Bispecific antibodies for the treatment of the autoimmune disease epidermolysis bullosa acquisita

用于治疗自身免疫性疾病大疱性表皮松解症的双特异性抗体

• 批准号: 387867769
• 负责人: Professor Dr. Ralf Joachim Ludwig
• 金额: --
• 依托单位: Lübecker Institut für Experimentelle Dermatologie (LIED)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/387867769?language=en
• 关键词: Bispecific; antibodies; treatment; autoimmune; disease

Autoimmune diseases have become a major health burden. Despite significant advances in treatment, patients with autoimmune diseases suffer from high (co)-morbidity and increased mortality. General immunosuppression remains the backbone of treatment despite its well-known adverse events that contribute substantially to patients morbidity and mortality. Hence, there is a great need for the development of new treatments for patients with autoimmune diseases. Ideally, these would be causative or, alternatively, directed toward the disease-causing, autoantigen-specific B and/or T cells (targeted treatment). Such a targeted treatment has recently been described in a pre-clinical mouse model of pemphigus, an autoimmune skin blistering disease characterized and caused by autoantibodies against Dsg3. In brief, based on chimeric antigen receptor (CAR) technology, human T cells expressing a chimeric autoantibody receptor (CAAR) consisting of the pemphigus autoantigen Dsg3 fused to the CD137-CD3zeta signaling domains were generated. These Dsg3 CAAR-T cells showed specific cytotoxicity against cells expressing anti-Dsg3 BCRs in vitro and expanded, persisted, and specifically eliminated Dsg3-specific B cells in vivo. Thus, the Dsg3 CAAR-T cells prevented the induction of experimental pemphigus in mice, which was induced by injection of lymphoma cells producing anti-Dsg3 antibodies. However, the efficacy of CAAR-T cells remains to be evaluated in a therapeutic experimental setting. Furthermore, given successful evaluation in therapeutic settings, CAAR-T cells would need to be engineered for each patient, which would be a potential hindrance to the broader application of this treatment. To address this translational gap, we aim to develop bispecific T cell engagers (BiTEs) that specifically eliminate autoreactive B cells. We will engineer BiTEs consisting of anti-mouse CD3 fused to an immunodominat fragment of mouse type VII collagen (COL7) (anti-CD3xCOL7 BiTEs). The therapeutic efficacy of the anti-CD3xCOL7 BiTEs will be evaluated in our well-established immunization-induced epidermolysis bullosa acquisita (EBA) mouse model. The advantage of this model is the causal relationship between the presence of autoantibodies against COL7 and the manifestation of clinical disease. We expect that anti-CD3xCOL7 BiTEs will induce a complete and persistent cure for immunization-induced EBA. Confirmation of our hypothesis would open up novel avenues for the treatment of autoimmune diseases with a clear pathogenic link between the autoimmune response and clinical presentation.

自身免疫性疾病已成为主要的健康负担。尽管在治疗方面取得了显著进展，但患有自身免疫性疾病的患者遭受高（共）发病率和增加的死亡率。全身免疫抑制仍然是治疗的支柱，尽管其众所周知的不良事件，大大有助于患者的发病率和死亡率。因此，非常需要开发用于患有自身免疫性疾病的患者的新疗法。理想情况下，这些将是致病的，或者，可替代地，针对致病的自身抗原特异性B和/或T细胞（靶向治疗）。最近在天疱疮的临床前小鼠模型中描述了这种靶向治疗，天疱疮是一种自身免疫性皮肤起泡疾病，其特征在于并由针对Dsg 3的自身抗体引起。简而言之，基于嵌合抗原受体（CAR）技术，产生了表达嵌合自身抗体受体（CAAR）的人T细胞，所述嵌合自身抗体受体（CAAR）由融合至CD 137-CD 3 ζ信号传导结构域的天疱疮自身抗原Dsg 3组成。这些Dsg 3 CAAR-T细胞在体外显示出针对表达抗Dsg 3 BCR的细胞的特异性细胞毒性，并在体内扩增、持续存在和特异性消除Dsg 3特异性B细胞。因此，Dsg 3 CAAR-T细胞防止小鼠中实验性天疱疮的诱导，所述天疱疮通过注射产生抗Dsg 3抗体的淋巴瘤细胞诱导。然而，CAAR-T细胞的功效仍有待在治疗实验环境中评估。此外，鉴于在治疗环境中的成功评估，需要为每个患者设计CAAR-T细胞，这将是这种治疗更广泛应用的潜在障碍。为了解决这个翻译缺口，我们的目标是开发特异性消除自身反应性B细胞的双特异性T细胞抑制剂（BiTE）。我们将设计由抗小鼠CD 3融合到小鼠VII型胶原蛋白（COL 7）的免疫显性片段组成的BiTE（抗CD 3xCOL 7 BiTE）。将在我们完善的免疫诱导的获得性大疱性表皮细胞瘤（EBA）小鼠模型中评估抗CD 3xCOL 7 BiTE的治疗功效。该模型的优点是针对COL 7的自身抗体的存在与临床疾病的表现之间的因果关系。我们预期抗CD 3xCOL 7 BiTE将诱导免疫诱导的EBA的完全和持久治愈。证实我们的假设将开辟新的途径，治疗自身免疫性疾病的自身免疫反应和临床表现之间有明确的致病联系。