Localization of Therapeutic Fab-CHP Conjugates to Sites of Denatured Collagen for the Treatment of Rheumatoid Arthritis.,Bioconjugate Chemistry

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Localization of Therapeutic Fab-CHP Conjugates to Sites of Denatured Collagen for the Treatment of Rheumatoid Arthritis.
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-07-01 , DOI: 10.1021/acs.bioconjchem.0c00324
Keith J Arlotta ₁ , Boi Hoa San ₁ , Hong-Hua Mu ₂ , S Michael Yu _{1,

3} , Shawn C Owen _{1,

3}

Affiliation

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation in synovial joints and protease-induced cartilage degradation. Current biologic treatments for RA can effectively reduce symptoms, primarily by neutralizing the proinflammatory cytokine TNFα; however, continued, indiscriminate overinhibition of inflammatory factors can significantly weaken the host immune system, leading to opportunistic infections and interrupting treatment. We hypothesize that localizing anti-TNFα therapeutics to denatured collagen (dCol) present at arthritic joints, via conjugation with collagen-hybridizing peptides (CHPs), will reduce off-site antigen binding and maintain local immunosuppression. We isolated the antigen-binding fragment of the clinically approved anti-TNFα therapeutic infliximab (iFab) and prepared iFab-CHP conjugates via lysine-based conjugation with an SMCC linker. After successful conjugation, confirmed by LC-MS, the binding affinity of iFab-CHP was characterized by ELISA-like assays, which showed comparable antigen binding relative to infliximab, comparable dCol binding relative to CHP, and the hybrid ability to bind both dCol and TNFα simultaneously. We further demonstrated localization of Fab-CHP to areas of high dCol in vivo and promising therapeutic efficacy, assessed by histological staining (Safranin-O and H&E), in a pilot mouse study.

中文翻译：

治疗性 Fab-CHP 结合到变性胶原部位以治疗类风湿性关节炎的定位。

类风湿性关节炎 (RA) 是一种自身免疫性疾病，其特征是滑膜关节慢性炎症和蛋白酶诱导的软骨退化。目前 RA 的生物治疗可以有效减轻症状，主要是通过中和促炎细胞因子 TNFα；然而，持续、不分青红皂白地过度抑制炎症因子会显着削弱宿主免疫系统，导致机会性感染和治疗中断。我们假设，通过与胶原杂交肽 (CHP) 结合，将抗 TNFα 疗法定位于关节炎关节处的变性胶原 (dCol)，将减少异位抗原结合并维持局部免疫抑制。我们分离了临床批准的抗 TNFα 治疗性英夫利昔单抗 (iFab) 的抗原结合片段，并通过基于赖氨酸的缀合与 SMCC 接头制备了 iFab-CHP 缀合物。成功偶联后，通过 LC-MS 确认，iFab-CHP 的结合亲和力通过类似 ELISA 的测定法表征，其显示出与英夫利昔单抗相当的抗原结合，与 CHP 相当的 dCol 结合，以及结合 dCol 和肿瘤坏死因子α同时。我们通过组织学染色（Safranin-O 和 H&E）在小鼠试验研究中进一步证明了 Fab-CHP 定位于体内高 dCol 区域和有前景的治疗效果。其显示出与英夫利昔单抗相当的抗原结合，与 CHP 相当的 dCol 结合，以及同时结合 dCol 和 TNFα 的杂交能力。我们通过组织学染色（Safranin-O 和 H&E）在小鼠试验研究中进一步证明了 Fab-CHP 定位于体内高 dCol 区域和有前景的治疗效果。其显示出与英夫利昔单抗相当的抗原结合，与 CHP 相当的 dCol 结合，以及同时结合 dCol 和 TNFα 的杂交能力。我们通过组织学染色（Safranin-O 和 H&E）在小鼠试验研究中进一步证明了 Fab-CHP 定位于体内高 dCol 区域和有前景的治疗效果。

更新日期：2020-08-19

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