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Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The clinical potential of the mAbs Alirocumab (Sanofi Aventis) and Evolocumab (Amgen), in the management of lipid disorders has been reviewed by Gupta (2016) and Di Bartolo et al. (2017); Pfizer Inc. announced end of 2016 the discontinuation of the global clinical development program for their mAb bococizumab. The cost-effectiveness of PCSK9 mAb inhibitor therapy compared to that with statins and ezetimibe in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease has been discussed by Kazi et al. (2016). It is assumed that the mAbs act by blocking the interaction of PCSK9 with the LDL receptor thereby inhibiting its degradation; the detailed mechanism responsible needs to be elucidated. The antibodies are administered by subcutaneous injection every two to four weeks and used as monotherapy or in combination with statins achieve a LDL reduction of 50 to 70%. Lose of responsiveness during long-term application due to the induction of anti-drug antibodies cannot be excluded. PCSK9 inhibition also decreases Lp(a) by around 20–30% via a so far unknown mechanism (Kotani and Banach, 2017). Therapies to specifically reduce plasma Lp(a) levels are lacking, however, Graham et al. (2016) reported about inhibition of apo(a) mRNA translation with second generation ASOs to lower plasma Lp(a) levels.
Clinical Strategies for Managing Dyslipidemias
Published in James M. Rippe, Lifestyle Medicine, 2019
Ulf G. Bronas, Mary Hannan, Arthur S. Leon
The PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors are another newer class of medication that have shown benefit when added to a statin regimen. PCSK9 inhibitors are a human monoclonal antibody to PCSK9, which binds to PCSK9 and increases LDL receptors by increasing recycling of receptors to the cell surface, which should decrease LDL-C.18,20 Three trials have supported the use of PCSK9 inhibitors in decreasing CHD risk. The FOURIER trial, a placebo-controlled trial of over 27,000 patients, reported that the addition of evolocumab (PCSK9 inhibitor) to statin therapy lowered LDL by 59% and reduced the risk of cardiovascular events.21 The ODYSSEY trial, utilizing the PCSK9 inhibitor alirocumab on over 2,000 patients, reported that, at 2 4 weeks, the difference in LDL-C between the placebo and alirocumab group was 62%, and this effect remained at 78 weeks.22 The PCSK9 inhibitor, bococizumab was evaluated in the SPIRE-1 and SPIRE-2 trials, which found a 56% reduction in LDL-C, compared to the placebo group that had a 2.9% increase in patients with high cardiovascular risk at 14 weeks.23 Bococizumab further reduced risk of cardiovascular events in the high-risk patients (HR.79, p = 0.02) but not the low-risk group (HR .99, p = 0.94). The trial was, however, stopped prematurely due to the finding of high rates of antidrug antibodies.23
Immunogenicity risk assessment for biotherapeutics through in vitro detection of CD134 and CD137 on T helper cells
Published in mAbs, 2021
Sivan Cohen, Srividya Myneni, Anna Batt, Joyce Guerrero, Jochen Brumm, Shan Chung
Next, we compared the CD134/CD137 T cell activation assay with a proliferation assay using PBMCs from the second cohort of 40 donors. We used bococizumab as a biotherapeutic with a high immunogenic risk and bevacizumab as one with a low immunogenic risk. T cell activation was measured 2 days after exposure to the biotherapeutic and proliferation 7 days after exposure. Due to the high signal to noise of bevacizumab-treated PBMCs and high donor variability in this T cell proliferation assay, we could not set a threshold based on a tolerance to discriminate between bevacizumab and more immunogenic drugs. Therefore, to enable comparison of the discriminatory ability of the activation and proliferation assays, we determined receiver operating characteristic (ROC) curves for the sensitivity and specificity of both assays for bevacizumab and bococizumab. ROC curves showed a superior specificity and sensitivity of the CD134/CD137 T cell activation assay over the T cell proliferation assay (Supplementary Figure 2). The area under the curve (AUC) for the proliferation assay was 0.63 and the AUC for the CD134/CD137 T cell activation assay was 0.75. Interestingly, the optimal discriminatory cutoff to separate bevacizumab and bococizumab by ROC analysis for the CD134/CD137 T cell activation assay was close to 1.8, the threshold that was selected based on the tolerance interval.
Beyond affinity: selection of antibody variants with optimal biophysical properties and reduced immunogenicity from mammalian display libraries
Published in mAbs, 2020
Michael R. Dyson, Edward Masters, Deividas Pazeraitis, Rajika L. Perera, Johanna L. Syrjanen, Sachin Surade, Nels Thorsteinson, Kothai Parthiban, Philip C. Jones, Maheen Sattar, Gordana Wozniak-Knopp, Florian Rueker, Rachael Leah, John McCafferty
Bococizumab has been reported to be immunogenic and to induce anti-drug antibodies (ADAs) upon administration to humans. In a 4000 patient clinical trial, administration of bococizumab via subcutaneous injection was associated with the development of ADAs.11 At 12 weeks post administration of bococizumab, 48% of patients had detectable levels of ADAs, and of these 29% had high titer neutralizing ADAs, which resulted in a loss of efficacy with significant attenuation in the reduction of the total LDL cholesterol.11 The relationship between the propensity of therapeutic biologics, including antibodies, to self-interact and aggregate with their immunogenicity in vivo has been highlighted and reviewed by Ratanji et al.8 and Moussa et al.9 For example, biologics such as growth hormone, interferons and antibodies containing a greater proportion of aggregates are known to be more immunogenic. This may be because of the increased avidity of multivalent aggregates driving binding to dendritic cells via their surface-displayed innate receptors, resulting in their increased cellular update, antigen processing and increased peptide/MHC complex display. The multivalent aggregates may also directly stimulate B cells via specific B cell receptors to a greater extent than monomeric antibodies due to their avidity.
Efficacy and safety of PCSK9 monoclonal antibodies: an evidence-based review and update
Published in Journal of Drug Assessment, 2020
Rasha Kaddoura, Bassant Orabi, Amar M. Salam
In two meta-analyses1,79 of RCTs, treatment with PCSK9 inhibitors was not associated with the adverse effects commonly described with statin therapy such as myalgia and elevations in serum aminotransferases or creatine kinase, with overall serious adverse events that were comparable to the control group. The aforementioned meta-analyses did not report the injection site reactions which are the most frequent adverse events with the PCSK9 inhibitors use4. The allergic local injection-site reactions (e.g. itching, redness, swelling) rates were 3.8% in alirocumab group versus 2.1% in placebo (p < .001)99 and 5.9 versus 4.2% over a period of 78 weeks63. Injection-site reactions are usually mild and self-limited99. The reactions rates with evolocumab were 2.1% versus 1.6% in the placebo group98, and there was no increase in hypersensitivity with longer treatment120. Bococizumab caused higher injection-site reactions as compared to placebo (10.4 versus 1.3%, p < .001)104 and 12.7 per 100 person-years in six trials evaluating bococizumab. However, the rates did not increase with longer time121.