JTA–009, a fully human antibody against human AILIM/ICOS, ameliorates graft–vs–host reaction in SCID mice grafted with human PBMCs

Tajima, Naoki; Tezuka, Katsunari; Tanimoto, Atsuo; Miyai, Atsuko; Tanimoto, Minako; Maruhashi, Junji; Watanabe, Yoshihiro

doi:10.1016/j.exphem.2008.06.004

Cited by 15 publications

(11 citation statements)

References 43 publications

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“…Several murine studies have also shown that the ICOS pathway plays a detrimental role on GVHD, but whether GVL was maintained upon ICOS blockade was not addressed (15, 16, 28). To our knowledge, only one study reports that a humanized mAb directed against human ICOS partially protected SCID mice from a xenogeneic GVHD (29). However, the limited numbers of animals used in this study, the short duration of the follow-up, and some limitations with the CB17-SCID animal model render these data still preliminary.…”

Section: Discussionmentioning

confidence: 99%

Targeting the Human T-Cell Inducible COStimulator Molecule with a Monoclonal Antibody Prevents Graft-vs-Host Disease and Preserves Graft vs Leukemia in a Xenograft Murine Model

et al. 2017

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BackgroundGraft-vs-host disease (GVHD) is a major complication of allogenic bone marrow transplantation (BMT). Targeting costimulatory molecules with antagonist antibodies could dampen the excessive immune response that occurs, while preserving the beneficial graft vs leukemia (GVL) of the allogeneic response. Previous studies using a mouse model of GVHD have shown that targeting the T-cell Inducible COStimulator (ICOS, CD278) molecule is beneficial, but it is unclear whether the same applies to human cells.MethodsHere, we assessed whether a monoclonal antibody (mAb) to human ICOS was able to antagonize the costimulatory signal delivered in vivo to human T cells. To test this hypothesis, we used a xenogeneic model of GVHD where human peripheral blood mononuclear cells were adoptively transferred in immunocompromised NOD.SCID.gc-null mice (NSG).ResultsIn this model, control mice invariably lost weight and died by day 50. In contrast, 65% of the mice receiving a single injection of the anti-hICOS mAb survived beyond 100 days. Moreover, a significant improvement in survival was obtained in a curative xeno-GVHD setting. Mechanistically, administration of the anti-hICOS mAb was associated with a strong reduction in perivascular infiltrates in liver and lungs and reduction in frequencies and numbers of human T cells in the spleen. In addition, the mAb prevented T-cell expansion in the blood during xeno-GVHD. Importantly, GVHD-protected mice retained the ability to control the P815 mastocytoma cell line, mimicking GVL in humans.ConclusionA mAb-targeting human ICOS alleviated GVHD without impairing GVL in a xenograft murine model. Thus, ICOS represents a promising target in the management of BMT, preventing GVHD while preserving GVL.

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Section: Discussionmentioning

confidence: 99%

Targeting the Human T-Cell Inducible COStimulator Molecule with a Monoclonal Antibody Prevents Graft-vs-Host Disease and Preserves Graft vs Leukemia in a Xenograft Murine Model

et al. 2017

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“…Anti–murine-ICOS has been successfully used to alleviate murine GVHD (66) and a syngeneic mouse model of melanoma transplanted with Tc17 (59). Different clones of anti–human-ICOS have been successfully used to ameliorate GVHD in SCID mice grafted with human PBMCs (67) and in the context of tumoral microenvironment (68). …”

Section: Discussionmentioning

confidence: 99%

Proteomics analysis reveals a Th17-prone cell population in presymptomatic graft-versus-host disease

Li¹,

Liu²,

Gomez³

et al. 2016

JCI Insight

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Gastrointestinal graft-versus-host-disease (GI-GVHD) is a life-threatening complication occurring after allogeneic hematopoietic cell transplantation (HCT), and a blood biomarker that permits stratification of HCT patients according to their risk of developing GI-GVHD would greatly aid treatment planning. Through in-depth, large-scale proteomic profiling of presymptomatic samples, we identified a T cell population expressing both CD146, a cell adhesion molecule, and CCR5, a chemokine receptor that is upregulated as early as 14 days after transplantation in patients who develop GI-GVHD. The CD4+CD146+CCR5+ T cell population is Th17 prone and increased by ICOS stimulation. shRNA knockdown of CD146 in T cells reduced their transmigration through endothelial cells, and maraviroc, a CCR5 inhibitor, reduced chemotaxis of the CD4+CD146+CCR5+ T cell population toward CCL14. Mice that received CD146 shRNA–transduced human T cells did not lose weight, showed better survival, and had fewer CD4+CD146+CCR5+ T cells and less pathogenic Th17 infiltration in the intestine, even compared with mice receiving maraviroc with control shRNA– transduced human T cells. Furthermore, the frequency of CD4+CD146+CCR5+ Tregs was increased in GI-GVHD patients, and these cells showed increased plasticity toward Th17 upon ICOS stimulation. Our findings can be applied to early risk stratification, as well as specific preventative therapeutic strategies following HCT.

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“…Currently, more selective CD28 blockade rather than B7 blockade, e.g. belatacept and non-activating CD28-specific Ab, have been produced (45, 46), and a fully humanized Ab against human ICOS was also generated (47). These reagents can be used in the translation of our research finding into clinical practice in allogeneic HCT.…”

Section: Discussionmentioning

confidence: 99%

Roles of CD28, CTLA4, and Inducible Costimulator in Acute Graft-versus-Host Disease in Mice

Semple

Suh

et al. 2011

Biology of Blood and Marrow Transplantation

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T cells deficient for CD28 have reduced ability to expand and survive, but still cause graft-versus-host disease (GVHD). Inducible costimulator (ICOS), the third member of the CD28 family, is expressed on antigen-activated T cells and has unique roles in T-cell activation and effector function. We hypothesized that ICOS contributes to the development of GVHD in the absence of B7:CD28/CTLA4 costimulation. In this study, we evaluated the roles of CD28, CTLA4 and ICOS in the pathogenesis of acute GVHD under myeloablative allogeneic bone marrow transplantation (BMT). Unexpectedly, we found that blocking CD28 and CTLA4 signals using the clinically relevant reagent, CTLA4-Ig, results in the enhancement of GVHD severity mediated by CD4+ T cells, and such treatment does not add any benefit to blockade of ICOS. In contrast, selectively blocking CD28 and ICOS but not CTLA4 prevents GVHD more effectively than blocking either CD28 or ICOS alone. Taken together, these results indicate that CD28 and ICOS are synergistic in promoting GVHD, whereas the CTLA4-signal is required for T-cell tolerance regardless of ICOS signaling. Thus, blocking CD28 and ICOS while sparing CTLA4 represents a promising approach for abrogating pathogenic T-cell responses after allogeneic BMT.

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JTA–009, a fully human antibody against human AILIM/ICOS, ameliorates graft–vs–host reaction in SCID mice grafted with human PBMCs

Cited by 15 publications

References 43 publications

Targeting the Human T-Cell Inducible COStimulator Molecule with a Monoclonal Antibody Prevents Graft-vs-Host Disease and Preserves Graft vs Leukemia in a Xenograft Murine Model

Targeting the Human T-Cell Inducible COStimulator Molecule with a Monoclonal Antibody Prevents Graft-vs-Host Disease and Preserves Graft vs Leukemia in a Xenograft Murine Model

Proteomics analysis reveals a Th17-prone cell population in presymptomatic graft-versus-host disease

Roles of CD28, CTLA4, and Inducible Costimulator in Acute Graft-versus-Host Disease in Mice

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