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Cited by 47T-cell and B-cell ImmunologyMonoclonal and Polyclonal Antibodies ResearchImmunotoxicology and immune responses

The rise and fall of the CD 28 superagonist TGN 1412 and its return as TAB 08: a personal account

Open access
Hünig, Thomas·2016·The FEBS Journal
DOI 10.1111/febs.13754
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Abstract

Two decades ago, we discovered ‘superagonistic’ monoclonal antibodies specific for the CD 28 molecule which are able to polyclonally activate T cells, in particular regulatory T cells, and are therapeutically active in many rodent models of autoimmunity, inflammation, transplantation, and tissue repair. A phase I trial of the human CD 28 superagonist TGN 1412 failed in 2006 due to an unexpected cytokine release syndrome, but after it became clear that dose‐reduction allows to preferentially address regulatory T cells also in humans, clinical development was resumed under the name TAB 08. Here, I recount the story of CD 28 superagonist development from a personal perspective with an emphasis on the dramatic events during and after the 2006 phase I trial, the reasons for the failure of preclinical research to warn of the impending cytokine storm, and on the research which allowed resumption of clinical development.

AI snapshot

Written from the paper’s full text.

TL;DR

This first-person narrative traces CD28 superagonist antibodies from their discovery and preclinical promise through the 2006 TGN1412 phase I disaster to the resumed clinical development of TAB08. It argues that the 2006 cytokine storm arose because human tissue-resident CD4 effector memory T cells respond to CD28 superagonists, whereas cynomolgus macaque CD4 effector memory T cells down-regulate CD28 and therefore failed to predict the toxicity.

Key findings

  • CD28 superagonists were found to activate T cells without direct TCR engagement and, at low doses, to preferentially expand regulatory T cells in rats; this selectivity provided the rationale for treating autoimmune and inflammatory conditions.
  • In the March 2006 London phase I trial, all six healthy volunteers developed a severe cytokine release syndrome after receiving TGN1412 at 100 µg/kg; two cases were life-threatening, with multiorgan failure. The dose had been based on cynomolgus monkeys tolerating up to 50 mg/kg, i.e. 500-fold higher.
  • Later work indicated that the toxic cytokines came mainly from tissue-resident CD4 effector memory cells; cynomolgus CD4 effector memory cells down-regulate CD28, so this species could not reveal the human response. Fresh PBMC cultures also failed to respond to soluble TGN1412 unless the antibody was immobilized or the PBMC were precultured at high density.
  • A second phase I trial in 30 healthy volunteers used an initial dose of 0.1 µg/kg, 1000-fold lower than in London, escalating to 7 µg/kg with staggered slow infusion; it was well tolerated, with no detectable cytokines except transient IL-10 at the two highest dose groups. Definitive efficacy and safety in rheumatoid arthritis remain pending.

Methods

  • Single-author historical and personal review of CD28 superagonist development, covering the author’s laboratory discoveries, TeGenero’s TGN1412 program, the 2006 phase I trial, subsequent investigations, and TheraMab’s TAB08 program.
  • Evidence discussed includes rodent disease models, in vitro human PBMC assays, receptor-occupancy and cytokine-release studies, and a second phase I trial in 30 healthy volunteers; the account is narrative rather than systematic or quantitative.
  • The paper synthesizes published and unpublished work, including the author’s own laboratory findings and cited studies from other groups.

Limitations

  • Stated: the author presents a personal perspective, and the acknowledgements note that colleagues who checked the statements do not necessarily share all expressed views; negotiations with regulators are explicitly not reported.
  • Stated: proof of TAB08 efficacy and safety depends on ongoing rheumatoid arthritis trials, and the drug would face competition from existing biologicals; some patient-cohort observations in MS, SLE, and psoriasis are described as unpublished.
  • Evident from the text: this is a retrospective, single-author narrative with selective citation and no systematic search or formal bias assessment; the author also discloses a consultant role with TheraMab, which may shape interpretation.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1111/febs.13754

Cites

54 of 54 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 48 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    TGN1412 binding affinities to macaque and human CD28 are indistinguishable when measured by surface plasmon resonance and flow cytometry.

    “affinities of TGN1412 binding to macaque and human CD28 [measured by surface plasmon resonance (Biacore) and flow cytometry] are indistinguishable [39].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] 39. Hanke T (2006) Lessons from TGN1412. Lancet 368, 1569-1570; author reply 1570. source

      Not checked in the free run.

  • Findingown data

    Preculturing peripheral blood mononuclear cells at high density for two days sensitized them to respond vigorously to soluble TAB08 without any need for human vascular endothelial cells.

    “those precultured PBMC to our big surprise responded vigorously to soluble TAB08 without any need for HUVECS!”
    • Also stated in: § Chapter seven: Understanding the failure of preclinical tests to warn of a CRS · plain
      “Paula R€ omer, a PhD student from Venezuela, confirmed the phenomenon of sensitization by high-density preculture in a large number of PBMC samples, optimized it, and studied it mechanistically [45].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] 45. Romer PS, Berr S, Avota E, Na SY, Battaglia M, ten Berge I, Einsele H & Hunig T (2011) Preculture of PBMCs at high cell density increases sensitivity of T-cell responses, revealing cytokine release by CD28 superagonist TGN1412. Blood 118, 6772-6782. source

      Not checked in the free run.

  • Findingcitation

    Attempts to restore TGN1412 responses using full-blood assays or human vascular endothelial cell cocultures had poor results with respect to background, magnitude, composition, and kinetics of cytokine release.

    “several groups tried to solve the supposed problem of the 'missing partner cell' by doing either full-blood assays (including the granulocytes, on which the PBMC then most unnaturally sit), or by including human vascular endothelial cells (HUVEC), both with poor results regarding background, magnitude, composition, and the kinetics of cytokine release (summarized in [43]).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] 43. Finco D, Grimaldi C, Fort M, Walker M, Kiessling A, Wolf B, Salcedo T, Faggioni R, Schneider A, Ibraghimov A et al. (2014) Cytokine release assays: current practices and future directions. Cytokine 66, 143-155. source

      Not checked in the free run.

  • Findingcitation

    TGN1412 must be artificially immobilized on the plastic surface of a culture well to induce cytokine release in vitro.

    “In order for cytokine release to be induced, TGN1412 needs to be artificially immobilized on the plastic surface of the cell culture well [42]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] 42. Stebbings R, Findlay L, Edwards C, Eastwood D, Bird C, North D, Mistry Y, Dilger P, Liefooghe E, Cludts I et al. (2007) "Cytokine storm" in the phase I trial of monoclonal antibody TGN1412: better understanding the causes to improve preclinical testing of immunotherapeutics. J Immunol 179, 3325-3331. source

      Not checked in the free run.

  • Findingcitation

    Some rat CD28-specific monoclonal antibodies activated T cells without requiring simultaneous engagement of the T-cell receptor.

    “Unexpectedly, we found that some rat CD28-specific mAbs activated T cells without the need to also engage the TCR [1].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] 1. Tacke M, Hanke G, Hanke T & Hunig T (1997) CD28- mediated induction of proliferation in resting T cells in vitro and in vivo without engagement of the T cell receptor: evidence for functionally distinct forms of CD28. Eur J Immunol 27, 239-247. source

      Not checked in the free run.

  • May combine two claims. 17
  • Not yet classified. 10
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 3

  • May combine two claims.

    Findingcitation

    Cynomolgus monkeys received up to 50 mg per kg TGN1412 without an adverse response, which was 500-fold higher than the 100 microgram per kg dose later given in the trial and exceeded the usual safety margin for a first-in-human dose.

    “cynomolgus monkeys received up to 50 mg per kg body weight without an adverse response, i.e., 500-fold more than the 100 lgÁkg À1 dose later applied at the trial, exceeding the usual safety margin for a FIH dose [35].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] 35. Tegenero (2005) TGN1412 Investigator's Brochure. Tegenero, www.circare.org/foia5/tgn1412dossier.pdf.

      Not checked in the free run.

  • Not yet classified.

    Finding

    All volunteers were eventually released from the clinic thanks to the care they received.

    “Thanks to the excellent care at the hospital, all volunteersturned-patients were eventually released from the clinic.”
    Quote in the paperNot yet classified0 of 1 sources checked
    • cites [32] 32. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD & Panoskaltsis N (2006) Cytokine storm in a phase 1 trial of the anti- CD28 monoclonal antibody TGN1412. New England J Med 355, 1018-1028. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Soluble TGN1412 does not induce a cytokine storm in peripheral blood mononuclear cell cultures, which obscured its toxic potential in vivo.

    “Strangely, no in vitro 'cytokine storm' is observed if TGN1412 is added to PBMC cultures, obscuring its toxic potential in vivo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    The authors discovered monoclonal antibodies against CD28 that can activate T cells polyclonally, with a preference for regulatory T cells.

    “we discovered 'superagonistic' monoclonal antibodies specific for the CD28 molecule which are able to polyclonally activate T cells, in particular regulatory T cells”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    The entire external domain of cynomolgus macaque CD28, and also of rhesus macaque CD28, is identical to that of human CD28.

    “the entire external domain of cynomolgus macaque CD28 (and, indeed, also of the rhesus molecule; the published sequence on which the claim of poor binding was based is wrong) is identical to that of human CD28”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39] 39. Hanke T (2006) Lessons from TGN1412. Lancet 368, 1569-1570; author reply 1570. source

      Not checked in the free run.

  • Not yet classified.

    Finding

    The volunteers were transferred to the intensive care unit sixteen hours later and received expert treatment for cytokine release syndrome, with high-dose corticosteroids as a key component.

    “Sixteen hours later, the volunteers were transferred to the hospital's ICU, where they received expert treatment for CRS (with highdose corticosteroids as a key component) [32].”
    Quote in the paperNot yet classified0 of 1 sources checked
    • cites [32] 32. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD & Panoskaltsis N (2006) Cytokine storm in a phase 1 trial of the anti- CD28 monoclonal antibody TGN1412. New England J Med 355, 1018-1028. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    CD28 superagonist-triggered T-cell responses do not require overt T-cell receptor engagement, but T-cell receptor presence is needed to generate basal downstream substrate at the slp76 signalosome for CD28-mediated signal amplification.

    “although no overt engagement of the TCR is required to obtain CD28SA-triggered T-cell responses, its presence is needed to generate a basal level of downstream substrate at the slp76 signalosome for signal amplification by CD28 [13].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] 13. Dennehy KM, Elias F, Na SY, Fischer KD, Hunig T & Luhder F (2007) Mitogenic CD28 signals require the exchange factor Vav1 to enhance TCR signaling at the SLP-76-Vav-Itk signalosome. J Immunol 178, 1363-1371. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Removing Treg cells immediately before CD28SA treatment in mice produced measurable blood TNF, IL-2, and IL-6, but no visible distress.

    “when we removed Treg cells immediately before applying the CD28SA to mice, considerable amounts of circulating TNF, IL-2, and IL-6 became detectable [15], although this did not result in visible distress.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] 15. Gogishvili T, Langenhorst D, Luhder F, Elias F, Elflein K, Dennehy KM, Gold R & Hunig T (2009) Rapid regulatory T-cell response prevents cytokine storm in CD28 superagonist treated mice. PLoS One 4, e4643. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In rats, high doses of CD28 superagonist activated both conventional T cells and regulatory T cells, whereas low doses measurably expanded only regulatory T cells, providing a dose window for selective regulatory T-cell targeting.

    “Titration of the CD28SA in vivo revealed that at high doses, both conventional T cells and Treg cells were activated, whereas at low doses, only Treg cells expanded measurably, providing a window for selective targeting of that subset [3].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] 3. Beyersdorf N, Gaupp S, Balbach K, Schmidt J, Toyka KV, Lin CH, Hanke T, Hunig T, Kerkau T & Gold R (2005) Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis. J Exp Med 202, 445-455. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    All six healthy volunteers in the 2006 phase I trial developed cytokine release syndrome with multiorgan failure, life-threatening in two cases, after receiving TGN1412 as a rapid bolus intravenous injection.

    “all six volunteers experienced a terrible, and in two instances even life-threatening, cytokine release syndrome (CRS) with multiorgan failure, after having received the drug in quick succession as a bolus intravenous injection [32].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] 32. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD & Panoskaltsis N (2006) Cytokine storm in a phase 1 trial of the anti- CD28 monoclonal antibody TGN1412. New England J Med 355, 1018-1028. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    CD28 superagonists bind laterally to both subunits of the CD28 homodimer, unlike conventional CD28-specific antibodies that bind monovalently at the top, and this permits extensive CD28 crosslinking.

    “In particular, we showed that in contrast to conventional CD28-specific mAbs, which bind monovalently at the top of the homodimeric CD28 molecule, CD28SA bind laterally to both subunits [8,9] allowing extensive CD28 crosslinking”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] 8. Luhder F, Huang Y, Dennehy KM, Guntermann C, Muller I, Winkler E, Kerkau T, Ikemizu S, Davis SJ, Hanke T et al. (2003) Topological requirements and signaling properties of T cell-activating, anti-CD28 antibody superagonists. J Exp Med 197, 955-966. source

      Not checked in the free run.

    • cites [9] 9. Evans EJ, Esnouf RM, Manso-Sancho R, Gilbert RJ, James JR, Yu C, Fennelly JA, Vowles C, Hanke T, Walse B et al. (2005) Crystal structure of a soluble CD28-Fab complex. Nat Immunol 6, 271-279. source

      Not checked in the free run.

  • Not yet classified.

    Finding

    The 2006 phase I trial of TGN1412 failed because of an unexpected cytokine release syndrome.

    “A phase I trial of the human CD28 superagonist TGN1412 failed in 2006 due to an unexpected cytokine release syndrome”
    Quote in the paperNot yet classified

  • May combine two claims.

    Findingcitation

    The plastic-immobilization protocol produced TGN1412 responses that mirrored the phase I cytokine release syndrome well, indicating that peripheral blood mononuclear cells contain cells capable of mounting an in vitro cytokine storm under artificial antibody presentation.

    “the plastic-immobilization protocol championed by Stebbings and colleagues allowed TGN1412 responses which mirrored the CRS of the phase I study quite well [42], indicating that there are cells present in PBMC capable of responding to TGN1412 with an in vitro cytokine storm, albeit under artificial conditions of antibody presentation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] 42. Stebbings R, Findlay L, Edwards C, Eastwood D, Bird C, North D, Mistry Y, Dilger P, Liefooghe E, Cludts I et al. (2007) "Cytokine storm" in the phase I trial of monoclonal antibody TGN1412: better understanding the causes to improve preclinical testing of immunotherapeutics. J Immunol 179, 3325-3331. source

      Not checked in the free run.

  • The quote only partly states this claim.

    Findingcitation

    In the second phase I trial, TAB08 was well tolerated at the doses tested.

    “The recently published [53] results were a relief: not only was the drug well tolerated at these doses”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] 53. Tabares P, Berr S, Romer PS, Chuvpilo S, Matskevich AA, Tyrsin D, Fedotov Y, Einsele H, Tony HP & Hunig T (2014) Human regulatory T cells are selectively activated by low-dose application of the CD28 superagonist TGN1412/TAB 08. Eur J Immunol 44, 1225-1236. source

      Not checked in the free run.

    • Rests on an assumption: IL-10 is an anti-inflammatory mediator and a Treg signature cytokine.

  • May combine two claims.

    Findingcitation

    In the second phase I trial, healthy-volunteer plasma contained no measurable cytokines other than IL-10, which appeared transiently at significant levels in the two highest-dose groups.

    “scrutiny of the healthy volunteers 0 plasma revealed no detectable cytokines but one: the Treg signature cytokine IL-10, an important anti-inflammatory mediator which was transiently found at significant levels in the two groups receiving the highest doses of TAB08 (Fig. 3).”
    • Also stated in: § Closing remarks · plain
      “Dose-dependent release of IL-10, but not of cytokines causing a CRS, in second phase I study (from Ref.[53]).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] 53. Tabares P, Berr S, Romer PS, Chuvpilo S, Matskevich AA, Tyrsin D, Fedotov Y, Einsele H, Tony HP & Hunig T (2014) Human regulatory T cells are selectively activated by low-dose application of the CD28 superagonist TGN1412/TAB 08. Eur J Immunol 44, 1225-1236. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Adding methyl-prednisolone suppressed the in vitro cytokine storm caused by high CD28SA concentrations, while Treg activation and expansion remained partly intact.

    “inclusion of methyl-prednisolone, a corticosteroid routinely used to fight episodes of CRS in the clinic, effectively suppressed an in vitro cytokine storm triggered by high CD28SA concentrations while leaving Treg activation and expansion partially intact [53].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] 53. Tabares P, Berr S, Romer PS, Chuvpilo S, Matskevich AA, Tyrsin D, Fedotov Y, Einsele H, Tony HP & Hunig T (2014) Human regulatory T cells are selectively activated by low-dose application of the CD28 superagonist TGN1412/TAB 08. Eur J Immunol 44, 1225-1236. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    TAB08 response observations came from healthy-donor PBMCs and from patient cohorts with RA, MS, SLE, and psoriasis.

    “These observations were not only made with PBMC samples from healthy donors but also from cohorts of RA [53], MS, SLE, and psoriasis patients (unpublished).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] 53. Tabares P, Berr S, Romer PS, Chuvpilo S, Matskevich AA, Tyrsin D, Fedotov Y, Einsele H, Tony HP & Hunig T (2014) Human regulatory T cells are selectively activated by low-dose application of the CD28 superagonist TGN1412/TAB 08. Eur J Immunol 44, 1225-1236. source

      Not checked in the free run.

  • Not yet classified.

    Interpretation

    Endothelial cells first activated by proinflammatory cytokines can restore the in vitro TGN1412 response, suggesting that inflamed endothelium contributes to propagation rather than initiation of the cytokine release syndrome.

    “One exception is the ability of endothelial cells first activated by proinflammatory cytokines to restore the in vitro TGN1412 response, suggesting a contribution of inflamed endothelium to the propagation, rather than the initiation, of the CRS [44].”
    Quote in the paperNot yet classified0 of 1 sources checked
    • cites [44] 44. Weissmuller S, Semmler LY, Kalinke U, Christians S, Muller-Berghaus J & Waibler Z (2012) ICOS-LICOS interaction is critically involved in TGN1412-mediated T-cell activation. Blood 119, 6268-6277. source

      Not checked in the free run.

  • Not yet classified.

    Premise

    The first-in-human dose in the TGN1412 trial was based on the no observed adverse effect level method, which was considered best practice at that time.

    “In the case of the ill-fated TGN1412 phase I trial, the FIH dose had been based on the 'no observed adverse effect' (NOAEL) method [35], which at that point in time was considered best practice.”
    Quote in the paperNot yet classified0 of 1 sources checked
    • cites [35] 35. Tegenero (2005) TGN1412 Investigator's Brochure. Tegenero, www.circare.org/foia5/tgn1412dossier.pdf.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    CD28 superagonist treatment is therapeutically active in many rodent models of autoimmunity, inflammation, transplantation, and tissue repair.

    “are therapeutically active in many rodent models of autoimmunity, inflammation, transplantation, and tissue repair”
    Quote in the paperNot a substantial claim

  • Not yet classified.

    Study design and conduct

    The National Institute for Biological Standards and Control repeated key preclinical studies, including the cynomolgus macaque toxicity study used to calculate the first-in-human dose, and obtained results confirming those submitted by TeGenero.

    “were repeated by scientists at the UK's National Institute for Biological Standards and Control (NIBSC) with results confirming those submitted by TeGenero.”
    Quote in the paperNot yet classified

  • May combine two claims.

    Interpretationcitation

    The cytokine release syndrome was caused by CD28 superagonist activation of effector T cells that released proinflammatory cytokines such as TNF, interferon-gamma, IL-2, and IL-6, which were found at very high levels in blood shortly after dosing.

    “the known T cell-activating properties of the CD28SA must have activated the wrong type of T cells, i.e., effector T cells capable of releasing multiple proinflammatory cytokines such as TNF, interferon-c, IL-2, and IL-6, all of which were found at skyrocketing levels in blood samples taken only few hours after the drug had been applied [32].”
    • Also stated in: § Chapter four: Experts investigate and react · boosted
      “This, indeed, turned out to be true [33]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [32] 32. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD & Panoskaltsis N (2006) Cytokine storm in a phase 1 trial of the anti- CD28 monoclonal antibody TGN1412. New England J Med 355, 1018-1028. source

      Not checked in the free run.

    • cites [33] 33. Duff GWC (2006) Expert Scientific Group on Phase One Clinical Trials Final Report. Stationary Office, Norwich, UK.

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Tonic signaling and CD28 superagonist reactivity return when T cells reenter tissues, and the same occurs when peripheral blood mononuclear cells are cultured for two days at high cell density.

    “Of course, tonic signaling and CD28SA reactivity return when T cells reenter tissues, and this is also what happens when PBMCs are cultured for 2 days at a high cell density [45].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] 45. Romer PS, Berr S, Avota E, Na SY, Battaglia M, ten Berge I, Einsele H & Hunig T (2011) Preculture of PBMCs at high cell density increases sensitivity of T-cell responses, revealing cytokine release by CD28 superagonist TGN1412. Blood 118, 6772-6782. source

      Not checked in the free run.

  • Not yet classified.

    Interpretation

    The inability of T cells in freshly isolated peripheral blood mononuclear cells to respond to soluble CD28 superagonist results from the dependence of CD28 signal transduction on at least a weak T-cell receptor signal, which is then amplified by CD28-derived signals at the slp76 signalosome.

    “the inability of the T cells contained in freshly isolated PBMCs to respond to soluble CD28SA is the consequence of the dependence of CD28 signal transduction on at least a weak signal from the TCR, which is then amplified by CD28-derived signals at the level of the slp76 signalosome [13].”
    Quote in the paperNot yet classified0 of 1 sources checked
    • cites [13] 13. Dennehy KM, Elias F, Na SY, Fischer KD, Hunig T & Luhder F (2007) Mitogenic CD28 signals require the exchange factor Vav1 to enhance TCR signaling at the SLP-76-Vav-Itk signalosome. J Immunol 178, 1363-1371. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The TGN1412-triggered cytokine release syndrome was initiated in tissues rather than in the bloodstream, because only 1-2% of T cells are in circulation while the rest reside in tissues.

    “Only 1-2% of T cells are in circulation (and only very few of those interact with the endothelium at any given time, while the rest travels in suspension), whereas the rest reside in the tissues.It is there that the CRS was initiated after TGN1412 injection.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Circulating human T cells respond less strongly to activating stimuli than they do in tissue.

    “the responsiveness of circulating human T cells to activating stimuli underestimates their responsiveness in tissues.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    After the 2006 TGN1412 disaster, regulators acted promptly to make healthy-volunteer trials safer by requiring more data for first-in-human dose calculations and by strengthening on-site safety.

    “the regulatory authorities responded quickly to the disastrous TGN1412 trial of 2006 to improve the safety of healthy volunteers, implementing rules which extend the set of data to be requested for FIH calculations and improve safety onsite.”
    Quote in the paperNot a substantial claim

  • Not yet classified.

    Interpretation

    Primate testing cannot be relied on to reveal a biologic's potential toxicity, even when the target molecule matches the human one.

    “the use of primates to determine potential toxicity of biologicals cannot be trusted, even if the target molecule itself is identical to the human one”
    Quote in the paperNot yet classified

  • Not yet classified.

    Premise

    A single dose of the rat-specific CD28SA JJ316 rapidly expands splenic CD4+CD25+ regulatory T cells in rats.

    “Rapid expansion of regulatory T cells (here defined by FACS analyses as CD4+ CD25+ cells among splenic lymphocytes) in rats after a single injection of the rat-specific CD28SA JJ316.Modified from Ref.[2].”
    Quote in the paperNot yet classified0 of 1 sources checked
    • cites [2] 2. Lin C-H & Hunig T (2003) Efficient expansion of regulatory T-cells in vitro and in vivo with a CD28 superagonist. Eur J Immunol 33, 626-638. source

      Not checked in the free run.

  • Not yet classified.

    Interpretation

    The capillary leak syndrome in the 2006 London trial resulted indirectly from the large IL-2 release caused by the high TGN1412 dose.

    “including the capillary leakage syndrome also seen in the 2006 London trialan indirect effect of the massive IL-2 release induced by high-dose (from today 0 s perspective) TGN1412.”
    Quote in the paperNot yet classified
30 of 30

  • The paper relies on this without support.

    Regulatory T cells are dominant and essential controllers of autoimmunity, inflammation, and overshooting immune responses.

    “Given the enormous importance of Treg cells as dominant and essential controllers of autoimmunity, inflammation, and overshooting immune responses”

  • The paper relies on this without support.

    Dose reduction allows CD28 superagonist treatment to preferentially address regulatory T cells in humans.

    “after it became clear that dose-reduction allows to preferentially address regulatory T cells also in humans”

  • The paper relies on this without support.

    IL-10 is an anti-inflammatory mediator and a Treg signature cytokine.

    “the Treg signature cytokine IL-10, an important anti-inflammatory mediator which was transiently found at significant levels in the two groups receiving the highest doses of TAB08 (Fig. 3).”

  • The paper relies on this without support.

    The RESTORE in vitro assay's readouts are predictive of clinical responses to TAB08.

    “Our new in vitro assay using precultured PBMCdubbed RESTORE for resetting T cells to original reactivity [45]-allowed us to study the response of human T cells to soluble TAB08 at titrated concentrations”
4 of 4

Cites

Flagged first, then by citations

1 of the 55 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Duff GWC, 2006, Expert Scientific Group on Phase One Clinical Trials Final Report
  2. Tegenero, 2005, TGN1412 Investigator's Brochure

Cited by

Sorted by citations

Related

Authors
Hünig, T.
Affiliations
University of Würzburg (DE)
Corresponding author
Hünig, Thomas
Venue
The FEBS Journal
Publisher
Wiley
Published
2016-06-06
Volume
283
Issue
18
Pages
3325-3334
ISSN
  • 1742-464X (ISSN-L)
  • 1742-4658
DOI
10.1111/febs.13754
OpenAlex
W2404966097
Cited by
47
References
55
Citations by year
2026: 3 · 2025: 3 · 2024: 3 · 2023: 9 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 6 · 2018: 2 · 2017: 9 · 2016: 1 · 2015: 1
FWCI
3.63
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • FEBS Journal (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • TeGenero
  • TheraMab
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
Keywords
TGN1412, monoclonal antibodies, regulatory T cells, T cell activation, cytokine release syndrome, dose reduction, autoimmunity, transplantation, tissue repair, clinical development
MeSH terms
Animals, Drug Evaluation, Preclinical, Germany, Humans, London, Lymphocyte Activation, Mass Media, Cytokines, Treatment Failure, Clinical Trials, Phase I as Topic, CD28 Antigens, History, 20th Century, History, 21st Century, T-Lymphocytes, Regulatory, Mice, Rats, Antibodies, Monoclonal, Humanized, Healthy Volunteers

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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