Novel Bispecific Antibody for Synovial-Specific Target Delivery of Anti-TNF Therapy in Rheumatoid Arthritis.
Novel Bispecific Antibody for Synovial-Specific Target Delivery of Anti-TNF Therapy in Rheumatoid Arthritis.
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DOI：
10.3389/fimmu.2021.640070
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发表时间：
2021
影响因子：
7.3
通讯作者：
Pitzalis C
中科院分区：
文献类型：
--
作者：
Ferrari M;Onuoha SC;Fossati-Jimack L;Nerviani A;Alves PL;Pagani S;Deantonio C;Colombo F;Santoro C;Sblattero D;Pitzalis C
生物药物，特别是抗肿瘤坏死因子，被认为是治疗类风湿关节炎的金标准。然而，疗效不一致、感染发生率和高昂的费用是主要的担忧。新的组织特异性药物可以克服目前全身给药的局限性，提供更好的效力和安全性。我们研制了一种双功能抗体，通过滑膜特异性单链可变区A7抗体与肿瘤坏死因子α中和抗体结合到关节炎关节靶点，其结合/阻断能力与阿达利单抗免疫球蛋白G相当。在体外人关节炎滑膜和严重联合免疫缺陷(SCID)小鼠滑膜移植模型上证实了BsAb的组织靶向性。移植物蓄积高峰出现在注射后48h，持续超过阿达利玛单抗-Ig G 7d，可提高治疗效果，有效降低组织细胞密度和炎症标志物，与标准治疗相比效力更高。这项研究首次描述了一种能够给药，特别是对疾病组织的BsAb，并提供了对人类关节炎滑膜改善治疗效果的有力证据，并将其应用于其他现有的生物制剂。
Biologic drugs, especially anti-TNF, are considered as the gold standard therapy in rheumatoid arthritis. However, non-uniform efficacy, incidence of infections, and high costs are major concerns. Novel tissue-specific agents may overcome the current limitations of systemic administration, providing improved potency, and safety. We developed a bispecific antibody (BsAb), combining human arthritic joint targeting, via the synovial-specific single-chain variable fragment (scFv)-A7 antibody, and TNFα neutralization, via the scFv-anti-TNFα of adalimumab, with the binding/blocking capacity comparable to adalimumab -immunoglobulin G (IgG). Tissue-targeting capacity of the BsAb was confirmed on the human arthritic synovium in vitro and in a synovium xenograft Severe combined immune deficient (SCID) mouse model. Peak graft accumulation occurred at 48 h after injection with sustained levels over adalimumab-IgG for 7 days and increased therapeutic effect, efficiently decreasing tissue cellularity, and markers of inflammation with higher potency compared to the standard treatment. This study provides the first description of a BsAb capable of drug delivery, specifically to the disease tissue, and a strong evidence of improved therapeutic effect on the human arthritic synovium, with applications to other existing biologics.
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DOI：
10.1186/ar549
发表时间：
2002
期刊：
Arthritis research
影响因子：
--
作者：
Maini RN;Feldmann M
通讯作者：
Feldmann M
影响因子：
5.5
作者：
Catrina, AI;Lampa, J;Ulfgren, AK
通讯作者：
Ulfgren, AK
影响因子：
12.8
作者：
Colombo, Federico;Durigutto, Paolo;Macor, Paolo
通讯作者：
Macor, Paolo
影响因子：
13.3
作者：
Onuoha, Shimobi C.;Ferrari, Mathieu;Pitzalis, Costantino
通讯作者：
Pitzalis, Costantino
影响因子：
--
作者：
Macor，Paolo;Durigutto，Paolo;Tedesco，Francesco
通讯作者：
Tedesco，Francesco