246.6: Long-term Rejection Free Renal Allograft Survival With Fc-Modified Anti-CD154 Antibody Monotherapy in Nonhuman Primates

Lassiter, Grace; Hirose, Takayuki; D’Attilio, Ashley; Karadagi, Ahmad; Otsuka, Ryo; Tomosugi, Toshihide; Kawai, Tatsuo

doi:10.1097/01.tp.0000886172.50326.54

Cited by 4 publications

(10 citation statements)

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“…Our group and others have previously demonstrated that most NHPs treated with belatacept monotherapy will reject within the first 3 months ( 40 , 41 ). The 90-day endpoint also keeps with previous reports of anti-CD40L monotherapy in NHPs ( 28 , 42 ).…”

Section: Discussionsupporting

confidence: 85%

“…Sanofi also has multiple currently active phase 2 trials with a CD40L-blocking compound for Sjogren’s syndrome, systemic lupus erythematosus, and multiple sclerosis. Another Fc-modified anti-CD40L mAb developed by Tonix has been shown to prolong both renal ( 42 ) and cardiac ( 45 ) allograft survival in NHP models but has not yet been trialed in the clinic. Biological differences exist between anti-CD40L agents and are thought to lead to different efficacies ( 15 ).…”

Section: Discussionmentioning

confidence: 99%

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The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates

Anwar,

Berman,

DeLaura

et al. 2023

Sci. Transl. Med.

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Prior studies of anti-CD40 ligand (CD40L)–based immunosuppression demonstrated effective prevention of islet and kidney allograft rejection in nonhuman primate models; however, clinical development was halted because of thromboembolic complications. An anti-CD40L-specific monoclonal antibody, AT-1501 (Tegoprubart), was engineered to minimize risk of thromboembolic complications by reducing binding to Fcγ receptors expressed on platelets while preserving binding to CD40L. AT-1501 was tested in both a cynomolgus macaque model of intrahepatic islet allotransplantation and a rhesus macaque model of kidney allotransplantation. AT-1501 monotherapy led to long-term graft survival in both islet and kidney transplant models, confirming its immunosuppressive potential. Furthermore, AT-1501–based regimens after islet transplant resulted in higher C-peptide, greater appetite leading to weight gain, and reduced occurrence of cytomegalovirus reactivation compared with conventional immunosuppression. These data support AT-1501 as a safe and effective agent to promote both islet and kidney allograft survival and function in nonhuman primate models, warranting further testing in clinical trials.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates

Anwar,

Berman,

DeLaura

et al. 2023

Sci. Transl. Med.

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“…It has an antibody binding fragment (Fab) region of hu5C8 and a modified Fc region (type 4 immunoglobulin G [IgG4]) engineered to reduce FcγRIIa-binding associated with the risk of thrombosis. Efficacy of TNX-1500 has been tested in a heterotopic kidney 46 and heart 47 allotransplant model in NHPs. Lassiter et al demonstrate that monotherapy of TNX-1500 prolongs the renal allograft survival, whereas treatment with MMF resulted in increased allograft failure.…”

Section: Tnx-1500mentioning

confidence: 99%

“…Dazodalibep (HZN-4920/VIB4920) Kidney transplantation 45 Prevents renal allograft rejection Phase 2a TNX-1500 Kidney transplantation 46 Cardiac transplantation 47 Monotherapy prolongs the renal allograft survival without thrombotic complications SLE, systemic lupus erythematosus.…”

Section: Clinical Trial Statusmentioning

confidence: 99%

“…Lassiter et al demonstrate that monotherapy of TNX-1500 prolongs the renal allograft survival, whereas treatment with MMF resulted in increased allograft failure. 46 Miura et al also demonstrated that standard treatment of TNX-1500 mAb to NHPs prolongs allograft survival without TE complications. And TNX-1500 mAb also inhibits alloimmunity, alloantibody production, and class switching of immunoglobulin subtypes.…”

Section: Introductionmentioning

confidence: 98%

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CD40-CD40L Blockade: Update on Novel Investigational Therapeutics for Transplantation

et al. 2023

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Effective immune responses require antigen presentation by major histocompatibility complexes with cognate T-cell receptor and antigen-independent costimulatory signaling for T-cell activation, proliferation, and differentiation. Among several costimulatory signals, CD40-CD40L is of special interest to the transplantation community because it plays a vital role in controlling or regulating humoral and cellular immunity. Blockade of this pathway has demonstrated inhibition of donor-reactive T-cell responses and prolonged the survival of transplanted organs. Several anti-CD154 and anti-CD40 antibodies have been used in the transplantation model and demonstrated the potential of extending allograft and xenograft rejection-free survival. The wide use of anti-CD154 antibodies was hampered because of thromboembolic complications in transplant recipients. These antibodies have been modified to overcome the thromboembolic complications by altering the antibody binding fragment (Fab) and Fc (fragment, crystallizable) receptor region for therapeutic purposes. Here, we review recent preclinical advances to target the CD40-CD40L pair in transplantation.

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T cell responsiveness to IL-10 defines the immunomodulatory effect of costimulation blockade via anti-CD154 and impacts transplant survival

Iglesias,

Bibicheff,

Komin

et al. 2024

Preprint

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Costimulation blockade (CoB)-based immunotherapy is a promising alternative to immunosuppression for transplant recipients; however, the current limited understanding of the factors that impact its efficacy restrains its clinical applicability. In this context, pro- and anti-inflammatory cytokines are being recognized as having an impact on T cell activation beyond effector differentiation. This study aims at elucidating the impact of direct IL-10 signaling in T cells on CoB outcomes. We used a full-mismatch skin transplantation model where recipients had a T cell-restricted expression of a dominant negative IL-10 receptor (10R-DN), alongside anti-CD154 as CoB therapy. Unlike wild-type recipients, 10R-DN mice failed to benefit from CoB. This accelerated graft rejection correlated with increased accumulation of T cells producing TNF-α, IFN-γ, and IL-17. In vitro experiments indicated that while lack of IL-10 signaling did not change the ability of anti-CD154 to modulate alloreactive T cell proliferation, the absence of this pathway heightened TH1 effector cell differentiation. Furthermore, deficiency of IL-10 signaling in T cells impaired Treg induction, a hallmark of anti-CD154 therapy. Overall, these findings unveil an important and novel role of IL-10 signaling in T cells that defines the success of CoB therapies and identifies a target pathway for obtaining robust immunoregulation.

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246.6: Long-term Rejection Free Renal Allograft Survival With Fc-Modified Anti-CD154 Antibody Monotherapy in Nonhuman Primates

Cited by 4 publications

References 0 publications

The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates

The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates

CD40-CD40L Blockade: Update on Novel Investigational Therapeutics for Transplantation

T cell responsiveness to IL-10 defines the immunomodulatory effect of costimulation blockade via anti-CD154 and impacts transplant survival

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