Kristin E. Killoran

Leidos (United States)

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Edward Mitre

Uniformed Services University of the Health Sciences

Helene F. Rosenberg

National Institute of Allergy and Infectious Diseases

Joshua Kramer

Frederick National Laboratory for Cancer Research

Holly Evans

Pachyonychia Congenita Project

Marina N. Torrero

Uniformed Services University of the Health Sciences

Matthew W. Breed

Frederick National Laboratory for Cancer Research

Kimberly D. Dyer

National Institute of Allergy and Infectious Diseases

Marc P. Hübner

University Hospital Bonn

Anna Gutowska

National Cancer Institute

William D. Figg

National Cancer Institute

Cooperative Institutions

National Institutes of Health

National Cancer Institute

Center for Cancer Research

Uniformed Services University of the Health Sciences

Frederick National Laboratory for Cancer Research

National Institute of Allergy and Infectious Diseases

Leidos (United States)

Leidos Biomedical Research Inc. (United States)

Cancer Institute (WIA)

Johns Hopkins University

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EXTH-102. PLASMA AND CEREBROSPINAL FLUID (CSF) PHARMACOKINETICS (PK) OF MIRDAMETINIB IN A NON-HUMAN PRIMATE (NHP) MODEL

Neuro-Oncology (2022)

Cynthia Lester McCully Todd Shearer Andrea M. Gross Abraham J. Langseth Cody Peer

Abstract Mirdametinib is a MEK inhibitor with reported CSF penetration in pre-clinical models. Murine studies reported ERK phosphorylation inhibition in brain tissue at 1.15 nM (0.73 ng/mL) and tumor cell lines at 0.33–0.59 nM (0.16-0.28 ng/mL). A phase II clinical trial evaluating mirdametinib for neurofibromatosis type 1-related plexiform neurofibromas reported a 42% partial response rate and a mean plasma exposure (AUC0-12h) of 443 h*ng/mL. This study determined the plasma and CSF pharmacokinetic (PK) profile of mirdametinib in a non-human primate (NHP) model where CSF penetration serves as a proxy for CNS penetration. METHODS Four NHP received mirdametinib PO q.d, 0.50 mg/kg, in serial studies as a single dose (Single-Dose), three doses (Multiple-Dose), or IV, 0.20 mg/kg, followed by paired plasma and CSF sample collections through 96 hours. Mirdametinib was quantified by LC-MS/MS. PK parameters were calculated via noncompartmental methods. Plasma protein binding was determined by rapid equilibrium dialysis. RESULTS Mean □ standard deviation values reported. Three subjects were evaluable for both plasma (total and unbound) and CSF drug concentrations. Plasma – AUClast: Single-Dose 500.3 □ 253.4 and IV 552.3 □ 43 h*ng/mL; AUCtau: Multiple-Dose 456.3 □ 120.6 h*ng/mL. CSF Cmax (ng/mL): Single-Dose 0.43 □ 0.18, IV 2.0 □ 1.8, Multiple-Dose 0.56 □ 0.18. CSF Penetration (%): Single-Dose 1.3 □ 0.45, IV-1.6 □ 0.95 (AUCcsf-last:AUCplasma-last); Multiple-Dose 1.3 □ 0.56 (AUCcsf-tau:AUCplasma-tau). CSF/unbound plasma ratios ranged from 2.5-3.0 Plasma free fraction (%): 0.52 □ 0.1. CONCLUSION Notable mirdametinib CSF penetration was demonstrated in this NHP model. A higher CSF to unbound plasma ratio suggests that the efflux of mirdametinib from the CSF was delayed. The NHP CSF Cmax approached the ERK phosphorylation inhibition concentrations previously reported. The ability of this NHP model to predict human PK parameters was demonstrated via the comparable NHP to patient plasma exposure reported in the Phase II clinical trial.

Penetration (warfare)

10.1093/neuonc/noac209.900

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Role of innate immunity and altered intestinal motility in LPS- and MnCl₂-induced intestinal intussusception in mice

AJP Gastrointestinal and Liver Physiology (2014)

Kristin E. Killoran Amber Miller Karen Uray Norman W. Weisbrodt Robia G. Pautler

Intestinal intussusception (ISS) commonly causes intestinal obstruction in children. One mechanism that has been proposed to cause ISS is inflammation-induced alteration of intestinal motility. We investigated whether innate inflammatory factors or altered motility is required for induction of ISS by LPS. We compared rates of ISS among BALB/c and C57BL/6 mice, mice lacking lymphocytes or depleted of phagocytes, or mice with defects in the Toll-like receptor 4 (TLR4) signaling pathway following administration of LPS or the Ca 2+ analog MnCl 2 . At 6 or 2 h after administration of LPS or MnCl 2 , respectively, mice underwent image analysis to assess intestinal contraction rate or laparotomy to identify ISS. LPS-induced ISS (LPS-ISS) was observed in BALB/c mice, but not in C57BL/6 mice or any BALB/c mice with disruptions of TLR4 signaling. LPS-induced serum TNF-α, IL-6, and nitric oxide (NO) and intestinal NO levels were similar in BALB/c and C57BL/6 mice. The rate of LPS-ISS was significantly reduced in phagocyte-depleted, but not lymphocyte-deficient, mice. Intestinal contraction rates were reduced in LPS-ISS-susceptible BALB/c mice, but not in LPS-ISS-resistant C57BL/6 or TLR4 mutant mice, suggesting a role for reduced intestinal contraction rate in LPS-ISS susceptibility. This was tested with MnCl 2, a Ca 2+ antagonist that reduced intestinal contraction rates and induced ISS, irrespective of mouse strain. Therefore, LPS-ISS is initiated by innate immune signaling that requires TLR4 and phagocytes but may be independent of TNF-α, IL-6, and NO levels. Furthermore, alteration of intestinal motility, specifically, reduced intestinal contraction rate, is a key factor in the development of ISS.

Intestinal motility

10.1152/ajpgi.00264.2013

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Citations (13)

Depletion of alveolar macrophages prolongs survival in response to acute pneumovirus infection

Virology (2011)

Peter Rigaux Kristin E. Killoran Zhijun Qiu Helene F. Rosenberg

Proinflammatory cytokine

Alveolar macrophage

10.1016/j.virol.2011.10.031

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Citations (23)

Helminth Protection against Autoimmune Diabetes in Nonobese Diabetic Mice Is Independent of a Type 2 Immune Shift and Requires TGF-β

The Journal of Immunology (2011)

Marc P. Hübner Yinghui Shi Marina N. Torrero Ellen Mueller David Larson

Leading hypotheses to explain helminth-mediated protection against autoimmunity postulate that type 2 or regulatory immune responses induced by helminth infections in the host limit pathogenic Th1-driven autoimmune responses. We tested these hypotheses by investigating whether infection with the filarial nematode Litomosoides sigmodontis prevents diabetes onset in IL-4-deficient NOD mice and whether depletion or absence of regulatory T cells, IL-10, or TGF-β alters helminth-mediated protection. In contrast to IL-4-competent NOD mice, IL-4-deficient NOD mice failed to develop a type 2 shift in either cytokine or Ab production during L. sigmodontis infection. Despite the absence of a type 2 immune shift, infection of IL-4-deficient NOD mice with L. sigmodontis prevented diabetes onset in all mice studied. Infections in immunocompetent and IL-4-deficient NOD mice were accompanied by increases in CD4(+)CD25(+)Foxp3(+) regulatory T cell frequencies and numbers, respectively, and helminth infection increased the proliferation of CD4(+)Foxp3(+) cells. However, depletion of CD25(+) cells in NOD mice or Foxp3(+) T cells from splenocytes transferred into NOD.scid mice did not decrease helminth-mediated protection against diabetes onset. Continuous depletion of the anti-inflammatory cytokine TGF-β, but not blockade of IL-10 signaling, prevented the beneficial effect of helminth infection on diabetes. Changes in Th17 responses did not seem to play an important role in helminth-mediated protection against autoimmunity, because helminth infection was not associated with a decreased Th17 immune response. This study demonstrates that L. sigmodontis-mediated protection against diabetes in NOD mice is not dependent on the induction of a type 2 immune shift but does require TGF-β.

NOD mice

Regulatory T cell

10.4049/jimmunol.1100335

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Citations (96)

Measuring Local Anaphylaxis in Mice

Journal of Visualized Experiments (2014)

Holly Evans Kristin E. Killoran Edward Mitre

Allergic responses are the result of the activation of mast cells and basophils, and the subsequent release of vasoactive and proinflammatory mediators. Exposure to an allergen in a sensitized individual can result in clinical symptoms that vary from minor erythema to life threatening anaphylaxis. In the laboratory, various animal models have been developed to understand the mechanisms driving allergic responses. Herein, we describe a detailed method for measuring changes in vascular permeability to quantify localized allergic responses. The local anaphylaxis assay was first reported in the 1920s, and has been adapted from the technique published by Kojima et al. in 20071. In this assay, mice sensitized to OVA are challenged in the left ear with vehicle and in the right ear with OVA. This is followed by an intravenous injection of Evans Blue dye. Ten min after injecting Evans Blue, the animal is euthanized and the dye that has extravasated into the ears is extracted overnight in formamide. The absorbance of the extracted dye is then quantified with a spectrophotometer. This method reliably results in a visual and quantifiable manifestation of a local allergic response.

Evans Blue

Vascular permeability

Erythema

Proinflammatory cytokine

Vasoactive

10.3791/52005-v

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Citations (8)

Isolation of human eosinophils: microbead method has no impact on IL‐5 sustained viability

Experimental Dermatology (2009)

Caroline M. Percopo Kimberly D. Dyer Kristin E. Killoran Helene F. Rosenberg

Please cite this paper as: Isolation of human eosinophils: microbead method has no impact on IL‐5 sustained viability. Experimental Dermatology 2009; 19: 467–469. Abstract Background/purpose: In a recent issue of Experimental Dermatology (18, 2009, 654), Schefzyk et al. concluded that multi‐antibody eosinophil isolation (Miltenyi) should be abandoned, as differential purity was minimal, and eosinophils underwent accelerated apoptosis when compared with those isolated with traditional anti‐CD16 microbeads. Our intent was to investigate the universality of these findings. Methods: We isolated eosinophils from normal donor granulocyte packs using two methods, and evaluated purity, viability and annexin‐V/propidium‐iodide staining. Results: Purity was substantially greater when multi‐antibody isolation was used for eosinophil isolation from granulocyte packs (98% vs 69%). No differential survival was detected when eosinophils were maintained in culture with or without interleukin‐5. Conclusions: Multi‐antibody eosinophil isolation represents a substantial advantage over anti‐CD‐16 microbeads when isolating large numbers of eosinophils from concentrated leucocyte preparations. No differential survival was observed. While appropriate consideration of methods is always crucial, multi‐antibody eosinophil isolation should not be abandoned completely.

Propidium iodide

Isolation

Microbead (research)

10.1111/j.1600-0625.2009.00974.x

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Citations (14)

Pleural cavity type 2 innate lymphoid cells precede Th2 expansion in murine Litomosoides sigmodontis infection

Experimental Parasitology (2015)

Alexis Boyd Kristin E. Killoran Edward Mitre Thomas B. Nutman

Innate lymphoid cell

Pleural cavity

10.1016/j.exppara.2015.09.006

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Citations (13)

Rush desensitization with a single antigen induces subclinical activation of mast cells and protects against bystander challenge in dually sensitized mice

Clinical & Experimental Allergy (2018)

Kristin E. Killoran Laura E. Kropp Alyssa R. Lindrose Holly E. Curtis David J. Cook

Rush desensitization can provide short-term tolerance to individuals who are allergic to certain medications in instances where other therapeutic interventions are limited. While rush desensitization (DS) is typically successful in preventing adverse type I hypersensitivity reactions, the mechanism of allergic protection remains unknown. Given the rise in prevalence of individuals displaying multiple allergies, understanding the impact of rush DS on "bystander" allergens, or additional allergens to which an individual is sensitized, could help inform clinical recommendations.To evaluate the effect of rush DS on bystander sensitization.We used a murine model of rush DS, whereby BALB/c mice were sensitized to ovalbumin (OVA) and desensitized through repeated intraperitoneal injections of OVA. Using a local anaphylaxis assay, we measured ear swelling by Evans blue extravasation following intradermal challenge. In studies to measure the impact on bystander antigens, a modified protocol was used in which mice were dually sensitized to OVA and Keyhole limpet hemocyanin (KLH), and densensitized to either OVA or KLH prior to allergic challenge.The immunological effects of rush DS were independent of changes in Th1 and Th2 cytokine production and circulating OVA-IgE levels. Instead, rush DS resulted in subclinical degranulation of mast cells prior to challenge. In our dual sensitization model, rush DS with a single antigen conferred protection against allergic challenge to a secondary antigen. Bystander protection required prior sensitization, as DS with an irrelevant antigen did not impact allergic responsiveness.We reveal that a key mechanism of rush DS protection against allergic responsiveness may be the subclinical degranulation of mast cells. Therefore, performing rush DS to a single antigen to which one is IgE-sensitized may be sufficient to desensitize to multiple allergens. Future studies could lead to streamlined protocols of rush DS for patients with multiple allergies.

Bystander effect

Keyhole limpet hemocyanin

Subclinical infection

10.1111/cea.13323

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Citations (7)

Antigen profiles for the quantitative assessment of eosinophils in mouse tissues by flow cytometry

Journal of Immunological Methods (2011)

Kimberly D. Dyer Katia E. Garcia-Crespo Kristin E. Killoran Helene F. Rosenberg

10.1016/j.jim.2011.04.009

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Citations (44)

Long-acting lenacapavir protects macaques against intravenous challenge with simian-tropic HIV

EBioMedicine (2023)

Adrienne E. Swanstrom Robert J. Gorelick Jorden L. Welker Fabian Schmidt Bing Lu

Long-acting subcutaneous lenacapavir (LEN), a first-in-class HIV capsid inhibitor approved by the US FDA for the treatment of multidrug-resistant HIV-1 with twice yearly dosing, is under investigation for HIV-1 pre-exposure prophylaxis (PrEP). We previously derived a simian-tropic HIV-1 clone (stHIV-A19) that encodes an HIV-1 capsid and replicates to high titres in pigtail macaques (PTM), resulting in a nonhuman primate model well-suited for evaluating LEN PrEP in vivo.

Simian immunodeficiency virus

Subcutaneous injection

Pre-exposure prophylaxis

10.1016/j.ebiom.2023.104764

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Citations (3)