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 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 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 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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“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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“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 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
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“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
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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
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“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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“Stimulation of macaque lymphocytes with immobilized TGN1412 similarly induced significant up-regulation of the activation marker CD25 on CD4 ϩ T cells compared with controls (Fig. 5, C and D), but in contrast to human lymphocytes this was not accompanied by proliferation.”
- Also stated in: § Effect of TGN1412 in Cynomolgus macaques · boosted
“Compared with negative control (C), immobilized TGN1412 (D) strongly up-regulates expression of the activation marker CD25 (IL-2R␣) on macaque CD4 ϩ lymphocytes even though they do not undergo proliferation unless IL-2 is added to the cultures.”
§ "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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- Also stated in: § Effect of TGN1412 in Cynomolgus macaques · boosted
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In the paper
“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 > Activation and intracellular cytokine staining
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“Human lymphocytes stimulated with a combination of aqueous TGN1412 and aqueous anti-Fc Abs did not produce IL-2 (C).”
§ "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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“The level of IL-2 ϩ lymphocytes was equivalent to the response seen with the combined stimulation of PMA and ionomycin.”
§ "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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“Analysis of lymphocyte proliferation, quantified as precursor frequency of responding cells per 10 6 lymphocytes (Fig. 4, C and D), showed that immobilized TGN1412 stimulated proliferative responses in up to 35% of lymphocytes.”
§ "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 stark contrast, Cynomolgus macaque lymphocytes showed very little proliferative response to immobilized TGN1412 (Fig. 5A)”
§ "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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“TGN1412 (0.5-250 g/well ϭ 2.0 -1000 g/ml) added in aqueous solution and cultured for 16 -24 h with human PBMC (50,000 -200,000 PBMC/well) or human whole blood (20% v/v final concentration) did not stimulate the release of TNF-␣, IL-6, and IL-8 above basal values and responses to negative controls.”
§ "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 contrast, TGN1412 in aqueous solution, wet coated onto plates or cross-linked in aqueous solution with an anti-human Fc Ab, did not stimulate any significant proliferation of human lymphocytes.”
§ "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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“Additional testing revealed the TGN1412 to be free of”
§ "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 [3] 2003
- Not checked yetcites [4] 2004
- Not checked yetcites [5] 2005
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In the paper
“but is not supported by our finding that anti-CD3 and anti-CD28 costimulation strongly stimulate both human and Cynomolgus macaque lymphocytes.”
§ "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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“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
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“Second, we show that TGN1412 evokes cytokine release and lymphocyte proliferation in vitro only when presented to PBMC in the effective manner identified in these studies”
§ "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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“However, the IFN-␥ response was overall much smaller than that observed with the mitogens PMA and ionomycin, which stimulated ϳ5to 10-fold more CD8 ϩ lymphocytes to produce this cytokine.”
§ "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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“Stimulation of human lymphocytes with immobilized TGN1412 for 6 h resulted in significant production of IL-2 by CD4 ϩ lymphocytes compared with controls (Fig. 6, A and B).”
§ "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
“Also, there were no adverse reactions in Cynomolgus macaques following administration of syringe-derived material at the human dose (0.1 mg/kg): the”
§ "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
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In the paper
“Our in vitro proliferative responses to TGN1412 exhibited a bell-shaped dose-response curve, with a maximum response to a concentration of TGN1412 that we calculate to be approximately equivalent to the dose of 0.1 mg/kg given to the human volunteers.”
§ "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
“The level of proliferation induced by immobilized TGN1412 was profound and equivalent to the responses observed with the stimuli used as positive controls: PHA and mitogenic anti-CD3 Ab alone and in combination with conventional anti-CD28.”
§ "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 con-trast, all PHA-stimulated human lymphocyte day 3 culture supernatants were positive for IL-2 and IFN-␥ 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
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In the paper
“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).”
§ "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
“The striking difference between human and Cynomolgus macaques in terms of the in vivo toxicity of TGN1412 is, we believe, a consequence of the very different way in which white blood cells from humans and macaques respond to TGN1412.”
§ "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
“signaling a failure of preclinical safety testing.”
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In the paper
“Third, we show that white blood cells from Cynomolgus macaques do not respond to TGN1412 in the same way as human white blood cells, whether the cells are stimulated in vitro, using immobilized TGN1412, or in vivo.”
§ "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
“The novel procedures would have predicted the toxicity of this superagonist”
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In answer to this question, our study first provides convincing evidence that the in vitro protocols used before the present study failed to predict toxicity in vivo because they did not present the Ab to white blood cells in a manner that mimicked its presentation in vivo.”
§ "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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- Rests on an assumption: The in vitro presentation of TGN1412 to PBMC that elicits cytokine release and proliferation mimics the in vivo presentation that caused the clinical toxicity.
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In the paper
“Our in vitro proliferative responses to TGN1412 exhibited a bell-shaped dose-response curve, with a maximum response to a concentration of TGN1412 that we calculate to be approximately equivalent to the dose of 0.1 mg/kg given to the human volunteers.”
§ "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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- Rests on an assumption: The in vitro concentration of TGN1412 can be converted to an equivalent in vivo dose in humans.
In the paper
“the TGN1412 used in the trial was found not to be contaminated with endotoxin in the highly sensitive bacterial endotoxins (Limulus) test (2).”
§ "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 [2] 2005
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In the paper
“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”
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In the paper
“suggesting that the responses measured with air-dried (immobilized directly onto the plate) TGN1412 may be an underestimation of the magnitude of the maximum achievable response.”
§ "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 2006, these statements were contradicted when all six recipients of the CD28-specific mAb TGN1412 suffered life-threatening severe adverse events as a consequence of just such a cytokine storm (1).”
§ "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 [1] 2006
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In the paper
“Our in vitro data for Cynomolgus macaque white blood cells are entirely consistent with the data obtained in our new in vivo study in which the original in vivo preclinical study in Cynomolgus macaques that failed to predict the toxicity of TGN1412 was repeated and extended.”
§ "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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- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“and that TGN1412 is not a superagonist in nonhuman primates.”
plain- 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.
- Based: passes — The paper gives a reason why it holds.
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
“In summary, our data indicate that, in contrast to humans, TGN1412 is not a superagonist 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
hedged- 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.
- Based: passes — The paper gives a reason why it holds.
- 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
boosteddirect- 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.
- Based: passes — The paper gives a reason why it holds.
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.
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
plain- 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.
- Based: passes — The paper gives a reason why it holds.
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
“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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaindirect- 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.
- Based: passes — The paper gives a reason why it holds.
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
“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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Peak dose response for human lymphocytes was between 0.4 and 2 g/well (2-10 g/ml).”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Discussion
Not yet classified.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Myocarditis was observed in one animal in the control group and variable cardiac hypertrophy in some others, but no lesions that would correlate with the severe complications seen in the volunteers at the clinical trial were detected.”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Effect of TGN1412 in Cynomolgus macaques
plain- 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.
- Based: passes — The paper gives a reason why it holds.
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
“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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Phenotypic analysis of proliferating lymphocytes identified CD4 ϩ T cells as the principle responding population (ϳ85% of proliferating cells)”
§ "Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics > Lymphocyte proliferation
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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.
- Based: passes — The paper gives a reason why it holds.
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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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
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Loss of Siglec expression on T lymphocytes during human evolution
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Establishing risk of human experimentation with drugs: lessons from TGN1412
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A rapid ‘one-plate’ in vitro test for pyrogens
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Cited by
Sorted by citations
Morgan, R. A., Yang, J. C.-H., Kitano, M., Dudley, M. E., Laurençot, C. M., & Rosenberg, S. A. (2010) · Molecular Therapy · doi:10.1038/mt.2010.24 · Cited by 2,564
The safety and side effects of monoclonal antibodies
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Animal models in translational medicine: Validation and prediction
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Cytokines as biomarkers of nanoparticle immunotoxicity
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Why animal studies are often poor predictors of human reactions to exposure
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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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-09-28, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-09-28 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
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