The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index; 17 of the 50 sources its claims cite were checked for support.
Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T‐cells
Open accessAbstract
BACKGROUND AND PURPOSE: In 2006, a life-threatening 'cytokine storm', not predicted by pre-clinical safety testing, rapidly occurred in all six healthy volunteers during the phase I clinical trial of the CD28 superagonist monoclonal antibody (mAb) TGN1412. To date, no unequivocal explanation for the failure of TGN1412 to stimulate profound cytokine release in vitro or in vivo in species used for pre-clinical safety testing has been established. Here, we have identified a species difference almost certainly responsible for this disparate immunopharmacology. EXPERIMENTAL APPROACH: Polychromatic flow cytometry and intracellular cytokine staining were employed to dissect the in vitro immunopharmacology of TGN1412 and other therapeutic mAbs at the cellular level to identify differences between humans and species used for pre-clinical safety testing. KEY RESULTS: In vitro IL-2 and IFN-γ release from CD4+ effector memory T-cells were key indicators of a TGN1412-type response. This mechanism of cytokine release differed from that of other therapeutic mAbs, which can cause adverse reactions, because these other mAbs stimulate cytokine release primarily from natural killer cells. In contrast to humans, CD28 is not expressed on the CD4+ effector memory T-cells of all species used for pre-clinical safety testing, so cannot be stimulated by TGN1412. CONCLUSIONS AND IMPLICATIONS: It is likely that activation of CD4+ effector memory T-cells by TGN1412 was responsible for the cytokine storm. Lack of CD28 expression on the CD4+ effector memory T-cells of species used for pre-clinical safety testing of TGN1412 offers an explanation for the failure to predict a 'cytokine storm' in humans.
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Claims the paper makes
39 Own result · 25 Own interpretation · 7 Partly supported · 5 Supported so far · 5 Sources not found · 5 No full text of the sources · 4 Supported · 4 Not checked yet · 3 No basis given · 1 Not supported · 1 Own method · accuracy not yet measured
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“Effector memory CD4 + T-cells lacking CD28 expression have been reported in humans, but only in association with autoimmune diseases such as rheumatoid arthritis, Crohn's disease or multiple sclerosis (Markovic-Plese et al., 2001;Fasth et al., 2004;Garcia de Tena et al., 2004), and were not observed with the healthy donors used in this study.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
What the sources say
- Not matchedcites Markovic-Plese et al., 2001
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Disputedcites Fasth et al., 2004 sourceExperimental — accuracy not yet measured
The Introduction (page not specified) says CD28-negative CD4+ T cells have been described in healthy elderly adults as well as patients with inflammatory conditions. The paper studies these cells as an effector-memory population in rheumatoid arthritis, but it does not support—and its Introduction contradicts—the claim that they have been reported only in association with autoimmune disease. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
- Not checked — no full text of the sourcecites Garcia de Tena et al., 2004 source
plaincorrelational- 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.
- Not matched
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Importantly, IFN-g expression is largely limited to the CD4 + effector memory T-cells (Sallusto et al., 1999;Amyes et al., 2005).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
What the sources say
- Not checked — no full text of the sourcecites Sallusto et al., 1999 source
- Supportedcites Amyes et al., 2005 source
In the section on virus-specific CD4+ T-cell subsets, the paper says IFN-γ expression was usually associated with a CCR7− phenotype. The paper identifies CCR7− antigen-experienced cells as effector memory cells, supporting the claim’s qualified wording, “largely limited.” (LLM, conf=0.91)
plaincorrelational- 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 sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Differences in the proportions of CD4 + effector memory T-cells producing TNF-a, IL-2 and IFN-g combinations following TGN1412 stimulation may reflect the heterogeneous nature of this population which contains multiple functional subsets with different cytokine repertoires (e.g.Th1, Th2, Th9, Th17 and Th22) (Annunziato and Romagnani, 2009;Sallusto and Lanzavecchia, 2009).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
What the sources say
hedgedconditional- 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.
Every source the paper cites for this claim was checked and supports it.
In the 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.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
What the sources say
- Supportedcites Stebbings et al. (2007) source
The methods section describes Stebbings et al.’s in vitro procedures, including measurement of IL-2 and IFN-γ release. The Dose responses to TGN1412 section reports release of both cytokines from human lymphocytes exposed to immobilized TGN1412. The conclusion that those procedures apply to other therapeutic mAbs is presented as the citing authors’ finding, not as a result attributed to Stebbings et al.; page numbers were unavailable in our copy. (LLM, conf=0.88)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the 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).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Discussion
What the sources say
- Supportedcites Stebbings et al., 2007 source
The paper describes developing novel cell-based procedures to improve preclinical safety testing (introductory section) and specifies protocols using human PBMCs (Cytokine release studies using PBMC and whole blood). It says the procedures would have predicted TGN1412’s toxicity and were being applied to emerging immunotherapeutics (opening section), supporting the stated aim of avoiding a repeat incident. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites Findlay et al., 2010 source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the 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.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
What the sources say
- Supportedcites Stebbings et al., 2007 source
The “Dose responses to TGN1412” section reports that three-day culture supernatants from cynomolgus macaque lymphocytes stimulated with immobilized TGN1412 were negative for IL-2 by ELISA. It detected very low levels of intracellular IL-2-positive cells after six hours, but that does not contradict the claim about secretion. (LLM, conf=0.90)
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.
- Supported
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
“Second, we show that the new in vitro safety procedures are applicable to other therapeutic mAbs if interleukin (IL)-2 and interferon (IFN)-g are used as key markers for a TGN1412-type response.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Introduction
boostedconditional- 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 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 vitro IL-2 and IFN-g release from CD4+ effector memory T-cells were key indicators of a TGN1412-type response.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Abstract
plaincorrelational- 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 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
“First, we demonstrate that the cytokine release syndrome stimulated by TGN1412 is not mediated by the same mechanism(s) as those underlying adverse reactions to other therapeutic mAbs (e.g.Campath-1H and Mabthera).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Introduction
boosted- 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 result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, TNF-a and IL-8 responses were less discriminatory as substantial release was seen with TGN1412, Mabthera and Campath-1H.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Discussion
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.
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
“We also noted that a small proportion of TGN1412-mediated cytokine release originated from CD4 -lymphocytes, but at present it is unclear whether this occurs via the same mechanism underlying the cytokine release mediated by other therapeutic mAbs or not.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
plaindirect- 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.
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
“Within 30 min, both immobilized TGN1412 (directly coated onto wells; 3.63% Ϯ 0.90) and Fc-immobilized TGN1412 (captured from aqueous phase by anti-IgG Fc regionspecific mAb directly coated onto wells; 3.19% Ϯ 0.29) stimulated significant increases (both P < 0.0001) above those seen with control antibody (1.08% Ϯ 0.10), in the frequency of TNF-aproducing lymphocytes (Figure 1A).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > TGN1412 stimulates rapid cytokine expression in vitro
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.
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
“Human CD4 + effector memory T-cell enrichment produced cells that were on average 88.4% Ϯ 0.64 CD4 + CCR7 -.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > TGN1412 stimulates multiple cytokine release from CD4 + effector memory T-cells
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 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 less marked difference was seen with the frequency of TNF-a- producing CD4 + T-cells in the effector memoryenriched PBMCs (88.2 and 85.2%; Figure 5B) compared with (49.2 and 64.4%; Figure 5A) in effector memory-depleted PBMCs.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > TGN1412 stimulates multiple cytokine release from CD4 + effector memory T-cells
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.
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
“Moreover, the overall intensity of intracellular cytokine staining was greater for CD4 + memory T-cells compared to naive T-cells (Figure 4A, B and C).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > TGN1412 stimulates multiple cytokine release from CD4 + effector memory T-cells
plaincorrelational- 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.
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
“The majority of IFN-g-producing CD4 + T-cells in effector memory-enriched PBMCs also produced IL-2 and TNF-a (Figure 5B).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > TGN1412 stimulates multiple cytokine release from CD4 + effector memory T-cells
plaincorrelational- 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.
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
“Similarly, the naive and central memory CD4 + T-cells of both cynomolgus and rhesus macaques expressed CD28 (Figure 6A).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > CD28 is expressed by human, but not macaque, CD4 + effector memory T-cells
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.
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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
“When stimulated with a CD28 independent agent such as PMA and ionomycin for 4 h, both cynomolgus and rhesus macaque CD4 + CD28 -CCR7 -effector memory T-cells produced pro-inflammatory cytokines, such as IFN-g, demonstrating their functional ability (Figure 6B).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > CD28 is expressed by human, but not macaque, CD4 + effector memory T-cells
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.
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 with Fc-immobilized TGN1412 (0.37% Ϯ 0.05) and immobilized TGN1412 (0.32% Ϯ 0.02) both produced significant increases (above those seen with the control antibody, 0.13% Ϯ 0.03) in the frequency of IFN-g-producing lymphocytes within 90 min (both P < 0.0001; Figure 1B).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > TGN1412 stimulates rapid cytokine expression in vitro
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.
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
“Similarly, the proportion of CD4 + T-cells producing IL-2 in effector memory-enriched PBMCs (55.4 and 49.4%; Figure 5B) was far greater compared with effector memory-depleted PBMCs (both 10.2%; Figure 5A) following stimulation with TGN1412.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > TGN1412 stimulates multiple cytokine release from CD4 + effector memory T-cells
plaincorrelational- 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 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
“Effector memory CD4 + T-cells lacking CD28 expression have been reported in humans, but only in association with autoimmune diseases such as rheumatoid arthritis, Crohn's disease or multiple sclerosis (Markovic-Plese et al., 2001;Fasth et al., 2004;Garcia de Tena et al., 2004), and were not observed with the healthy donors used in this study.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
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.
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
“Interestingly, very low in vitro levels of IFN-g were detected with both Mabthera and Campath-1H, compared with TGN1412, which may prove a good correlate for the likelihood and severity of adverse reactions.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Discussion
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, when we subdivided CD4 + memory T-cells into CCR7 + central memory and CCR7 -effector memory cells, we were able to identify a difference in TGN1412-stimulated cytokine release that could account for low in vitro IFN-g release.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Concentrations of TNF-a measured by ELISA in culture supernatants collected 24 h after in vitro TGN1412 stimulation were also consistent with the peak concentrations reported in trial volunteers, with the considerable caveat that a comparison is being made between an in vitro system and an in vivo response.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
What the sources say
- Not checked — no full text of the sourcecites Suntharalingam et al., 2006 source
hedgedcorrelational- 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.
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
“Rapid expression of the genes for TNF-a, IL-2 and IFN-g was confirmed by RT-PCR following in vitro stimulation with immobilized TGN1412 (data not shown).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > TGN1412 stimulates rapid cytokine expression in vitro
boosteddirect- 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.
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
“Similarly, within the first hour of in vitro TGN1412 stimulation, we observed a rapid induction of TNF-a mRNA and protein expression, consistent with the rapid release of this cytokine in the trial volunteers.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
plaindirect- 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
“PBMCs depleted of CD4 + effector memory T-cells and stimulated with TGN1412 produced mainly TNF-a, some IL-2 and very little IFN-g (i.e.responses very similar to the responses of whole PBMCs).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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
“Only after prolonged in vitro stimulations for 48-72 h could high concentrations of IFN-g, equivalent to levels measured in the plasma of trial volunteers at 4 h, be achieved.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
hedgeddirect- 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 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
“The frequency of TNF-a, IFN-g and IL-2 producing CD4 + memory T-cells was greater compared with CD4 + naive T-cells (Figure 4A, B and C respectively).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > TGN1412 stimulates multiple cytokine release from CD4 + effector memory T-cells
plaincorrelational- 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 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
“Following stimulation with immobilized TGN1412, we identified that human CD4 + CD45RO + memory T-cells, rather than CD4 + CD45RO -naive T-cells, were the predominant source of TNF-a, IFN-g and IL-2 (data from two representative donors; similar data were achieved with six further donors; Figure 4A, B and C respectively).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > TGN1412 stimulates multiple cytokine release from CD4 + effector memory T-cells
plaindirectn = 2- 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 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 greater fraction of macaque CD4 + CD28 -T-cells produce IFN-g compared to CD4 + CD28 + T-cells following mitogen stimulation (similar data were obtained with two additional rhesus, two cynomolgus and two human donors).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
plaincorrelationaln = 2- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“In rodent models, treatment with CD28 superagonists orthologous to TGN1412 stimulated the release of anti-inflammatory cytokines and the expansion of regulatory T-cells believed to counter autoimmune responses (Rodríguez-Palmero et al., 1999;Lin and Hünig, 2003;Beyersdorf et al., 2005).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Introduction
What the sources say
- Not matchedcites Rodríguez-Palmero et al., 1999
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites Lin and Hünig, 2003 source
- Not matchedcites Beyersdorf et al., 2005
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Not matched
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
“This is a CD28-specific, rather than a general, difference affecting applicability of such models to the safety testing of new therapeutic mAbs and immunomodulatory biotherapeutic agents.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Introduction
plaincorrelational- 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 paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Pre-clinical safety testing of TGN1412 in cynomolgus macaques, at doses of up to 50 mg•kg -1 •week -1 , was well tolerated with no signs of toxicity or systemic immune stimulation.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Introduction
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
“Moreover, it appeared that in vitro TGN1412 stimulation greatly underestimated some in vivo cytokine responses compared with those reported in humans.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
hedgeddirect- 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
“PBMCs would also become enriched in effector memory T-cells follow-ing prolonged stimulation as activated naive and central memory T-cells matured into effector memory T-cells gaining their expanded cytokinesecreting potential, including IFN-g.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
hedgeddirect- 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
“Nevertheless, this is the only published method currently available to induce substantial cytokine release with TGN1412, and the conclusion that it is the CD4 + effector memory T-cells which make the pro-inflammatory cytokines in response to TGN1412 stimulation, but not in the case of other therapeutic mAbs studied, is likely to be correct.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
hedgeddirect- 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
“It is likely that activation of CD4+ effector memory T-cells by TGN1412 was responsible for the cytokine storm.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Abstract
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.
- Rests on an assumption: The in vitro responses to immobilized TGN1412 reflect the mechanism of the in vivo cytokine storm 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
“This delayed release of high levels of IFN-g was presumably due to a requirement for expansion of low initial numbers of IFN-g producing T-cells through differentiation of stimulated T-cells and/or cell proliferation.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
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.
None of the sources cited for this claim have been checked yet.
In the paper
“Conversely, central and effector memory T-cells show a different pattern of distribution within the tissues compared with peripheral blood (Campbell et al., 2001;Picker, 2006).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
What the sources say
- Not checked — no full text of the sourcecites Campbell et al., 2001 source
- Not matchedcites Picker, 2006
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- 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.
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
“These apparently disparate results did not seem to support our hypothesis that in vitro TGN1412 stimulation is a model of in vivo responses seen in man.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
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.
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 'cytokine storm' caused by TGN1412 appeared to be mediated by a mechanism of action different from that responsible for the adverse reactions seen with other therapeutic mAbs.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Discussion
hedgeddirect- 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
“Identification of the central role of CD4 + effector memory T-cells in TGN1412-mediated cytokine release provides an explanation for the failure of pre-clinical testing using non-human primate models to predict human responses.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
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.
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
“The rapid nature of this response suggested direct stimulation of pro-inflammatory cytokineproducing cells, rather than a cascade of cytokine release (with each cytokine produced stimulating the release of another cytokine or cytokines).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
hedgeddirect- 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
“Thus, it can be concluded that the cytokine release stimulated by TGN1412 was mediated via a mechanism distinct from that underlying cytokine release stimulated by the other two therapeutic mAbs tested here, because different cell types were involved.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
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.
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
“This would explain why in vitro stimulation with TGN1412 for 24 h initially produced only low levels of IFN-g compared to very high levels at 72 h.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
hedgeddirect- 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
“Lack of CD28 expression on the CD4+ effector memory T-cells of species used for pre-clinical safety testing of TGN1412 offers an explanation for the failure to predict a 'cytokine storm' in humans.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Abstract
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.
- Rests on an assumption: No unequivocal explanation for the failure of TGN1412 to stimulate profound cytokine release in vitro or in vivo in species used for pre-clinical safety testing has been established.
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
“If infusion of TGN1412 caused high concentrations of cytokines to be rapidly released into the blood by the large numbers of CD4 + effector memory T-cells within the tissues, then this would explain why in vitro procedures using peripheral blood containing few of these cells greatly underestimated some cytokine responses such as IFN-g in comparison with responses observed in vivo.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
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.
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
“This finding suggests that the 'cytokine storm' observed in trial participants likely involved TGN1412 stimulation of effector memory T-cells in peripheral tissues such as the lungs and gut, resulting in secretion of high levels of cytokines into the blood.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
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.
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, it is unlikely that TGN1412-mediated IL-8 and TNF-a release in vitro was predominately an Fc region-mediated mechanism as no responses were seen with the IgG4k isotype-matched control.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Discussion
hedged- 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.
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
“The new in vitro procedures described here show that TGN1412-mediated cytokine release evokes a unique mechanism that can be discriminated from the cytokine release observed with the other therapeutic mAbs tested.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
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.
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
“We now offer an explanation for why pre-clinical testing in nonhuman primate models failed to predict a 'cytokine storm' in humans that is based upon a species difference in CD28 expression on CD4 + effector memory T-cells and that is specific for TGN1412 and other CD28-specific therapeutic mAbs.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
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.
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
“The likelihood that another mAb or immunomodulatory biotherapeutic agent could stimulate a TGN1412-like adverse response can now be linked to the ability to activate CD4 + effector memory T-cells.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
hedgedcorrelational- 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. 38
- Probably not a substantial claim. 9
- The quote only partly states this claim. 1
- Not yet classified. 3
The cited sources support only part of this claim — read each source’s verdict below.
In the 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).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Introduction
What the sources say
- Not matchedcites Duff, 2006
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Partly supportedcites Stebbings et al., 2007 sourceExperimental — accuracy not yet measured
The introductory section (page not available) says TGN1412 used in the trial tested negative for endotoxin and describes subsequent analysis at NIBSC. The passages available from our copy do not establish that the trial material was correctly formulated, met its product specification, or was free of all pro-inflammatory contaminants; a negative endotoxin test supports only the narrower contamination claim. (LLM, conf=0.84)
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.
- Not matched
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“TGN1412 was called a 'superagonist' because it could activate T-cells without the need for prior engagement of the T-cell receptor complex (Tacke et al., 1997;Lühder et al., 2003).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Introduction
What the sources say
- Not checked — no full text of the sourcecites Tacke et al., 1997 source
- Partly supportedcites Lühder et al., 2003 sourceExperimental — accuracy not yet measured
The Introduction defines anti-CD28 superagonists as antibodies that fully activate resting T cells without TCR signaling, and the Figure 4 caption describes human T-cell stimulation without TCR triggering. Our copy does not identify TGN1412, so it supports the reason for the label but not the claim about that specific antibody. (LLM, conf=0.85)
plaindirect- 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 cited sources support only part of this claim — read each source’s verdict below.
In the 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).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Introduction
What the sources say
- Not matchedcites Duff, 2006
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Partly supportedcites Stebbings et al., 2007 sourceExperimental — accuracy not yet measured
The Lymphocyte proliferation section reports very little proliferation of cynomolgus macaque lymphocytes with immobilized TGN1412, and the Discussion says all tested in vivo doses were well tolerated. But the Activation and intracellular cytokine staining section reports significant up-regulation of an activation marker in macaque T cells. Thus, saying the cells were not stimulated at all overstates the in vitro finding. Page numbers are unavailable in our copy. (LLM, conf=0.88)
plaincorrelational- 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.
- Not matched
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This is because we and others (Pitcher et al., 2002;Moniuszko et al., 2004) have shown that cynomolgus and rhesus macaque CD4 + effector memory T-cells do not express CD28; therefore, they cannot be stimulated by CD28 superagonists including TGN1412.”
- Also stated in: § Figure 6 · plain
“In contrast, both cynomolgus and rhesus effector memory T-cells (CCR7 -CD28 -) do not express CD28.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
What the sources say
- Not checked — no full text of the sourcecites Pitcher et al., 2002 source
- Partly supportedcites Moniuszko et al., 2004 sourceExperimental — accuracy not yet measured
The Results (page unavailable) describe effector memory T cells in Indian rhesus macaques as CD28-low or CD28-negative, supporting the CD28-expression point only in qualified form. The cited paper does not establish that all CD4+ effector memory T cells in both rhesus and cynomolgus macaques lack CD28, or test whether they can be stimulated by CD28 superagonists such as TGN1412. (LLM, conf=0.88)
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: § Figure 6 · plain
Every source the paper cites for this claim was checked and supports it.
In the 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).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Discussion
What the sources say
- Supportedcites Stebbings et al., 2007 source
The citation is attached to the description of lymphoproliferation and IL-2 release as features of TGN1412 stimulation, not to the citing authors’ results for Mabthera and Campath-1H. The source’s “Lymphocyte proliferation” and “Activation and intracellular cytokine staining” sections report both responses in human lymphocytes stimulated with immobilized TGN1412. Page numbers are not provided in our copy. (LLM, conf=0.92)
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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Moreover, peripheral blood contains just 2-5% of all lymphocytes, while the lungs and gastrointestinal mucosa harbour up to 90% of the body's lymphocytes (Cerf-Bensussan and Guy-Grand, 1991;Smit-McBride et al., 1998).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
What the sources say
- Not checked — no full text of the sourcecites Cerf-Bensussan and Guy-Grand, 1991 source
- Partly supportedcites Smit-McBride et al., 1998 sourceExperimental — accuracy not yet measured
The Abstract states that peripheral blood contains 2–5% of total lymphocytes and that the gastrointestinal tract harbors over 90%. It does not mention the lungs, and its figure is “over 90%,” rather than “up to 90%.” (LLM, conf=0.85)
plain- 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. It may state two separate claims as one.
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the 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).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
What the sources say
- Not checked — no full text of the sourcecites Sallusto et al., 1999 source
- Not matchedcites [2004]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Supportedcites Stebbings et al., 2007 source
The Stebbings citation is attached to the human-versus-macaque response, not the preceding characterization of central memory T cells. The Lymphocyte proliferation section reports pronounced proliferation of human lymphocytes with immobilized TGN1412, but very little proliferation of cynomolgus macaque lymphocytes under the same condition. It notes that macaque cells did proliferate when IL-2 was added. (LLM, conf=0.91)
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.
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“This notion is also consistent with the known capability of CD4 + T-cell subsets to produce cytokines (i.e.naive and central memory CD4 + T-cell subsets both have limited potential for cytokine expression, whereas the effector memory subset has a considerable capability for cytokine production, with IL-2 being a major component of this) (Sallusto et al., 1999;Amyes et al., 2005).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
What the sources say
- Not checked — no full text of the sourcecites Sallusto et al., 1999 source
- Supportedcites Amyes et al., 2005 source
The section on cytokine-expression capacity reports limited expression in the CCR7-positive subsets, which include naive and central memory cells. It also reports good cytokine-expression capacity in CCR7-negative subsets and says IL-2 expression was most common in subset IIIa, supporting the claim about effector memory cells. Page numbers are unavailable in our copy. (LLM, conf=0.91)
boostedcorrelational- 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.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“All human CD4 + T-cell memory subsets (naive, central and effector) expressed high levels of CD28 with the effector memory subset defined by a lack of CCR7 expression (Sallusto et al., 1999;2004; Figure 6A).”
- Also stated in: § CD28 is expressed by human, but not macaque, CD4 + effector memory T-cells · plain
“However, we found that the CD4 + effector memory T-cell subsets of both cynomolgus and rhesus macaques did not express CD28, as previously reported for rhesus macaques (Pitcher et al., 2002;Moniuszko et al., 2004; Figure 6A).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > CD28 is expressed by human, but not macaque, CD4 + effector memory T-cells
What the sources say
- Not checked — no full text of the sourcecites Pitcher et al., 2002 source
- Partly supportedcites Moniuszko et al., 2004 sourceExperimental — accuracy not yet measured
The Results (page unavailable) characterize rhesus macaque CD4+ effector memory T cells as CD28-low or CD28-negative, supporting only the rhesus portion in qualified form. The copy does not establish CD28 expression in human effector memory T cells or the claimed CD28 status of cynomolgus CD4+ effector memory T cells; it also does not say all rhesus cells lack CD28. (LLM, conf=0.86)
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: § CD28 is expressed by human, but not macaque, CD4 + effector memory T-cells · plain
Every source the paper cites for this claim was checked and supports it.
In the paper
“Moreover, it has been previously published that ANC28.1 induces greater or similar in vitro cytokine release than TGN1412 (Waibler et al., 2008), which is in contrast to our findings here that TGN1412 is far more potent than ANC28.1.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
What the sources say
- Supportedcites Waibler et al., 2008 source
The Results section on in vitro cytokine production reports higher TNF-α, IFN-γ, IL-2, and IL-4 with ANC28.1 than with TGN1412 at the tested concentration. It also reports an exception: TGN1412 induced more IL-10. The citing authors’ contrasting finding is their own, not a finding attributed to Waibler et al. (LLM, conf=0.90)
plaindirect- 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. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the 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).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
What the sources say
- Partly supportedcites Stebbings et al., 2007 sourceExperimental — accuracy not yet measured
The Activation and intracellular cytokine staining section reports that immobilized TGN1412 activated macaque CD4+ T cells without inducing proliferation. The Lymphocyte proliferation section reports proliferation after recombinant IL-2 was added, but says that response was only about 10% of the human response or the macaque mitogen response; calling it “marked” overstates the finding. (LLM, conf=0.87)
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- Partly supported
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 mechanism of cytokine release differed from that of other therapeutic mAbs, which can cause adverse reactions, because these other mAbs stimulate cytokine release primarily from natural killer cells.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Abstract
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In the paper
“In contrast to humans, CD28 is not expressed on the CD4+ effector memory T-cells of all species used for pre-clinical safety testing, so cannot be stimulated by TGN1412.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Abstract
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In the paper
“In contrast, other therapeutic mAbs that we tested only stimulated CD4 -lymphocyte cytokine release that comprised high levels of TNF-a, but very low levels of IFN-g and no IL-2.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
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In the paper
“Initial data showed that human CD4 + CD45RO + memory T-cells were the predominant source of cytokines following TGN1412 stimulation, but this did not explain why in vitro IFN-g levels were low when compared with TNF-a levels.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
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In the paper
“As for human cells, we found that both cynomolgus and rhesus macaque CD4 + effector memory T-cells lack CCR7 expression; however, a population of CD28 + CCR7 -were noted that have previously been described as a transitional central memory subset in rhesus macaques (Picker et al., 2006).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > CD28 is expressed by human, but not macaque, CD4 + effector memory T-cells
What the sources say
- Not matchedcites Picker et al., 2006
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
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- Not matched
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In the paper
“In contrast, TGN1412 stimulated a large increase in the frequency of IL-2producing lymphocytes of which the majority were CD4 + (Figure 3A; data from two representative donors) and a small proportion were CD4 -, from the same two representative donors (Figure 3A).”
- Also stated in: § Cytokine release from CD4 + T-cells is characteristic of a TGN1412-type response · plain
“In contrast, stimulation with Mabthera or Campath-1H stimulated increases in the frequency of CD4 -, but not CD4 + TNF-aproducing lymphocytes (Figure 3B).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Cytokine release from CD4 + T-cells is characteristic of a TGN1412-type response
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- Also stated in: § Cytokine release from CD4 + T-cells is characteristic of a TGN1412-type response · 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
“Substantial quantities of IFN-g were detected in culture supernatants following 24 h in vitro stimulation with immobilized TGN1412 and much more after 48 and 72 h (Figure 2B).”
- Also stated in: § Substantial IL-2 and IFN-g release is characteristic of a TGN1412-type response · plain
“Substantial concentrations of IL-2 were detected in culture supernatants following 24 h in vitro stimulation with immobilized TGN1412, and these decreased at 48 and 72 h (Figure 2C).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Substantial IL-2 and IFN-g release is characteristic of a TGN1412-type response
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- Also stated in: § Substantial IL-2 and IFN-g release is characteristic of a TGN1412-type response · 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
“Similarly, the expression of IL-2 following in vitro TGN1412 stimulation showed similar kinetics to its appearance in humans, but the concentrations in cell supernatants were lower than expected.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In marked contrast, PBMCs enriched for CD4 + effector memory T-cells produced high levels of TNF-a, IL-2 and IFN-g, when stimulated with TGN1412, with a large proportion of cells simultaneously producing all three cytokines.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
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In the paper
“However, despite similar in vitro expression kinetics for IFN-g following TGN1412 stimulation, the concentrations of IFN-g were far lower than TNF-a responses in vitro, and an order of magnitude lower than concentrations of IFN-g predicted from in vivo responses in trial participants (Suntharalingam et al., 2006).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
What the sources say
- Not checked — no full text of the sourcecites Suntharalingam et al., 2006 source
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
“TGN1412-mediated cytokine release predominantly originated from CD4 + memory T-cells, which produced high levels of TNF-a, IL-2 and IFN-g.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
plaindirect- 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
“The cytokine gene expression that showed the greatest increase following TGN1412 stimulation was TNF-a, followed by IL-2 and then IFN-g (data not shown).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > TGN1412 stimulates rapid cytokine expression in vitro
plaindirect- 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. 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
“Within 90 min, both immobilized TGN1412 and Fc-immobilized TGN1412 stimulated significant increases (above those seen with the control antibody) in the frequency of IL-2-producing lymphocytes (both P < 0.0001; Figure 1C).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > TGN1412 stimulates rapid cytokine expression in vitro
Not yet classified.
None of the sources cited for this claim have been checked yet.
In the paper
“In contrast, the CD4 + effector memory T-cells of humans express high levels of CD28 on their surface (Sallusto et al., 1999;2004), so therefore can be stimulated by TGN1412.”
- Also stated in: § Figure 6
“Human, cynomolgus and rhesus macaque naive CD4 + T-cells (CCR7 + CD28 + ) and central memory T-cells (CCR7 + CD28 + ), macaque transitional memory T-cells (CCR7 -CD28 + ) and human effector memory CD4 + T-cells (CCR7 -CD28 + ) all express CD28.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
What the sources say
- Not checked — no full text of the sourcecites Sallusto et al., 1999 source
- Not matchedcites [2004]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Not yet classified.
- Also stated in: § Figure 6
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
“Increased levels of TNF-a gene expression were detected 30 min after stimulation with TGN1412, and increased IL-2 and IFN-g gene expression at 60 min.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > TGN1412 stimulates rapid cytokine expression in vitro
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Human CD4 + T-cells constitutively express CD28, so IFN-g staining stems only from the CD28 + population.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, it should be noted that macaque T-cells are not 'less responsive' to in vitro stimulation with TGN1412, but 'non-responsive'.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
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
“Macaque CD4 + T-cells can be subdivided into CD28 + (naive, central and transitional memory T-cell) and CD28 -(effector memory T-cell) populations, both of which produce IFN-g following PMA and ionomycin stimulation for 4 h.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
plaincorrelational- 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, ANC28.1 is a superagonist in vitro in both aqueous phase and when immobilized, whereas we found that TGN1412 was only a superagonist when immobilized.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In 2006, a life-threatening 'cytokine storm', not predicted by pre-clinical safety testing, rapidly occurred in all six healthy volunteers during the phase I clinical trial of the CD28 superagonist monoclonal antibody (mAb) TGN1412.”
- Also stated in: § Introduction · plain
“A near-fatal systemic inflammatory immune response, termed a 'cytokine storm', began 1 h after infusion of TGN1412 in all six healthy recipients, and all became critically ill within 12-16 h (Suntharalingam et al., 2006).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Abstract
What the sources say
- Not checked — no full text of the sourcecites Suntharalingam et al., 2006 source
plainn = 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: § Introduction · plain
In the paper
“TGN1412 is a superagonist CD28-specific monoclonal antibody (mAb) developed as an immunotherapeutic for the purpose of balancing the immune system (TeGenero, 2005).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Introduction
What the sources say
- Not matchedcites TeGenero, 2005
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
- Not matched
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
“Here, we have identified a species difference almost certainly responsible for this disparate immunopharmacology.”
- Also stated in: § Introduction · hedged
“Third, we identify a species difference in CD28 expression on the CD4 + effector memory T-cell subset as being most likely responsible for the failure of pre-clinical safety testing of TGN1412 in cynomolgus macaques.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: No unequivocal explanation for the failure of TGN1412 to stimulate profound cytokine release in vitro or in vivo in species used for pre-clinical safety testing has been established.
- Also stated in: § Introduction · hedged
In the paper
“However, macaque CD4 + transitional memory T-cells are functionally different to macaque CD4 + effector memory T-cells; IL-2 preferentially induces macaque transitional memory T-cells to proliferate, whereas macaque effector memory T-cells are poorly responsive and vice versa for IL-15 (Picker et al., 2006).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
What the sources say
- Not matchedcites Picker et al., 2006
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Not matched
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
“However, it should be noted that immobilizing mAb to a plastic surface is a highly artificial means of stimulation that is unlikely to simulate what is happening inside the body.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
hedged- 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.
In the paper
“One of the most striking features of the TGN1412-mediated 'cytokine storm' observed in humans was substantial TNF-a release within the first hour of infusion followed by dramatic increases in IFN-g, IL-2, IL-6, IL-8 and IL-10 plasma concentrations within 4 h (Suntharalingam et al., 2006).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
What the sources say
- Not checked — no full text of the sourcecites Suntharalingam et al., 2006 source
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
“If the explanation were as simple as differences in cell numbers, then all cytokine responses would have been equally lower, but they were not.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
plainconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“We also did not understand why TGN1412 bound to human and macaque CD28 with equal affinity (TeGenero, 2005), yet caused a 'cytokine storm' only in humans.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Discussion
What the sources say
- Not matchedcites TeGenero, 2005
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
- Not matched
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
“Within blood, multiple cell types and their subsets can release different cytokines with overlapping repertoires which are not discriminated by ELISA assessment of culture supernatants from mixed cell populations stimulated with mAbs, whereas phenotypic analysis of cytokine-producing cells using flow cytometry, as is shown here, has allowed the dissection of different effector mechanisms.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Similar to human CD4 + effector memory T-cells, macaque CD4 + transitional memory T-cells lack CCR7 expression and express CD28 (Picker et al., 2006).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
What the sources say
- Not matchedcites Picker et al., 2006
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Not matched
None of the sources cited for this claim have been checked yet.
In the paper
“The lymph nodes and tonsils are enriched in central memory CD4 + T-cells, whereas the lungs and gastrointestinal mucosa contain mainly effector memory CD4 + T-cells (Campbell et al., 2001;Picker, 2006).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
What the sources say
- Not checked — no full text of the sourcecites Campbell et al., 2001 source
- Not matchedcites Picker, 2006
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Not yet classified.
In the paper
“The evolutionary reason for this subtle comparative immunological difference in receptor expression is unclear, but retention of CD28 expression on human CD4+ effector T-cells would allow the required co-stimulatory signals to reduce activation thresholds (Fraser et al., 1991).”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
What the sources say
- Not checked — no full text of the sourcecites Fraser et al., 1991 source
hedgeddirect- 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.
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
“This difference not only questioned the suitability and validity of existing pre-clinical non-human primate models for the safety testing of therapeutic mAbs, but also for other immunomodulatory biological agents.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > 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
“Therefore, it is likely that ANC28.1 binds to a different region of CD28 from that binding TGN1412, which may explain why lower responses were observed.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
hedgedconditional- 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.
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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
“While much of the immunopharmacology of cytokine release syndrome in humans remains largely unknown, pre-clinical safety testing in non-human primate models will still be useful, but needs to be interpreted in conjunction with subtleties in antigen expression on target cells in pre-clinical models.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check 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 be too vague to check against evidence. 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
“Nevertheless, ANC28.1 does stimulate release of the same pattern of cytokines as TGN1412 so is likely to activate the same pro-inflammatory pathways.”
§ Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cellsb ph_922 512..526 > Figure 6
hedgedconditional- 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.
The paper relies on this without support.
No unequivocal explanation for the failure of TGN1412 to stimulate profound cytokine release in vitro or in vivo in species used for pre-clinical safety testing has been established.
“To date, no unequivocal explanation for the failure of TGN1412 to stimulate profound cytokine release in vitro or in vivo in species used for pre-clinical safety testing has been established.”
The paper relies on this without support.
The in vitro responses to immobilized TGN1412 reflect the mechanism of the in vivo cytokine storm in humans.
“To determine if in vitro stimulation with immobilized TGN1412 (Stebbings et al., 2007) induces rapid cytokine expression, with kinetics similar to the 'cytokine storm' caused by this mAb in humans, we looked at early responses within the first 6 h following stimulation using intracellular cytokine staining and RT-PCR for cytokine mRNAs.”
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
“Rather, IL-2 release and lymphoproliferation are optimal readouts of a TGN1412-like pro-inflammatory response.”
From After TGN1412: Recent developments in cytokine release assays (2013) · cites this paper as Eastwood et al., 2010
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
“High concentrations (> 5000 pg/ml) of the cytokines TNFα, IL-2, and IFNγ were measured in the plasma of trial volunteers within 4 h of TGN1412 infusion (Suntharalingam et al., 2006).”
From After TGN1412: Recent developments in cytokine release assays (2013) · cites this paper as Eastwood et al., 2010
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
“Subsequently, both interferon (IFN)-γ and IL-2 were found to be better predictive markers of a TGN1412-like cytokine release using immobilized mAbs (Eastwood et al., 2010).”
From After TGN1412: Recent developments in cytokine release assays (2013) · cites this paper as Eastwood et al., 2010
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
“TGN1412 (Section 7.2) is a target- and immune-mediated failure, in which receptor biology rather than pharmacokinetics governed the outcome and which only MABEL-anchored dosing could have contained.”
From Beyond Body Weight: A Comprehensive Review of Allometric Scaling in Drug Development for Human Dose Predictions (2026) · cites this paper as [72]
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 2006 TGN1412 phase I trial produced life-threatening cytokine storm in all six healthy volunteers at a dose 500-fold below the no-observed-adverse-effect level (NOAEL) in cynomolgus monkeys.”
From Beyond Body Weight: A Comprehensive Review of Allometric Scaling in Drug Development for Human Dose Predictions (2026) · cites this paper as [72]
Experimental — accuracy not yet measured
The cited source says what the claim attributes to it.
In the citing paper
“The non-predictive result obtained from pre-clinical safety testing in cynomolgus macaques has now been attributed to a lack of CD28 expression on CD4+ effector memory T-cells that therefore cannot be stimulated by TGN1412.”
From After TGN1412: Recent developments in cytokine release assays (2013) · cites this paper as Eastwood et al., 2010
The cited source says what the claim attributes to it.
In the citing paper
“In contrast, high levels of CD28 are expressed on human CD4+ effector memory T-cells, the source of most TGN1412-stimulated pro-inflammatory cytokines.”
From After TGN1412: Recent developments in cytokine release assays (2013) · cites this paper as Eastwood et al., 2010
The cited source says what the claim attributes to it.
In the citing paper
“It has emerged that the mechanism of pro-inflammatory cytokine release stimulated by TGN1412 is different to that of other therapeutic mAbs, such that standard pro-inflammatory markers such as TNFα and IL-8 are not discriminatory.”
From After TGN1412: Recent developments in cytokine release assays (2013) · cites this paper as Eastwood et al., 2010
The cited source says what the claim attributes to it.
In the citing paper
“The search for an explanation of this led to the identification of CD4+ effector memory T-cells being the source of TGN1412-stimulated IFNγ release (Eastwood et al., 2010; Figure 5).”
From After TGN1412: Recent developments in cytokine release assays (2013) · cites this paper as Eastwood et al., 2010
The cited source says what the claim attributes to it.
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 Eastwood et al., 2010
The cited source says what the claim attributes to it.
In the citing paper
“However, cynomolgus macaques were the wrong species for pre-clinical safety testing of TGN1412 because the CD4+ effector memory sub-set of this species does not express CD28 and, therefore, cannot be stimulated by anti-CD28 agonists (Eastwood et al., 2010; Figure 1).”
From After TGN1412: Recent developments in cytokine release assays (2013) · cites this paper as Eastwood et al., 2010
The cited source says what the claim attributes to it.
In the citing paper
“This result does not correlate well with the severity of the response to TGN1412 compared to Campath-1H and Rituximab, so TNFα and IL-8 release are poorly predictive of the severity of response (Eastwood et al., 2010).”
From After TGN1412: Recent developments in cytokine release assays (2013) · cites this paper as Eastwood et al., 2010
The cited source says what the claim attributes to it.
In the citing paper
“the choice of animal model chosen for pre-clinical safety testing of TGN1412, cynomolgus macaques, had been inappropriate because the CD4+ effector memory T-cell subset of this species does not express CD28 and, therefore, cannot be stimulated by CD28 agonists 5 .”
From Severity of the TGN 1412 trial disaster cytokine storm correlated with IL‐2 release (2013) · cites this paper as [5]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“In contrast the CD4+ effector memory T-cell subset of man expresses high levels of CD28 and, therefore, can be stimulated by TGN1412, causing rapid release of high levels of pro-inflammatory cytokines 5 .”
From Severity of the TGN 1412 trial disaster cytokine storm correlated with IL‐2 release (2013) · cites this paper as [5]
The cited source says what the claim attributes to it.
In the citing paper
“The failure stemmed from fundamental immunological differences: the distribution of the CD28 receptor on effector memory T cells in humans versus non-human primates produced a qualitatively different pharmacological response [54,71,72].”
From Beyond Body Weight: A Comprehensive Review of Allometric Scaling in Drug Development for Human Dose Predictions (2026) · cites this paper as [72]
In the citing paper
“they found that cynomolgus macaque, but not human, CD4EM cells down-regulate the CD28 molecule and hence cannot be addressed by the CD28SA.”
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 [47]
In the citing paper
“the cell type we [45] and the Stebbings group [47] had identified as the source of the multiple toxic cytokines released in response to TAB08, i.e., the mostly tissue-resident CD4 effector memory (CD4EM) cells”
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 [47]
Citations
Cites
Two subsets of memory T lymphocytes with distinct homing potentials and effector functions
Sallusto, F., Lenig, D., Förster, R., Lipp, M., & Lanzavecchia, A. (1999) · Nature · doi:10.1038/44385 · Cited by 5,846 · cited 11×
“In contrast, the CD4+ effector memory T-cells of humans express high levels of CD28 on their surface (Sallusto et al., 1999; 2004), so therefore can be stimulated by TGN1412.”
BackgroundMethodInfluentialCentral Memory and Effector Memory T Cell Subsets: Function, Generation, and Maintenance
Sallusto, F., Geginat, J., & Lanzavecchia, A. (2004) · Annual Review of Immunology · doi:10.1146/annurev.immunol.22.012703.104702 · Cited by 3,067
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 · cited 4×
“One of the most striking features of the TGN1412-mediated ‘cytokine storm’ observed in humans was substantial TNF-a release within the first hour of infusion followed by dramatic increases in IFN-g, IL-2, IL-6, IL-8 and IL-10 plasma concentrations within 4 h (Suntharalingam et al., 2006).”
BackgroundResultInfluentialGuide to receptors and channels (GRAC), 5th edition
Alexander, S., Mathie, A., & Peters, J. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01649_1.x · Cited by 1,947
Regulation of Interleukin-2 Gene Enhancer Activity by the T Cell Accessory Molecule CD28
Fraser, J. D., Irving, B. A., Crabtree, G. R., & Weiss, A. (1991) · Science · doi:10.1126/science.1846244 · Cited by 641
Two subsets of memory T lymphocytes with distinct homing potentials and effector functions
Sallusto, F., Lenig, D., Förster, R., Lipp, M., & Lanzavecchia, A. (1999) · Nature · doi:10.1038/35005534 · Cited by 474
Development and Homeostasis of T Cell Memory in Rhesus Macaque
Pitcher, C. J., Hagen, S. I., Walker, J. M., Lum, R., Mitchell, B. L., Maino, V. C., Axthelm, M. K., & Picker, L. J. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.1.29 · Cited by 467
Predictors of major infections in systemic lupus erythematosus
Ruiz‐Irastorza, G., Olivares, N., Ruiz‐Arruza, I., Martínez-Berriotxoa, A., Egurbide, M.-V., & Aguirre, C. (2009) · Arthritis Research & Therapy · doi:10.1186/ar2764 · Cited by 371
Heterogeneity of CD4+ memory T cells: Functional modules for tailored immunity
Sallusto, F., & Lanzavecchia, A. (2009) · European Journal of Immunology · doi:10.1002/eji.200939722 · Cited by 348
CCR7 Expression and Memory T Cell Diversity in Humans
Campbell, J. J., Murphy, K. E., Kunkel, E. J., Brightling, C. E., Soler, D., Shen, Z., Boisvert, J., Greenberg, H. B., Vierra, M. A., Goodman, S. B., et al. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.2.877 · Cited by 335
Cited by
Sorted by citations
Animal models of human disease: challenges in enabling translation
McGonigle, P., & Ruggeri, B. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.08.006 · Cited by 610
The ‘cytokine storm’: molecular mechanisms and therapeutic prospects
Karki, R., & Kanneganti, T. (2021) · Trends in Immunology · doi:10.1016/j.it.2021.06.001 · Cited by 464
“response to TGN1412 was deemed to be due to a lack of CD28 expression on CD4 effector memory T cells in macaques, preventing TGN1412 from activating these cells and inducing cytokine production [66].”
BackgroundBaker, K. F., & Isaacs, J. D. (2017) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2017-211555 · Cited by 383
The promise and challenges of immune agonist antibody development in cancer
Mayes, P. A., Hance, K. W., & Hoos, A. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.75 · Cited by 367
B7 family checkpoint regulators in immune regulation and disease
Ceeraz, S., Nowak, E. C., & Noelle, R. J. (2013) · Trends in Immunology · doi:10.1016/j.it.2013.07.003 · Cited by 323
Metadata
- Authors
- Eastwood, D., Findlay, L., Poole, S., Bird, C., Wadhwa, M., Moore, M., Burns, C., Thorpe, R., & Stebbings, R.
- Affiliations
- National Institute for Biological Standards and Control (GB)
- Corresponding author
- Stebbings, R
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2010-09-03
- Volume
- 161
- Issue
- 3
- Pages
- 512-526
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC2990151
- OpenAlex
- W1490736032
- Cited by
- 300
- References
- 43
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 18 · 2023: 15 · 2022: 13 · 2021: 16 · 2020: 18 · 2019: 13 · 2018: 20 · 2017: 31 · 2016: 16 · 2015: 19 · 2014: 24 · 2013: 29 · 2012: 27
- FWCI
- 9.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- 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 storm, CD4+ effector memory T cells, species differences, IL-2 release, IFN-gamma release, T cell activation, immunopharmacology, adverse drug reactions
- MeSH terms
- Animals, Antibodies, Monoclonal, Cells, Cultured, Humans, Immunologic Memory, Interferon-gamma, Interleukin-2, Lymphocyte Activation, Macaca, Macaca fascicularis, Species Specificity, T-Lymphocytes, CD4-Positive T-Lymphocytes, Cytokines, Clinical Trials, Phase I as Topic, CD28 Antigens, Toxicity Tests, 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).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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