Effects of AVX-470, an Oral, Locally Acting Anti-Tumour Necrosis Factor Antibody, on Tissue Biomarkers in Patients with Active Ulcerative Colitis
Effects of AVX-470, an Oral, Locally Acting Anti-Tumour Necrosis Factor Antibody, on Tissue Biomarkers in Patients with Active Ulcerative Colitis
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DOI：
10.1093/ecco-jcc/jjw026
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发表时间：
2016-06-01
影响因子：
8
通讯作者：
Fox, Barbara S.
中科院分区：
文献类型：
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作者：
Hartman, Deborah S.;Tracey, Daniel E.;Fox, Barbara S.
AVX-470 是一种口服、牛源性抗肿瘤坏死因子 (TNF) 抗体，在胃肠道中具有局部活性。在 AVX-470 治疗活动性溃疡性结肠炎的首次人体临床试验中，我们评估了结肠组织中的炎症生物标志物，作为疾病活动性和早期治疗反应的指标。36 名患者在 4 周内接受活性药物（AVX-470 0.2、1.6 或 3.5g/天）或安慰剂。在基线和第 4 周从结肠的 5 个区域收集结肠活检样本。通过免疫组织化学和定量逆转录聚合酶链反应 (qRT-PCR) 评估组织炎症生物标志物，通过末端脱氧核苷酸转移酶 dUTP 缺口末端标记 (TUNEL) 评估上皮细胞凋亡，并通过免疫组织化学和质谱评估牛免疫球蛋白。由中央读数器评估结肠镜检查时每个结肠区域的内镜活动（溃疡性结肠炎内镜严重程度指数[UCEIS]）。在给药前后在活检组织的固有层和粘膜下层的粘膜组织中观察到牛免疫球蛋白。远端结肠组织中 TNF、髓过氧化物酶 (MPO)、CD68 和白细胞介素 (IL)-1 β 以及较小程度的 IL-6 mRNA 的基线水平比近端结肠组织高 2 至 3 倍，对应于内镜评分基线严重程度的 2 至 3 倍差异。 AVX-470 3.5g/天治疗 4 周后，近端和远端结肠活检中观察到 TNF 减少 > 10 倍，MPO 和上皮细胞凋亡减少超过 10 倍。 TNF 评分的降低与 MPO 和 CD3 免疫组织化学评分的变化相关。这些结果与溃疡性结肠炎患者结肠粘膜组织中口服 AVX-470 的抗 TNF 活性一致，并证明了组织生物标志物在早期临床研究中评估疾病和治疗反应的效用。该试验在 ClinicalTrials.gov 注册为研究 NCT01759056，并在 EudraCT 注册为研究2012-004859-27。
AVX-470 is an orally administered, bovine-derived, anti-tumour necrosis factor (TNF) antibody with local activity in the gastrointestinal tract. In the first-in-human clinical trial of AVX-470 in active ulcerative colitis, we evaluated inflammatory biomarkers in colon tissue as measures of disease activity and early response to treatment.Thirty-six patients received active drug (AVX-470 at 0.2, 1.6 or 3.5g/day) or placebo over 4 weeks. Colon biopsy samples were collected from 5 regions of colon at baseline and week 4. Tissue inflammatory biomarkers were evaluated by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), epithelial cell apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) and bovine immunoglobulin by immunohistochemistry and mass spectrometry. Endoscopic activity (Ulcerative Colitis Endoscopic Index of Severity [UCEIS]) at colonoscopy was assessed in each colonic region by a central reader.Bovine immunoglobulin was observed in mucosal tissue before and after dosing in lamina propria and submucosal layers of biopsy tissue. Baseline levels of TNF, myeloperoxidase (MPO), CD68 and interleukin (IL)-1 beta and, to a lesser extent, IL-6 mRNA were 2- to 3-fold higher in distal vs proximal colon tissue, corresponding to the 2- to 3-fold differences in baseline severities of endoscopic scores. Reductions of > 10-fold in TNF and, to lesser extents, in MPO and epithelial cell apoptosis were observed in proximal and distal colon biopsies after 4 weeks of AVX-470 3.5g/day treatment. Reductions in TNF scores were correlated with changes in MPO and CD3 immunohistochemistry scores.These results are consistent with anti-TNF activity of orally administered AVX-470 in colon mucosal tissue in ulcerative colitis patients and demonstrate the utility of tissue biomarkers in assessing disease and treatment response in early clinical studies.This trial was registered with Clinicaltrials.gov as study NCT01759056 and with EudraCT as study 2012-004859-27.