development-of-recombinant-proteins-to-treat-chronic-pain

Development of Recombinant Proteins to Treat Chronic Pain

Chronic pain is difficult to treat and new approaches to resolve persistent pain are urgently needed. Anti-inflammatory cytokines are promising candidates ...

University Medical Center Utrecht, Utrecht University

  Hereditary angioedema (HAE) is a heterozygous deficiency of first component of complement-inhibitor (C1INH). Insufficient C1INH activity leads to uncontrolled activation of plasma cascade systems, which results in acute angioedema attacks in patients with HAE. Plasma-derived or recombinant C1INH products are approved for the treatment of such angioedema attacks. The target level of C1INH activity needed to achieve optimal efficacy, however, remains unknown. We determined the plasma level of C1INH associated with optimal clinical efficacy in the treatment of angioedema attacks.

Target levels of functional C1-inhibitor in hereditary angioedema.

Recombinant human C1-inhibitor (rhC1INH) is used to treat acute angioedema attacks in hereditary angioedema (HAE) due to a genetic C1INH deficiency. Recombinant proteins in general may induce antibody responses and therefore evaluation of such responses in the target population is an essential step in the clinical development program of a recombinant protein. Here we report the assessment of the immunogenicity of rhC1INH in symptomatic HAE patients.

Immunogenicity assessment of recombinant human c1-inhibitor: an integrated analysis of clinical studies.

Recombinant human C1-inhibitor (rhC1INH) purified from milk of transgenic rabbits is used for the treatment of acute attacks in patients with hereditary angioedema (HAE) due to C1-inhibitor (C1INH) deficiency.

Immunosafety of recombinant human C1-inhibitor in hereditary angioedema: evaluation of ige antibodies.

Hereditary angioedema (HAE) caused by a deficiency of functional C1-inhibitor (C1INH) becomes clinically manifest as attacks of angioedema. C1INH is the main inhibitor of the contact system. Poor control of a local activation process of this system at the site of the attack is believed to lead to the formation of bradykinin (BK), which increases local vasopermeability and mediates angioedema on interaction with BK receptor 2 on the endothelium. However, several observations in patients with HAE are difficult to explain from a pathogenic model claiming a local activation process at the site of the angioedema attack. Therefore we postulate an alternative model for angioedema attacks in patients with HAE, which assumes a systemic, fluid-phase activation of the contact system to generate BK and its breakdown products. Interaction of these peptides with endothelial receptors that are locally expressed in the affected tissues rather than with receptors constitutively expressed by the endothelium throughout the whole body explains that such a systemic activation process results in local manifestations of an attack. In particular, BK receptor 1, which is induced on the endothelium by inflammatory stimuli, such as kinins and cytokines, meets the specifications of the involved receptor. The pathogenic model discussed here also provides an explanation for why angioedema can occur at multiple sites during an attack and why HAE attacks respond well to modest increases of circulating C1INH activity levels because inhibition of fluid-phase Factor XIIa and kallikrein requires lower C1INH levels than inhibition of activator-bound factors.

Eric Hack

Laboratory of Translational Immunology

University Medical Center Utrecht, Utrecht University

Development of Recombinant Proteins to Treat Chronic Pain