The Role of Anti-Drug Antibodies in the Pharmacokinetics, Disposition, Target Engagement, and Efficacy of a GITR Agonist Monoclonal Antibody in Mice

Brunn, Nicholas D; Mauze, Smita; Gu, Danling; Wiswell, Derek; Ueda, Roanna; Hodges, Douglas; Beebe, Amy M.; Zhang, Shuli; Escandón, Enrique

doi:10.1124/jpet.115.229864

Cited by 15 publications

(11 citation statements)

References 55 publications

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“…The use of a therapeutic antibody of certain isotypes is linked with direct, complement mediated, and/or cell-mediated cytotoxicity (Brunn et al 2016 ; Murphy et al 2014 ). For the DTA-1 mAb, it is known that binding to its target elicits cytolytic effects (Coe et al 2010 ) that are proportional to the density of GITR on the cell surface.…”

Section: Discussionmentioning

confidence: 99%

Anti-GITR Antibody Treatment Increases TCR Repertoire Diversity of Regulatory but not Effector T Cells Engaged in the Immune Response Against B16 Melanoma

Ścirka

Szurek

Pietrzak³

et al. 2017

Arch. Immunol. Ther. Exp.

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Crosslinking of glucocorticoid-induced TNF family-related receptor (GITR) with agonist antibodies restores cancer immunity by enhancing effector T cell (Teff) responses while interfering with intra-tumor regulatory T cell (Treg) stability and/or accumulation. However, how anti-GITR antibody infusion changes T cell receptor (TCR) repertoire of Teffs and Tregs engaged in anti-tumor immune response is unclear. Here, we used a transgenic mouse model (TCRmini) where T cells express naturally generated but limited TCR repertoire to trace the fate of individual T cells recognizing B16 melanoma in tumor-bearing mice, treated or non-treated with an anti-GITR monoclonal antibody DTA-1. Analysis of TCRs of CD4+ T cells from these mice revealed that the TCR repertoire of dominant tumor-reactive Teff clones remained rather similar in treated and non-treated mice. In contrast, both tumor-associated and peripheral TCR repertoire of Tregs, which were mostly distinct from that of Teffs, underwent DTA-1 mediated remodeling characterized by depletion of dominant clones and an emergence of more diverse, low-frequency clones bearing increased numbers of TCRs shared with Teffs. We conclude that the DTA-1 infusion eliminates activated Tregs engaged in the initial maintenance of tolerogenic niche for tumor growth, but over time, it favors tumor replenishment by Tregs expressing an array of TCRs able to compete with Teffs for recognition of the same tumor antigens which may prevent its complete eradication.Electronic supplementary materialThe online version of this article (doi:10.1007/s00005-017-0479-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Anti-GITR Antibody Treatment Increases TCR Repertoire Diversity of Regulatory but not Effector T Cells Engaged in the Immune Response Against B16 Melanoma

Ścirka

Szurek

Pietrzak³

et al. 2017

Arch. Immunol. Ther. Exp.

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“…IC, where the drug is in complex with nonneutralizing ADAs. The uptake and degradation of DTA-1-induced IC through FcgR recognition and internalization by Kupffer cells (reticuloendothelial system) have been recently reviewed in detail by Brunn et al (54). The experimental assessment that we used to characterize ADAs shows typical analytical challenges, especially clear limitations to differentiate between bivalent and multivalent ADAs.…”

Section: Discussionmentioning

confidence: 99%

Murinization and H Chain Isotype Matching of the Anti-GITR Antibody DTA-1 Reduces Immunogenicity-Mediated Anaphylaxis in C57BL/6 Mice

Belmar

Chan

Fox

et al. 2017

The Journal of Immunology

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Recent advances in immuno-oncology have shown that the immune system can be activated to induce long-term, durable antitumor responses. For immuno-oncology drug development, immune activation is often explored using rat Abs in immunocompetent mouse models. Although these models can be used to show efficacy, antidrug immune responses to experimental protein-based therapeutics can arise. Immunogenicity of surrogate Abs may therefore represent an important obstacle to the evaluation of the antitumor efficacy of immunomodulator Abs in syngeneic models. A recent publication has shown that anti-glucocorticoid–induced TNFR family–related protein agonistic Ab DTA-1 (rat or murinized IgG2a) can induce the development of anaphylaxis in C57BL/6 mice upon repeated i.p. dosing because of an anti-idiotypic anti-drug Ab immune response. This study was undertaken to address the impact of the immunogenicity derived from the Fc and variable domains. To this end, chimerized (rat V domains/mouse constant regions) and murinized (95% mouse sequence) DTA-1–based surrogate Abs with a murine IgG2c H chain isotype were created. Chimerization and murinization of DTA-1 did not affect receptor binding and glucocorticoid-induced TNFR family–related protein–induced T cell agonistic properties. Similar in vivo antitumor efficacy and intratumoral CD8+/regulatory T cells were also observed. Finally, treatment of C57BL/6 mice with the chimerized and murinized DTA-1 Abs on a C57BL/6-matched IgG2c isotype resulted in reduced development and severity of anaphylaxis as measured by decline of body temperature, behavioral effects, serum IL-4, IgE, and anti-drug Ab levels. These results suggest that careful murinization and selection of a strain-matched H chain isotype are critical to generate ideal surrogate Abs for testing immuno-oncology mechanisms in vivo.

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“…GITR stimulation is capable of activating T effector cells (59), by upregulation of IL2Rα and production of IL-2 and IFN-γ (56,60), while inhibiting Tregs functions with FOXP3 suppression (61)(62)(63). Early preclinical data in several solid tumor models confirmed the therapeutic antitumor potential of GITR stimulation, especially in combination with other immune-modulatory agents (64)(65)(66)(67)(68)(69)(70)(71). Notably, the beneficial effect of GITR agonists included also poorly immunogenic models that were limitedly affected by the activation of other stimulatory pathways like that of OX40 (65)(66)(67)(68)(69)(70)(71).…”

Section: Glucocorticoid-induced Tnf Receptor-related Gene (Gitr)mentioning

confidence: 95%

Next generation immune-checkpoints for cancer therapy

Donini¹,

D’Ambrosio²,

Grignani³

et al. 2018

J. Thorac. Dis.

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The discovery and clinical application of immune-checkpoint inhibitors has dramatically improved the treatments, outcomes and therapeutic concepts in multiple tumor settings. This breakthrough was mainly based on monoclonal antibodies blocking the inhibitory molecule CTLA-4 and or the PD-1/PD-L1 axis, with the aim of counteracting major tumor immune evasion mechanisms. Even acknowledging these important successes, not all the patients benefit from these treatments. Translational and clinical research efforts are ongoing to explore the potentialities of a new generation of immune-modulatory molecules to extend current clinical applications and contrast the unsolved issues of resistance and disease relapse that still affects a considerable rate of patients. New immune-checkpoints, with either stimulatory or inhibitory functions are emerging with key roles in regulating T cell response but also affecting other crucial effectors belonging to the innate immune response (e.g., natural killer). Their therapeutic exploitation, either alone or in strategical combinations, is providing important preclinical results, holding promises currently explored in initial clinical trials. The first results point toward favorable safety profiles with selective hints of activity in challenging settings. Important issues regarding the dose, schedule and rational combinations remain open and data from the clinical studies are needed. Here we provide an overview of the main emerging stimulatory or inhibitory immune-checkpoints exploitable in cancer treatment, briefly reporting their biological function, preclinical activity and preliminary clinical data.

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The Role of Anti-Drug Antibodies in the Pharmacokinetics, Disposition, Target Engagement, and Efficacy of a GITR Agonist Monoclonal Antibody in Mice

Cited by 15 publications

References 55 publications

Anti-GITR Antibody Treatment Increases TCR Repertoire Diversity of Regulatory but not Effector T Cells Engaged in the Immune Response Against B16 Melanoma

Anti-GITR Antibody Treatment Increases TCR Repertoire Diversity of Regulatory but not Effector T Cells Engaged in the Immune Response Against B16 Melanoma

Murinization and H Chain Isotype Matching of the Anti-GITR Antibody DTA-1 Reduces Immunogenicity-Mediated Anaphylaxis in C57BL/6 Mice

Next generation immune-checkpoints for cancer therapy

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