Last update 01 Nov 2024

Lymphoproliferative Syndrome, X-Linked, 2

Last update 01 Nov 2024

Basic Info

Synonyms

LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 2, Lymphoproliferative Syndrome, X-Linked, 2, X-linked Lymphoproliferative Syndrome 2

+ [9]

Introduction

A condition of decreased or absent presence of baculoviral IAP repeat-containing protein 4. Deficiency of this protein is associated with X-linked lymphoproliferative syndrome 2.

Drugs associated with Lymphoproliferative Syndrome, X-Linked, 2

Tadekinig alfa(AB2 Bio SA)

Target

IL-18

Mechanism

IL-18 inhibitors

Active Org.

AB2 Bio SA

Originator Org.

AB2 Bio SA

Active Indication

Lymphoproliferative Syndrome, X-Linked, 2 [+1]

Inactive Indication

Autoinflammatory disease [+1]

Drug Highest PhasePhase 3

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

MAS-825

Target

IL-18 x IL-1β

Mechanism

IL-18 inhibitors [+1]

Active Org.

Novartis Pharmaceuticals Corp. [+1]

Originator Org.

Novartis Pharmaceuticals Corp.

Active Indication

Coronary Disease [+4]

Inactive Indication

COVID-19 [+1]

Drug Highest PhasePhase 2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with Lymphoproliferative Syndrome, X-Linked, 2

NCT06309823 / CompletedPhase 3IIT

A Single-patient Clinical Trial of MAS825 in a Patient With XIAP Deficiency

MAS825 is a bi-specific IgG1 monoclonal antibody that simultaneously targets IL-1 beta and IL-18, thereby neutralizing both cytokines that are thought to be integral to the pathogenesis of XLP-2. Clinical trials are currently examining its efficacy in other diseases associated with elevations of these cytokines, including NLRC4-associated disease and hidradenitis suppurativa. This study proposes to assess the effectiveness of MAS825 in a single patient with XLP-2, who has previously demonstrated response to blockade of IL-1 beta and IL-18. Given the lack of alternative pharmaceutical options for XLP-2, this represents the only known medication option that avoids the toxicity associated with high-dose corticosteroids and the morbidity associated with hematopoietic stem cell transplantation.

Start Date08 Feb 2023

Sponsor / Collaborator

The Hospital for Sick Children

NCT04641442 / RecruitingPhase 2

A Three-period Multicenter Study, With a Randomized-withdrawal, Double-blind, Placebo-controlled Design to Evaluate the Clinical Efficacy, Safety and Tolerability of MAS825 in Patients With Monogenic IL-18 Driven Autoinflammatory Diseases, Including NLRC4-GOF, XIAP Deficiency, or CDC42 Mutations

This study is a Phase 2 trial designed to evaluate the clinical efficacy, safety, and tolerability of MAS825 in patients with NLRC4-GOF, XIAP deficiency, or CDC42 mutations.

Start Date18 Dec 2020

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

NCT03512314 / Active, not recruitingPhase 3

Open-label Extension Study With Tadekinig Alfa (r-hIL-18BP) to Monitor Safety and Tolerability in Patients With IL-18 Driven Monogenic Autoinflammatory Conditions: NLRC4 Mutation and XIAP Deficiency

This is an open-label extension study for patients previously enrolled in the AB2 Bio Ltd. ongoing Phase III clinical trial NLRC4/XIAP.2016.001 (IND N° 127953). This OLE study will evaluate the long-term safety and tolerability of Tadekinig alfa in patients suffering from pediatric monogenic autoinflammatory diseases harboring deleterious mutations of NLRC4 and XIAP.

Start Date24 Jan 2018

Sponsor / Collaborator

AB2 Bio SA

100 Clinical Results associated with Lymphoproliferative Syndrome, X-Linked, 2

100 Translational Medicine associated with Lymphoproliferative Syndrome, X-Linked, 2

0 Patents (Medical) associated with Lymphoproliferative Syndrome, X-Linked, 2

120

Literatures (Medical) associated with Lymphoproliferative Syndrome, X-Linked, 2

12 Sep 2024·Blood

Interleukin-1–mediated hyperinflammation in XIAP deficiency is associated with defective autophagy

Article

Author: Marshall, Christian ; Firouzabady, Ashkan ; Freeman, Spencer A. ; Laxer, Ronald M. ; de Paz Linares, Guillermo A. ; Dissanayake, Dilan ; Massumi, Mohammad ; Yeung, Rae S. M.

AbstractDeficiency of X-linked inhibitor of apoptosis protein (XIAP) is a rare genetic condition that can present with recurrent episodes of hemophagocytic lymphohistiocytosis (HLH), though the exact mechanisms leading to this hyperinflammatory disorder are unclear. Understanding its biology is critical to developing targeted therapies for this potentially fatal disease. Here, we report on a novel multiexonic intragenic duplication leading to XIAP deficiency with recurrent HLH that demonstrated complete response to interleukin (IL)-1β blockade. We further demonstrate using both primary patient cells and genetically modified THP-1 monocyte cell lines that, contrary to what has previously been shown in mouse cells, XIAP-deficient human macrophages do not produce excess IL-1β when stimulated under standard conditions. Instead, nucleotide-binding oligomerization domain–like receptor family pyrin domain containing 3 (NLRP3) inflammasome–mediated hyperproduction of IL-1β is observed only when the XIAP-deficient cells are stimulated under autophagy-promoting conditions and this correlates with defective autophagic flux as measured by decreased accumulation of the early autophagy marker LC3-II. This work, therefore, highlights IL-1β blockade as a therapeutic option for patients with XIAP deficiency experiencing recurrent HLH and identifies a critical role for XIAP in promoting autophagy as a means of limiting IL-1β–mediated hyperinflammation during periods of cellular stress.

01 Sep 2024·Cytometry Part B: Clinical Cytometry

CD62‐L down‐regulation after L18‐MDP stimulation as a complementary flow cytometry functional assay for the diagnosis of XIAP deficiency

Article

Author: Prieto, Emma ; Bernasconi, Andrea R. ; Rossi, Jorge G. ; Goris, Verónica ; Rizzo, Agustín D. ; Sajaroff, Elisa O. ; Prado, Damian A. ; Sanz, Marianela ; Roffe, Georgina

AbstractX‐linked inhibitor of apoptosis (XIAP) deficiency is an infrequent inborn error of immunity caused by mutations in XIAP gene. Most cases present with absence of XIAP protein which can be detected by flow cytometry (FC), representing a rapid diagnostic method. However, since some genetic defects may not preclude protein expression, it is important to include a complementary functional test in the laboratory workup of these patients. L‐selectin (CD62‐L) is a molecule that is cleaved from the surface membrane of leukocytes upon stimulation of different receptors such as toll like receptors (TLRs) and nucleotide‐binding oligomerization domain‐like receptors (NLRs), including NOD2. Considering that XIAP deficiency impairs NOD2 signaling, we decided to assess CD62‐L down‐regulation by FC post‐stimulation of neutrophils and monocytes with L18‐muramyl Di‐Peptide (L18‐MDP), a NOD2 specific agonist, in order to develop a novel assay for the functional evaluation of patients with suspicion of XIAP defects. Whole blood samples from 20 healthy controls (HC) and four patients with confirmed molecular diagnosis of XIAP deficiency were stimulated with 200 ng/mL of L18‐MDP for 2 h. Stimulation with 100 ng/mL of lipopolysaccharide (LPS) was carried out in parallel as a positive control of CD62‐L shedding. CD62‐L expression was evaluated by FC using an anti CD62‐L‐ antibody and down‐regulation was assessed by calculating the difference in CD62‐L expression before and after stimulation, both in terms of percentage of CD62‐L expressing cells (Δ%CD62‐L) and median fluorescence intensity (ΔMFI%). Neutrophils and monocytes from XIAP deficient patients displayed a significantly diminished response to L18‐MDP stimulation compared with HC (p < 0.0001), indicating a severely altered mechanism of CD62‐L down‐regulation following activation of NOD2‐XIAP axis. On the other hand, the response to LPS stimulation was comparable between patients and heathy controls, suggesting preserved CD62‐L shedding with a different stimulus. FC detection of CD62‐L down‐regulation in monocytes and neutrophils after whole blood stimulation with L18‐MDP results in an effective and rapid functional test for the identification of XIAP deficient patients.

19 Jun 2024·Cureus

X-linked Inhibitor of Apoptosis (XIAP) Deficiency Complicated by Hemophagocytic Lymphohistiocytosis on Immunotherapy Leading to Acute Respiratory Distress Syndrome and Multiorgan Failure Secondary to Opportunistic Infections

Article

Author: Zolotov, Eli ; Liu, Stephanie ; Kim, David ; Padalkar, Roma

X-linked inhibitor of apoptosis (XIAP) deficiency is a rare primary immunodeficiency with a broad spectrum of clinical manifestations, including susceptibility to hemophagocytic lymphohistiocytosis (HLH), inflammatory bowel disease (IBD), hypogammaglobulinemia, and severe infections. We present a case of a 39-year-old male with a past medical history of XIAP deficiency complicated by HLH, Crohn's disease, and hypogammaglobulinemia, who developed acute respiratory distress syndrome (ARDS) due to Pneumocystis jiroveci pneumonia (PJP) and concurrent multiorgan failure due to disseminated Mycobacterium avium intracellulare (MAI) infection. This case highlights the challenges in managing XIAP deficiency, emphasizing the importance of early recognition, and the need for further research to improve outcomes in this population.

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Lymphoproliferative Syndrome, X-Linked, 2

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