Search

Berotralstat is a novel, targeted oral long-term prophylactic (LTP) treatment for hereditary angioedema (HAE). Real-world evidence comparing WAO/EAACI recommended first-line HAE LTP therapies is limited. We investigated adherence and persistence following initiation of berotralstat, lanadelumab, and subcutaneous plasma-derived C1-inhibitor (SC-pdC1-INH).

CTLA-4 haploinsufficiency is caused by heterozygous mutations in CTLA4, a negative regulator of immune responses. Hypogammaglobulinemia, infections, and autoimmune cytopenias can be seen. Here, we describe a patient with history of ITP who presented with neutropenic fever, lymphopenia, and hypogammaglobulinemia in the setting of COVID-19 with a VUS in CTLA4.

The signaling mechanisms utilized by bradykinin (BK) to activate the transcription factor nuclear factor kappaB (NF-kappaB) are poorly defined. We previously demonstrated that BK-stimulated NF-kappaB activation requires the small GTPase RhoA. We present evidence that BK-induced NF-kappaB activation both activates and requires phosphatidylinositol 3-kinase (PI 3-kinase) in A549 human epithelial cells. Pre-treatment with the PI 3-kinase-specific inhibitors, wortmannin, and LY294002 effectively blocked BK-induced PI 3-kinase activity. Wortmannin and LY294002 also abolished BK-induced NF-kappaB activation, as did transient transfection with a dominant negative mutant of the p85 subunit. BK-stimulated PI 3-kinase activity and NF-kappaB activation were sensitive to pertussis but not cholera toxin, suggesting that the B2 BK receptors transducing the response were coupled to Galphai or Galphao heterotrimeric G proteins. Tumor necrosis factor alpha (TNFalpha) also stimulated increased PI 3-kinase activity, however TNFalpha-stimulated NF-kappaB activation was not affected by the PI 3-kinase inhibitors or the p85 dominant negative mutant. These findings provide evidence that BK-induced NF-kappaB activation utilizes a signaling pathway that requires activity of both RhoA and PI 3-kinase and is distinct from the signaling pathway utilized by TNFalpha. Furthermore, we show that the p85 regulatory subunit is required for activation of PI 3-kinase activity by this G protein-coupled receptor.

Purified human high-mol-wt kininogen (HMWK), the cofactor of the contact phase of blood coagulation, migrated as a single band (approximately 110,000 mol wt) in a continuous buffer sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), but appeared as two separated bands (approximately 120,000 and 105,000 mol wt) when analyzed in a discontinuous buffer SDS-PAGE system. After elution from SDS polyacrylamide gels, each of the two bands showed coagulant activity. Six murine monoclonal antibodies (Mabs) against HMWK were produced and purified. In immunoblotting studies, three Mabs bound to the isolated alkylated heavy chain and one to the alkylated light chain of HMWK, whereas the remaining two bound only to the single-chain or unreduced two-chain molecule. None of the Mabs inhibited the clotting activity of HMWK or its binding to kaolin. Two of the Mabs, one directed against the light chain and one against the heavy chain, were used as specific probes to study HMWK in plasma samples using an immunoblotting technique. The anti-light chain Mab identified two distinct bands (approximately 120,000 and approximately 105,000 mol wt) in normal human plasma, but not in plasma from patients with hereditary HMWK deficiency. The anti-heavy chain Mab detected two additional bands (approximately 60,000 and approximately 54,000 mol wt) corresponding to low-mol-wt kininogen (LMWK) in normal plasma. A sensitive and specific quantitative immunoblotting assay of HMWK antigen in plasma was developed. Moreover, the immunoblotting technique with the anti-light chain Mab was used to detect the cleavage of HMWK in plasma samples after in vitro or in vivo activation of the contact system. The anti- light chain Mab demonstrated in vivo activation and cleavage of HMWK during an angioedema attack in a patient with hereditary angioedema and C1-inhibitor deficiency.

Experiments are presented herein that demonstrate the capacity to stimulate human peripheral mononuclear cells to synthesize and secrete significant quantities of IgE molecules in vitro by exposure to appropriate concentrations of 2,4-dinitrophenyl (DNP)-protein conjugates, pokeweed mitogen (PWM), or a combination of DNP-proteins and PWM. Cultures stimulated in this fashion synthesize increased quantities of both total IgE and DNP-specific IgE antibody molecules. This in vitro human IgE antibody system should provide a useful tool for further exploration of regulatory control of IgE responses in both normal humans and those manifesting various forms of IgE-mediated allergic disorders.

In the HELP Study (NCT02586805), treatment with lanadelumab (a monoclonal antibody inhibitor of plasma kallirein) 150 mg q4wks, 300 mg q4wks, or 300 mg q2wks significantly decreased attack rates over 26 weeks. We evaluated the relationship between lanadelumab exposure and efficacy during steady state (days 70-182) among the 3 dose groups.

Replacement therapy with subcutaneous C1-esterase inhibitor (C1-INH[SC]) 60 IU/kg twice weekly is approved for routine prophylaxis to prevent hereditary angioedema (HAE) attacks. Coagulation and fibrinolytic parameters levels tend to be elevated in HAE patients. We evaluated the effects of C1-INH(SC) on these parameters.

Lanadelumab, a highly specific, fully human monoclonal antibody targeting plasma kallikrein, demonstrated sustained and well-tolerated prophylaxis against hereditary angioedema (HAE) attacks in the phase 3 HELP Study (NCT02586805). Three dosing regimens were investigated; here we report further efficacy findings for lanadelumab 300mg every 2 weeks (q2wks).

Lanadelumab, a fully human monoclonal antibody targeting plasma kallikrein, effectively prevented attacks in patients with hereditary angioedema (HAE) in the phase 3 HELP Study (NCT02586805).

Low levels of C1-esterase inhibitor (C1-INH) and concomitant reduced complement 4 (C4) concentrations have been identified in patients with hereditary angioedema (HAE). C4 constitutes a promising candidate for a biomarker of disease activity. This investigation aims to determine the relationship between C1-INH functional activity levels (C1-INH[f]) and C4 antigen concentrations in patients with HAE treated with subcutaneous (SC) C1-INH, inferring significance for clinical practice.

Subcutaneous human C1-inhibitor [C1-INH(SC)] is approved for prevention of angioedema attacks based on the Phase 3 COMPACT trial results. This extension study provides long-term data on efficacy and safety of C1-INH(SC).