2018年2月16日金曜日

喘息:モノクローナル抗体製剤のImmunogenicity(免疫原性)に関する問題

モノクローナル抗体製剤のImmunogenicity(免疫原性)に関する問題


ファセンラ:Benralizumabの攻撃対象題材となるかもしれない


Immunogenicity :antidrug antibody (ADA) assay


Understanding the Supersensitive Anti-Drug Antibody Assay: Unexpected High Anti-Drug Antibody Incidence and Its Clinical Relevance
Journal of Immunology Research Volume 2016 (2016), Article ID 3072586, 8 pages
http://dx.doi.org/10.1155/2016/3072586

最近の免疫原性検査で異常に効率に免疫原性陽性率認めることがあり、完全ヒト型抗体でさえ、検出される。supersensitiveな検査から、ADAが容易に検出されるようになった。


時代背景から、喘息関連のBio製剤でも問題になってきた


Benralizumab
Out of 19 subjects treated with multiple doses of benralizumab, 4 exhibited evidence of immunogenicity (as measured by anti-drug antibodies).
In the 10-mg group, ADAs were detected in 3 subjects on day 8. One of these 3 subjects also tested positive for ADAs on day 29. No ADAs were detected after day 29.
One subject in the 75-mg group and 1 subject in the 250-mg group tested positive for ADAs on day 8; both subjects tested negative at the later times. No ADAs were detected in any subjects in the 750-mg or placebo group up to day 151 postdose. None of the samples that tested ADA positive tested positive for neutralizing activity.
Benralizumab – a humanized mAb to IL-5Rα with enhanced antibody-dependent cell-mediated cytotoxicity – a novel approach for the treatment of asthma
Aasia Ghazi, et al.
Expert Opin Biol Ther. Author manuscript; available in PMC 2013 Mar 4.



Overall, treatment-emergent anti-drug antibody response developed in 13% of patients treated with FASENRA at the  recommended dosing regimen during the 48 to 56 week treatment period. A total of 12% of patients treated with  FASENRA developed neutralizing antibodies. Anti-benralizumab antibodies were associated with increased clearance of  benralizumab and increased blood eosinophil levels in patients with high anti-drug antibody titers compared to antibody  negative patients. No evidence of an association of anti-drug antibodies with efficacy or safety was observed.  The data reflect the percentage of patients whose test results were positive for antibodies to benralizumab in specific  assays. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761070s000lbl.pdf



ヌーカラ
Pharmacokinetics and Pharmacodynamics of Mepolizumab, an Anti–Interleukin 5 Monoclonal Antibody, in HealthyJapanese Male Subjects
Naohiro Tsukamoto, et al.
Clinical Pharmacology in Drug Development
Submitted for publication 14 January 2015; accepted 4 June 2015




Overall, 15/260 (6%) of subjects treated with NUCALA developed anti-mepolizumab antibodies. The reported frequency may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentration. Neutralizing antibodies were detected in 1 subject receiving mepolizumab. Anti-mepolizumab antibodies slightly increased (approximately 20%) the clearance of mepolizumab. There was no evidence of a correlation between anti-mepolizumab antibody titers and change in eosinophil level. The clinical relevance of the presence of anti-mepolizumab antibodies is not known.
The data reflect the percentage of patients whose test results were positive for antibodies to mepolizumab in specific assays. The observed incidence of antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125526Orig1s000Lbl.pdf


ゾレア


Immunogenicity
No  anti -therapeutic  antibodies  (ATAs ) against  omalizumab  were  detected  across  all four  CIU studies.  Overall,  adequate  clinical  pharmacology  information  was  provided  in  support  of  this  supplemental BLA. 
https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM393855.pdf

超加工食品:10%比率増加毎、がん全体及び乳がん10%超増加



Ultra-processed food :

archive.wphna.org/wp-content/uploads/2016/01/WN-2016-7-1-3-28-38-Monteiro-Cannon-Levy-et-al-NOVA.pdf
Group 4: Ultra-processed food and drink products 
総脂肪、飽和脂肪、糖添加・塩添加、線維成分・ビタミン少ない
栄養成分以外に、新合成構成物、その中には発癌性を有するもの、例えばアクリルアミド、ヘテロサイクリックアミン(英: Heterocyclic amine、略称: HCA)、 多環芳香族炭化水素英:polycyclic aromatic hydrocarbon、PAHなどが、熱処理された食品に生じ、メイラード反応を生じる。2つめに、発癌性・内分泌攪乱特性を有する、例えば、ビスフェノールAなど。認可されているが、議論のある、加工肉内の次亜硝酸ナトリウムなどの添加物、酸化チタン((TiO2, 白色剤)これらは動物モデル、細胞モデルで発癌性示されている


Consumption of ultra-processed foods and cancer risk: results from NutriNet-Santé prospective cohort
Thibault Fiolet, et al.
BMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k322 (Published 14 February 2018)

Ultra-processed food 摂取は、包括的癌リスク増加と相関 (n=2228 cases; 食品中比率10%増加毎のハザード比  1.12 (95% 信頼区間 1.06 to 1.18); P = 0.02

これらの結果は、食品中の栄養の質(主要成分分析による脂質、ナトリウム、炭水化物摂取 and/or Western patte食)に関するいくつかのマーカー補正後も有意性残存





糖質制限流行だが、加工食品や超加工食品が大量に入り込む可能性がある

RCT:変形性膝関節症へのアーユルヴェーダ”治療



変形性膝関節症へのアーユルヴェーダ”治療



Effectiveness of an Ayurveda Treatment Approach in Knee Osteoarthritis – a Randomized Controlled Trial

Christian S. Kessler,  et al.
Osteoarthritis and Cartilage
DOI: https://doi.org/10.1016/j.joca.2018.01.02
Open Access
www.oarsijournal.com/article/S1063-4584(18)30082-7/fulltext


According to

American College of Rheumatology (ACR) criteria に従い、OA患者への多施設ランダム化対照かオープンラベル・トライアル(ドイツの2病院クリニック、2プライベート外来クリニック)

multi-modal Ayurvedic treatment or multi-modal conventional care
12週間15回の治療

プライマリアウトカムは、12週後のWestern Ontario and McMaster University Osteoarthritis (WOMAC) Index
セカンダリアウトカムは、WOMAC subscale;疼痛性障害指数、疼痛経験スケール、疼痛・睡眠の質NRS(数値評価スケール)、QOL、気分、レスキュー薬剤使用、安全性評価



151名の被検者、Ayurveda n=77, 通常ケア n=74
WOMAC指数 ベースラインから12週での変化は、Ayurveda群で通常ケア群より影響大  (mean difference 61.0 [95%CI: 52.4;69.6 vs 32.0 [95%CI: 21.4;42.6]) ;群間差有意  (p<0 .001="" 0.68="" ci:0.35="" d="" effect="" ohen="" p="" s="" size="">
12週後の全てのセカンダリアウトカムも同様

効果はフォローアップ6ヶ月、12ヶ月後維持



変形性関節症への漫然と行われている日本での“整形リハビリ"よりは、科学的根拠ありと言わざる得ない・・・と書こうと思ったが・・・ 反発ありそうで書き込まない

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