Lymphatic delivery of etanercept via nanotopography improves response to collagen-induced arthritis

Aldrich, Melissa B.; Velasquez, Fred Christian; Kwon, Sunkuk; Azhdarinia, Ali; Pinkston, Kenneth L.; Harvey, Barrett R.; Chan, Wenyaw; Rasmussen, John C.; Ross, Robert T.; Fife, Caroline E.; Sevick‐Muraca, Eva M.

doi:10.1186/s13075-017-1323-z

Cited by 19 publications

(18 citation statements)

References 37 publications

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“…The ability to clinically evaluate lymphatic function in "point-of-care" studies could accelerate more effective strategies to treat these diseases. For example, we recently used NIRF-LI techniques to demonstrate the lymphatic delivery of a TNF inhibitor to restore contractile lymphatic function in an animal model of rheumatoid arthritis [118] and of a checkpoint blockade inhibitor to more effectively suppress primary tumor growth and arrest metastasis than from systemic administration [142]. The ability to develop more effective treatments for chronic conditions requires the ability to visualize the function and anatomy of the lymphatics in disease progression and in response to treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Lymphatic dysfunction has also been linked to rheumatoid arthritis [116][117][118][119], with LE a known comorbidity [120] and dermal backflow evident on lymphoscintigraphy [121]. Other inflammatory disorders are also associated with LE [122,123], suggesting that, again, the pro-inflammatory state is associated with lymphatic dysfunction.…”

Section: Inflammatory/rheumatological Diseasesmentioning

confidence: 99%

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The Development and Treatment of Lymphatic Dysfunction in Cancer Patients and Survivors

Aldrich

Rasmussen

Fife

et al. 2020

Cancers

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Breast-cancer-acquired lymphedema is routinely diagnosed from the appearance of irreversible swelling that occurs as a result of lymphatic dysfunction. Yet in head and neck cancer survivors, lymphatic dysfunction may not always result in clinically overt swelling, but instead contribute to debilitating functional outcomes. In this review, we describe how cancer metastasis, lymph node dissection, and radiation therapy alter lymphatic function, as visualized by near-infrared fluorescence lymphatic imaging. Using custom gallium arsenide (GaAs)-intensified systems capable of detecting trace amounts of indocyanine green administered repeatedly as lymphatic contrast for longitudinal clinical imaging, we show that lymphatic dysfunction occurs with cancer progression and treatment and is an early, sub-clinical indicator of cancer-acquired lymphedema. We show that early treatment of lymphedema can restore lymphatic function in breast cancer and head and neck cancer patients and survivors. The compilation of these studies provides insights to the critical role that the lymphatics and the immune system play in the etiology of lymphedema and associated co-morbidities.

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Section: Discussionmentioning

confidence: 99%

Section: Inflammatory/rheumatological Diseasesmentioning

confidence: 99%

The Development and Treatment of Lymphatic Dysfunction in Cancer Patients and Survivors

Aldrich

Rasmussen

Fife

et al. 2020

Cancers

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“…14,15 Initial trials assessed dose levels between 9 and 300 µg and revealed that the first administration induced symptoms similar to those associated with gluten exposure in CeD. 14,15 Initial trials assessed dose levels between 9 and 300 µg and revealed that the first administration induced symptoms similar to those associated with gluten exposure in CeD.…”

Section: Introductionmentioning

confidence: 99%

“…Prior Nexvax2 clinical studies in HLA-DQ2.5+ patients used intradermal administration with the assumption that exposure to cutaneous antigen-presenting cells (eg dendritic or Langerhans cells), and subsequent transit via regional lymphatics, might be important in inducing nonresponsiveness (and potentially tolerance). 14,15 Initial trials assessed dose levels between 9 and 300 µg and revealed that the first administration induced symptoms similar to those associated with gluten exposure in CeD. These were accompanied by an underlying cytokine response, characterised by pronounced increases in serum interleukin-2 within 2 hours of dosing.…”

Section: Introductionmentioning

confidence: 99%

Randomised clinical trial: a placebo‐controlled study of subcutaneous or intradermal NEXVAX2, an investigational immunomodulatory peptide therapy for coeliac disease

Truitt¹,

Daveson

et al. 2019

Aliment Pharmacol Ther

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Background: Nexvax2 contains three gluten-derived peptides, intended to tolerize coeliac disease patients to gluten. Sequences cover six epitopes that trigger immune activation in human leucocyte antigen-DQ2.5-positive patients, most notably after an initial dose. Patients experience gastrointestinal symptoms with increases in serum interleukin-2. Consistent with Nexvax2's induction of non-responsiveness, reactivity disappears after repeated doses, or is avoided with gradual dose escalation.Early clinical trials used intradermal dosing, but pharmacokinetics and rapid onset of effect suggest that subcutaneous delivery may also be effective. Aims:To document the relative bioavailability of Nevax2 peptides after subcutaneous and intradermal dosing, and the tolerability and ability of subcutaneous dosing to induce non-responsiveness to Nexvax2 peptides. Methods:A randomised, double-blind, placebo-controlled study was conducted to assess plasma pharmacokinetics after subcutaneous and intradermal Nexvax2 dosing in HLA DQ2.5-positive patients, who had symptoms after an oral gluten challenge.Randomisation was to semi-weekly Nexvax2 (n = 12) or placebo (n = 2) injections, over a 5-week subcutaneous dose escalation and 2-week maintenance period, the latter with four doses of 900 µg, two subcutaneous and two intradermal. Post-dose circulating peptide and interleukin-2 levels were assessed. Investigators recorded adverse events experienced by patients.Results: Subcutaneous dosing resulted in slightly greater exposure. Interleukin-2 responses were seen with the gluten challenge but not after subcutaneous or intradermal dosing of 900 µg. Adverse events were generally mild and self-limited.Conclusions: Subcutaneous and intradermal dosing of Nexvax2 yield similar bioavailability of constituent peptides; subcutaneous dose escalation avoids an immune response to dominant gluten epitopes.

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“…Methods to stimulate drainage in the CSF drainage pathways could include pneumatic compression devices (Gutierrez et al, 2019) or manual lymphatic drainage techniques. While pro-inflammatory cytokines inhibit lymphatic function and drainage (Aldrich & Sevick-Muraca, 2013;Aldrich et al, 2017;Scallan, Zawieja, Castorena-Gonzalez, & Davis, 2016), till date there are limited studies on how to pharmacologically stimulate lymphatic drainage, particularly those draining the intracranial space. Finally, while mucosal injection into the palatine tonsils may provide convenient access to the drainage pathway shared by CSF outflow, it remains to be validated as a robust diagnostic.…”

Section: Discussionmentioning

confidence: 99%

Assessing lymphatic route of CSF outflow and peripheral lymphatic contractile activity during head‐down tilt using near‐infrared fluorescence imaging

et al. 2020

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Evidence overwhelmingly suggests that the lymphatics play a critical role in the clearance of cerebrospinal fluid (CSF) from the cranial space. Impairment of CSF outflow into the lymphatics is associated with a number of pathological conditions including spaceflight‐associated neuro‐ocular syndrome (SANS), a problem that limits long‐duration spaceflight. We used near‐infrared fluorescence lymphatic imaging (NIRFLI) to dynamically visualize the deep lymphatic drainage pathways shared by CSF outflow and disrupted during head‐down tilt (HDT), a method used to mimic the cephalad fluid shift that occurs in microgravity. After validating CSF clearance into the lymph nodes of the neck in swine, a pilot study was conducted in human volunteers to evaluate the effect of gravity on the flow of lymph through these deep cervical lymphatics. Injected into the palatine tonsils, ICG was imaged draining into deep jugular lymphatic vessels and subsequent cervical lymph nodes. NIRFLI was performed under HDT, sitting, and supine positions. NIRFLI shows that lymphatic drainage through pathways shared by CSF outflow are dependent upon gravity and are impaired under short‐term HDT. In addition, lymphatic contractile rates were evaluated from NIRFLI following intradermal ICG injections of the lower extremities. Lymphatic contractile activity in the legs was slowed in the gravity neutral, supine position, but increased under the influence of gravity regardless of whether its force direction opposed (sitting) or favored (HDT) lymphatic flow toward the heart. These studies evidence the role of a lymphatic contribution in SANS.

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Lymphatic delivery of etanercept via nanotopography improves response to collagen-induced arthritis

Cited by 19 publications

References 37 publications

The Development and Treatment of Lymphatic Dysfunction in Cancer Patients and Survivors

The Development and Treatment of Lymphatic Dysfunction in Cancer Patients and Survivors

Randomised clinical trial: a placebo‐controlled study of subcutaneous or intradermal NEXVAX2, an investigational immunomodulatory peptide therapy for coeliac disease

Assessing lymphatic route of CSF outflow and peripheral lymphatic contractile activity during head‐down tilt using near‐infrared fluorescence imaging

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