Immunomodulatory activity of humanized anti–IL-7R monoclonal antibody RN168 in subjects with type 1 diabetes

Herold, Kevan C.; Bucktrout, Samantha; Wang, Xiao; Bode, Bruce W.; Gitelman, Stephen E.; Gottlieb, Peter A.; Hughes, Jing W.; Joh, Tenshang; McGill, Janet B.; Pettus, Jeremy; Potluri, Shobha; Schatz, Desmond; Shannon, Megan; Udata, Chandrasekhar; Wong, Gilbert Y.; Levisetti, Matteo; Ganguly, Bishu; Garzone, Pamela D.

doi:10.1172/jci.insight.126054

Cited by 26 publications

(18 citation statements)

References 37 publications

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“…The study was a phase 1b, multi-center, within cohort randomized, double-blind (sponsor-open), placebo-controlled study in adults with T1D. Additional details of the study design, as well as the safety and immunogenicity results of this study, are presented separately [14]. Briefly, eligible participants were adults (aged ≥ 18 years) with a diagnosis of T1D based on the American Diabetes Association criteria within 2 years of randomization; confirmation of at least one T1D-related autoantibody (i.e., GAD, ICA512/IA2, anti-ZnT8, or insulin autoantibodies (provided insulin therapy of less than 14-day duration)) present either at screening or documented history within 2 years of randomization; peak stimulated C-peptide levels ≥ 0.15 ng/mL measured during a mixed-meal tolerance test (MMTT) prior to randomization; body mass index (BMI) of 18.5 to 32 kg/m 2 ; and total body weight ≥ 40 kg and ≤ 120 kg.…”

Section: Methodsmentioning

confidence: 99%

“…A breakdown of the number of subjects by cohort and the number of PK and PD measurements is provided in Table I. The overall demographics of subjects enrolled in the study are described elsewhere [14].…”

Section: Subjects and Data Set Characteristicsmentioning

confidence: 99%

“…PF-06342674 is a fully human immunoglobulin G1 (IgG1) mAb that binds to IL-7Rα blocking cognate binding of IL-7 and inhibiting IL-7Rα signaling and function. PF-06342674 has previously been evaluated following single ascending doses by either subcutaneous (SC) or intravenous (IV) routes of administration in healthy volunteers (ClinicalTrials.gov, NCT01740609), and following multiple ascending doses (MAD) administered by subcutaneous injection in adults with T1D (ClinicalTrials.gov, NCT02038764) [14]. In the MAD study, the safety and tolerability of multiple SC doses of PF-06342674 were evaluated in adults diagnosed with T1D within 2 years of study entry.…”

Section: Introductionmentioning

confidence: 99%

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Model-Based Characterization of the Pharmacokinetics, Target Engagement Biomarkers, and Immunomodulatory Activity of PF-06342674, a Humanized mAb Against IL-7 Receptor-α, in Adults with Type 1 Diabetes

Williams

Udata

Ganguly

et al. 2020

AAPS J

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IL-7 receptor-α (IL-7Rα) blockade has been shown to reverse autoimmune diabetes in the non-obese diabetic mouse by promoting inhibition of effector T cells and consequently altering the balance of regulatory T (T reg ) and effector memory (T EM ) cells. PF-06342674 is a humanized monoclonal antibody that binds to and inhibits the function of IL-7Rα. In the current phase 1b study, subjects with type 1 diabetes (T1D) received subcutaneous doses of either placebo or PF-06342674 (1, 3, 8 mg/kg/q2w or 6 mg/kg/q1w) for 10 weeks and were followed up to 18 weeks. Nonlinear mixed effects models were developed to characterize the pharmacokinetics (PK), target engagement biomarkers, and immunomodulatory activity. PF-06342674 was estimated to have 20-fold more potent inhibitory effect on T EM cells relative to T reg cells resulting in a non-monotonic dose-response relationship for the T reg :T EM ratio, reaching maximum at~3 mg/kg/q2w dose. Target-mediated elimination led to nonlinear PK with accelerated clearance at lower doses due to high affinity binding and rapid clearance of the drug-target complex. Doses ≥ 3 mg/kg q2w result in sustained PF-06342674 concentrations higher than the concentration of cellular IL-7 receptor and, in turn, maintain near maximal receptor occupancy over the dosing interval. The results provide important insight into the mechanism of IL-7Rα blockade and immunomodulatory activity of PF-06342674 and establish a rational framework for dose selection for subsequent clinical trials of PF-06342674. Furthermore, this analysis serves as an example of mechanistic modeling to support dose selection of a drug candidate in the early phases of development.

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Section: Methodsmentioning

confidence: 99%

Section: Subjects and Data Set Characteristicsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Model-Based Characterization of the Pharmacokinetics, Target Engagement Biomarkers, and Immunomodulatory Activity of PF-06342674, a Humanized mAb Against IL-7 Receptor-α, in Adults with Type 1 Diabetes

Williams

Udata

Ganguly

et al. 2020

AAPS J

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“…Indeed, the protective effect induced by anti-CD127 mAb in NOD mice is reversed by treatment with a PD-1 blocking mAb, known to rescue exhausted T cells ( 203 ). T1D patients treated with the anti-IL-7Rα mAb RN168 show a reduction in Tmem and activated T cells while the FOXP3 + Treg pool is maintained ( 205 ). Nevertheless, C-peptide levels are not markedly altered, which may reflect the dose and/or duration of RN168 administered.…”

Section: The Application Of Nondepleting Mab For T1dmentioning

confidence: 99%

Evolving Antibody Therapies for the Treatment of Type 1 Diabetes

et al. 2021

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Type 1 diabetes (T1D) is widely considered to be a T cell driven autoimmune disease resulting in reduced insulin production due to dysfunction/destruction of pancreatic β cells. Currently, there continues to be a need for immunotherapies that selectively reestablish persistent β cell-specific self-tolerance for the prevention and remission of T1D in the clinic. The utilization of monoclonal antibodies (mAb) is one strategy to target specific immune cell populations inducing autoimmune-driven pathology. Several mAb have proven to be clinically safe and exhibit varying degrees of efficacy in modulating autoimmunity, including T1D. Traditionally, mAb therapies have been used to deplete a targeted cell population regardless of antigenic specificity. However, this treatment strategy can prove detrimental resulting in the loss of acquired protective immunity. Nondepleting mAb have also been applied to modulate the function of immune effector cells. Recent studies have begun to define novel mechanisms associated with mAb-based immunotherapy that alter the function of targeted effector cell pools. These results suggest short course mAb therapies may have persistent effects for regaining and maintaining self-tolerance. Furthermore, the flexibility to manipulate mAb properties permits the development of novel strategies to target multiple antigens and/or deliver therapeutic drugs by a single mAb molecule. Here, we discuss current and potential future therapeutic mAb treatment strategies for T1D, and T cell-mediated autoimmunity.

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“…Another mAb (PF-06342674/RN168) developed by Pfizer has completed a phase I clinical trial in healthy volunteers. While the MS clinical trial was terminated by Pfizer themselves, the T1D phase I clinical trial evaluated the safety and tolerability of multiple SC doses in type 1 diabetes patients and showed that certain dose of mAb selectively inhibits survival and activity of memory T cells while preserving naive T cells and T reg ( 172 ). Additional model study of its pharmacokinetics showed that it has a 20-fold more potent inhibitory effect on T EM cells relative to T reg cells at a similar dose confirming the implication that these effects could serve to eliminate pathologic T cells in autoimmune diseases ( 173 ) ( Table 2 ).…”

Section: Modulators Of Il-7 Signalingmentioning

confidence: 99%

Modulation of Signaling Mediated by TSLP and IL-7 in Inflammation, Autoimmune Diseases, and Cancer

Marković

Savvides

2020

Front. Immunol.

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Thymic Stromal Lymphopoietin (TSLP) and Interleukin-7 (IL-7) are widely studied cytokines within distinct branches of immunology. On one hand, TSLP is crucially important for mediating type 2 immunity at barrier surfaces and has been linked to widespread allergic and inflammatory diseases of the airways, skin, and gut. On the other hand, IL-7 operates at the foundations of T-cell and innate lymphoid cell (ILC) development and homeostasis and has been associated with cancer. Yet, TSLP and IL-7 are united by key commonalities in their structure and the structural basis of the receptor assemblies they mediate to initiate cellular signaling, in particular their cross-utilization of IL-7Rα. As therapeutic targeting of TSLP and IL-7 via diverse approaches is reaching advanced stages and in light of the plethora of mechanistic and structural data on receptor signaling mediated by the two cytokines, the time is ripe to provide integrated views of such knowledge. Here, we first discuss the major pathophysiological roles of TSLP and IL-7 in autoimmune diseases, inflammation and cancer. Subsequently, we curate structural and mechanistic knowledge about receptor assemblies mediated by the two cytokines. Finally, we review therapeutic avenues targeting TSLP and IL-7 signaling. We envision that such integrated view of the mechanism, structure, and modulation of signaling assemblies mediated by TSLP and IL-7 will enhance and fine-tune the development of more effective and selective approaches to further interrogate the role of TSLP and IL-7 in physiology and disease.

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Immunomodulatory activity of humanized anti–IL-7R monoclonal antibody RN168 in subjects with type 1 diabetes

Cited by 26 publications

References 37 publications

Model-Based Characterization of the Pharmacokinetics, Target Engagement Biomarkers, and Immunomodulatory Activity of PF-06342674, a Humanized mAb Against IL-7 Receptor-α, in Adults with Type 1 Diabetes

Model-Based Characterization of the Pharmacokinetics, Target Engagement Biomarkers, and Immunomodulatory Activity of PF-06342674, a Humanized mAb Against IL-7 Receptor-α, in Adults with Type 1 Diabetes

Evolving Antibody Therapies for the Treatment of Type 1 Diabetes

Modulation of Signaling Mediated by TSLP and IL-7 in Inflammation, Autoimmune Diseases, and Cancer

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