient induction of proinflammator…”
BackgroundMethodResultInfluentialVidal, J.-M., Kawabata, T. T., Thorpe, R., Lima, B. S., Cederbrant, K., Poole, S., Mueller-Berghaus, J., Pallardy, M. J., & van der Laan, J. W. (2010) · Cytokine · doi:10.1016/j.cyto.2010.04.008 · Cited by 43
Self-citationBreaking through the therapeutic ceiling of inflammatory bowel disease: Dual-targeted therapies
Feng, Z., Kang, G., Wang, J., Gao, X., Wang, X., Ye, Y., Liu, L., Zhao, J., Liu, X., Huang, H., et al. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.114174 · Cited by 46
TGN1412 Induces Lymphopenia and Human Cytokine Release in a Humanized Mouse Model
Weißmüller, S., Kronhart, S., Kreuz, D., Schnierle, B. S., Kalinke, U., Kirberg, J., Hanschmann, K.-M. O., & Waibler, Z. (2016) · PLoS ONE · doi:10.1371/journal.pone.0149093 · Cited by 43
Bartholomaeus, P., Semmler, L. Y., Bukur, T., Boisguerin, V., Römer, P. S., Tabares, P., Chuvpilo, S., Tyrsin, D. Y., Matskevich, A., Hengel, H., et al. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1302461 · Cited by 40
“T cells enriched from freshly isolated PBMCs are not strongly activated upon treatment with soluble superagonistic anti-CD28 mAb TGN1412 (8, 16).”
BackgroundApplication of microphysiological systems in biopharmaceutical research and development
Peterson, N. C., Mahalingaiah, P. K. S., Fullerton, A. M., & Piazza, M. (2020) · Lab on a Chip · doi:10.1039/c9lc00962k · Cited by 42
Primate Models in Organ TransplantationPreprint
Anderson, D. J., & Kirk, A. D. (2013) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a015503 · Cited by 39
“Although several recommendations have been made for the design of future trials to avoid a repeat of the TGN141 trial (Stebbings et al. 2007; Findlay et al. 2010), there has been, understandably, extreme caution in developing antibodies against CD28.”
BackgroundStorm forecasting: additional lessons from the CD28 superagonist TGN1412 trial
Horvath, C. J., Andrews, L., Baumann, A., Black, L. E., Blanset, D. L., Cavagnaro, J. A., Hastings, K. L., Hutto, D., MacLachlan, T. K., Milton, M., et al. (2012) · Nature reviews. Immunology · doi:10.1038/nri3192-c1 · Cited by 37
Hedgecoe, A. M. (2013) · Social Studies of Science · doi:10.1177/0306312713506141 · Cited by 37
“In terms of biology, what went wrong swiftly became clear (Stebbings et al., 2007).”
BackgroundREPRINT: Inflammatory findings on species extrapolations: humans are definitely no 70-kg mice 1
Leist, M. (2013) · ALTEX · doi:10.14573/altex.2013.2.227 · Cited by 35
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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