Explore chapters and articles related to this topic
Serum Amyloid P Component as a Therapeutic Target in Amyloidosis
Published in Gilles Grateau, Robert A. Kyle, Martha Skinner, Amyloid and Amyloidosis, 2004
In collaboration with F Hoffmann-la Roche & Co Ltd we have developed a new chemical entity, carboxy pyrrolidone hexanoyl pyrrolidone carboxylic acid (CPHPC), that inhibits binding of SAP to amyloid fibrils in vitro with approximately micromolar IC50. Administration of a sufficient dose to amyloidotic mice in vivo completely removes mouse SAP from the deposits (1). Human SAP binds CPHPC much more avidly than does mouse SAP and the stable complex that forms in vivo between 2 human SAP molecules and 5 CPHPC molecules is immediately cleared by the liver, leading to swift depletion of all circulating SAP for as long as the drug is administered (2). This is the first example of a novel pharmacological mechanism in which a pathological human protein is depleted by a low molecular weight drug. However ex vivo dissociation of human SAP that has already bound to amyloid deposits in vivo, requires millimolar CPHPC concentrations. Nevertheless, since circulating SAP is made exclusively in the liver, is the sole source of SAP in the amyloid deposits, and is in dynamic equilibrium with the amyloid SAP pool, sustained plasma depletion should eventually clear all the SAP from the deposits. CPHPC for treatment of amyloidosis is licensed exclusively to a UCL spinout company and we now have about 30 patient years of experience of CPHPC administration to patients with various forms of systemic amyloidosis. There have been no drug related adverse effects, nor any toxicity or abnormal investigational findings. CPHPC is not metabolised and is very rapidly cleared, mostly by the kidney, with a plasma half life of about 1.5 h. Thus although the modest CPHPC doses deployed so far maintain complete depletion of plasma SAP and cause measurable depletion of SAP from the amyloid deposits (2), significant amounts of SAP remain in the deposits even after months of treatment. Consequently we have not yet effectively tested the hypothesis that complete removal of SAP from amyloid deposits would reduce new amyloid deposition and/or promote amyloid regression with clinical benefit. We are therefore currently exploring alternative dose regimes and routes of CPHPC administration in order to achieve the high blood and tissue concentrations of the drug required for clearance of all SAP from the tissue amyloid deposits. We are also conducting a preliminary study in Alzheimer’s disease, in which the amyloid deposits are many orders of magnitude smaller than in systemic amyloidosis, and where depletion of circulating SAP should be sufficient to deplete SAP from the cerebrospinal fluid and the deposits.
Aiming for protective T-cell responses: a focus on the first generation conserved-region HIVconsv vaccines in preventive and therapeutic clinical trials
Published in Expert Review of Vaccines, 2019
There are licensed veterinary DNA vaccines for horses, dogs and salmon, but for reasons not well understood, DNA vaccines are only very weakly immunogenic in humans. Indeed in our hands, previous intramuscular injection of DNA to humans primed immune responses, but this was only demonstrated by increased magnitude of a subsequent heterologous boost [87,96–98]; DNA vaccines alone induced barely detectable frequencies of HIVconsv-specific T cells. Serum amyloid P component (SAP) is the single normal DNA-binding protein in human plasma and drug called CPHPC or miridesap, developed for treatment of systemic amyloidosis and Alzheimer’s disease, potently and safely depletes circulating SAP for as long as the drug is administered [99]. Transgenic mouse model demonstrated that DNA immunogenicity was attenuated by DNA binding to human SAP. The proof-of-concept trial HIV-CORE 003 (NCT02425241) was a randomized, double-blind, placebo-controlled clinical study (n = 40) in London, UK, which tested whether or not a 24-hour SAP depletion by CPHPC prior to intramuscular DNA administration enhances the immune induction in humans. Note that oral delivery of CPHPC is now possible. Volunteers in each arm received DDDC(M) regimens with CPHPC or placebo pre-DNA treatment (Table 1) and, while the HIVconsv vaccine immunogenicity was confirmed, no benefit to DNA priming or subsequent boosts was detected [81].
Advances in pharmacotherapy for cardiac amyloidosis
Published in Expert Opinion on Pharmacotherapy, 2021
R. Spoladore, G. Falasconi, M. Marcatti, S. Di Maio, G. Fiore, M. Slavich, A. Margonato, A. Turco, G. Fragasso
Miridesap (CPHPC) a molecule able to deplete circulating serum amyloid P component (SAP), a glycoprotein associated to amyloid deposits, has been tested, together with dezamizumab (a fully humanized monoclonal IgG1 anti-SAP antibody) in a two-part, first in man, phase 1 trial (NCT01777243). Infusion of anti-SAP triggered transient early inflammatory cytokine release, improving organ function and with moderate side effects, in AL patients [53,54]. However, despite these positive preliminary results, further trials were stopped, according to the risk/benefit profile assessment of this therapy.
New concepts in the treatment and diagnosis of amyloidosis
Published in Expert Review of Hematology, 2018
Paolo Milani, Giovanni Palladini, Giampaolo Merlini
The reabsorption of the amyloid deposits is another important target. The London group developed a palindromic compound CPHPC that is a competitive inhibitor of the binding of serum amyloid P component (SAP) to amyloid fibrils, which protects them from degradation and is able to remove SAP from the bloodstream [110]. A Phase I trial using a combination of CPHPC and anti-SAP antibodies showed safely triggered clearance of visceral amyloid deposits from the liver, kidney, and lymph node [111]. A clinical trial in treated patients with AL amyloidosis is ongoing (NCT03044353) (Table 1).