Selective <scp>CD</scp>28 antagonist prevents Aldara‐induced skin inflammation in non‐human primates

Poirier, Nicolas; Chevalier, Melanie; Mary, Caroline; Hervouet, Jérémy; Minault, David; Bas‐Bernardet, Stéphanie Le; Belarif, Lyssia; Daguin, Véronique; Cassagnau, E.; Vanhove, Bernard; Blancho, Gilles

doi:10.1111/exd.12891

Cited by 7 publications

(7 citation statements)

References 9 publications

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“…Sections were saturated with PBS containing 10% baboon serum, 2% normal goat and donkey serum, and 4% BSA. Sections were incubated overnight with primary Abs at 4 °C, followed by fluorescent secondary Abs as previously described 45 , 69 . T cell infiltration analysis was performed using rabbit anti-human CD3 Ab (Dako), and macrophage infiltration using a mouse anti-human CD68 Ab (clone KP1; Dako).…”

Section: Methodsmentioning

confidence: 99%

IL-7 receptor blockade blunts antigen-specific memory T cell responses and chronic inflammation in primates

et al. 2018

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Targeting the expansion of pathogenic memory immune cells is a promising therapeutic strategy to prevent chronic autoimmune attacks. Here we investigate the therapeutic efficacy and mechanism of new anti-human IL-7Rα monoclonal antibodies (mAb) in non-human primates and show that, depending on the target epitope, a single injection of antagonistic anti-IL-7Rα mAbs induces a long-term control of skin inflammation despite repeated antigen challenges in presensitized monkeys. No modification in T cell numbers, phenotype, function or metabolism is observed in the peripheral blood or in response to polyclonal stimulation ex vivo. However, long-term in vivo hyporesponsiveness is associated with a significant decrease in the frequency of antigen-specific T cells producing IFN-γ upon antigen restimulation ex vivo. These findings indicate that chronic antigen-specific memory T cell responses can be controlled by anti-IL-7Rα mAbs, promoting and maintaining remission in T-cell mediated chronic inflammatory diseases.

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Section: Methodsmentioning

confidence: 99%

IL-7 receptor blockade blunts antigen-specific memory T cell responses and chronic inflammation in primates

et al. 2018

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“…Non-activating antagonist monovalent Ab fragments against CD28 prevented allograft rejection in mice (18) as well as in non-human primates with a higher efficacy than with CTLA4-Ig reagents (5,(19)(20)(21). Besides transplantation, preclinical proofs of concept have also been obtained in non-human primate models of multiple sclerosis (22), rheumatoid arthritis (23), and psoriasis (24). Mechanistically, selective CD28 antagonists have demonstrated their potential to induce long-term Ag-specific unresponsiveness in a cutaneous delayed type hypersensitivity model (25) and after kidney transplantation in non-human primates (19).…”

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confidence: 99%

First-in-Human Study in Healthy Subjects with FR104, a Pegylated Monoclonal Antibody Fragment Antagonist of CD28

Poirier

Blancho

Hiance

et al. 2016

The Journal of Immunology

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FR104 is a monovalent pegylated Fab' Ab, antagonist of CD28, under development for treatment of transplant rejection and autoimmune diseases. In contrast to CD80/86 antagonists (CTLA4-Ig), FR104 selectively blunts CD28 costimulation while sparing CTLA-4 and PD-L1 coinhibitory signals. In the present work, FR104 has been evaluated in a first-in-human study to evaluate the safety, pharmacokinetics, pharmacodynamics, and potency of i.v. administrations in healthy subjects. Sixty-four subjects were randomly assigned to four single ascending dose groups, two double dose groups and four single ascending dose groups challenged with keyhole limpet hemocyanin. Subjects were followed up over a maximum of 113 d. Overall, the pharmacokinetics of FR104 after a single and double infusions was approximately linear at doses ≥0.200 mg/kg. CD28 receptor occupancy by FR104 was saturated at the first sampling time point (0.5 h) at doses above 0.02 mg/kg and returned to 50% in a dose-dependent manner, by day 15 (0.020 mg/kg) to 85 (1.500 mg/kg). FR104 was well tolerated, with no evidence of cytokine-release syndrome and no impact on blood lymphocyte subsets. Inhibition of anti-keyhole limpet hemocyanin Ab response was dose-dependent in FR104 recipients and was already apparent at a dose of 0.02 mg/kg. Abs to FR104 were detected in 22/46 (48%) of FR104 recipients and only 1/46 (2.2%) was detected during drug exposure. In conclusion, selective blockade of CD28 with FR104 was safe and well tolerated at the doses tested. The observed immunosuppressive activity indicated that FR104 has potential to show clinical activity in the treatment of immune-mediated diseases.

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“…Topical treatment of mouse skin with Aldara was reported as a novel mouse skin inflammatory model with histology that closely resembles psoriasis inducing acanthosis, parakeratosis, and a mixed inflammatory infiltrate with a predominance of the IL23/IL-17 axis similar to humans [49,50,51]. We found that daily topical application over 2 weeks to baboons also induced chronic erythema, as well as skin thickening and scaling, with a histology which resembled psoriasis and lichenoid lesions, and with a predominance of the IL-23/IL-17 molecular axis [52]. Skin inflammation resolved spontaneously after arrest of Aldara application, allowing us to perform different cycles of Aldara over months to model relapse phases in patients.…”

Section: Models Of Immune-mediated Diseases Of the Skinmentioning

confidence: 88%

Antagonist Anti-CD28 Therapeutics for the Treatment of Autoimmune Disorders

et al. 2017

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Abstract:The effector functions of T lymphocytes are responsible for most autoimmune disorders and act by directly damaging tissues or by indirectly promoting inflammation and antibody responses. Co-stimulatory and co-inhibitory T cell receptor molecules are the primary pharmacological targets that enable interference with immune-mediated diseases. Among these, selective CD28 antagonists have drawn special interest, since they tip the co-stimulation/co-inhibition balance towards efficiently inhibiting effector T cells while promoting suppression by pre-existing regulatory T-cells. After having demonstrated outstanding therapeutic efficacy in multiple models of autoimmunity, inflammation and transplantation, and safety in phase-I studies in humans, selective CD28 antagonists are currently in early clinical development for the treatment of systemic lupus erythematous and rheumatoid arthritis. Here, we review the available proof of concept studies for CD28 antagonists in autoimmunity, with a special focus on the mechanisms of action.

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Selective CD28 antagonist prevents Aldara‐induced skin inflammation in non‐human primates

Cited by 7 publications

References 9 publications

IL-7 receptor blockade blunts antigen-specific memory T cell responses and chronic inflammation in primates

IL-7 receptor blockade blunts antigen-specific memory T cell responses and chronic inflammation in primates

First-in-Human Study in Healthy Subjects with FR104, a Pegylated Monoclonal Antibody Fragment Antagonist of CD28

Antagonist Anti-CD28 Therapeutics for the Treatment of Autoimmune Disorders

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