Although disease in a majority of rheumatoid arthritis (RA) patients is often initially limited to one or a few joints, currently approved medications including anti-tumor necrosis factor-α antibody (α-TNF) are injected systemically. Given that α-TNF systemic injection typically does not cure RA and involves risk of treatment-related adverse events, one possible approach to enhance therapeutic efficacy and reduce α-TNF systemic exposure is to retain the antibodies in arthritic joints after local administration. The aim of this study was to evaluate the approach of conferring extracellular matrix (ECM) binding affinity to α-TNF antibodies in a RA model. α-TNF was chemically conjugated with a promiscuous ECM-binding peptide derived from placenta growth factor 2 (PlGF-2123-144). The binding activity of PlGF-2123-144-conjugated α-TNF (PlGF-2123-144-α-TNF) against ECM proteins was assessed by ELISA and by immunostaining on human cartilage specimens. The effect of conjugation on antibody function was assessed as a neutralizing activity against osteoclast differentiation. Retention at the injection site and therapeutic efficacy of PlGF-2123-144-α-TNF were tested in a collagen antibody-induced arthritis (CAIA) model in the mouse. PlGF-2123-144 peptide conjugation conferred α-TNF with affinity to ECM proteins without impairment of antigen recognition. PlGF-2123-144-α-TNF locally injected at a paw in the CAIA model was retained for at least 96 h at the injection site, whereas unmodified α-TNF was dispersed rapidly after injection. Local treatment with unmodified α-TNF did not suppress the arthritis score relative to isotype controls. By contrast, local administration of PlGF-2123-144-α-TNF suppressed arthritis development almost completely in the treated paw even at a 1000× lower dose. These data demonstrate that retention of α-TNF in arthritic joints can suppress arthritis development and enhance therapeutic efficacy. This simple bioengineering approach of ECM-binding peptide conjugation offers a powerful and clinically translational approach to treat RA.

中文翻译：

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赋予细胞外基质亲和力可增强类风湿关节炎小鼠模型中抗TNF-α抗体的局部治疗功效

尽管大多数类风湿关节炎（RA）患者的疾病最初通常仅限于一个或几个关节，但目前已系统性地注射了包括抗肿瘤坏死因子-α抗体（α-TNF）在内的当前批准的药物。鉴于α-TNF全身注射通常不能治愈RA并涉及与治疗相关的不良事件的风险，因此提高治疗效果并减少α-TNF全身暴露的一种可能方法是在局部给药后将抗体保留在关节炎的关节中。这项研究的目的是评估在RA模型中赋予细胞外基质（ECM）与α-TNF抗体结合亲和力的方法。α-TNF与衍生自胎盘生长因子2（PlGF-2123-144）的混杂ECM结合肽化学缀合。通过ELISA和通过在人软骨样品上进行免疫染色，评估了结合有PlGF-2123-144的α-TNF（PlGF-2123-144-α-TNF）对ECM蛋白的结合活性。缀合对抗体功能的影响被评估为对破骨细胞分化的中和活性。在小鼠的胶原蛋白抗体诱导的关节炎（CAIA）模型中测试了PlGF-2123-144-α-TNF在注射部位的保留和治疗功效。PlGF-2123-144肽的缀合赋予了α-TNF对ECM蛋白亲和力而又不损害抗原识别的能力。在CAIA模型中局部注射的PlGF-2123-144-α-TNF在注射部位保留至少96小时，而未修饰的α-TNF在注射后迅速分散。相对于同种型对照，未经修饰的α-TNF的局部治疗不能抑制关节炎评分。相反，即使以低1000倍的剂量局部施用PlGF-2123-144-α-TNF，也几乎完全抑制了治疗足中的关节炎发展。这些数据表明，α-TNF在关节炎关节中的保留可以抑制关节炎的发展并增强治疗效果。这种简单的ECM结合肽缀合物生物工程方法为治疗RA提供了强大且临床上可转化的方法。