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

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重大进展，但自身免疫性疾病患者的发病率很高，死亡率也增加了。全身免疫抑制仍然是治疗的支柱，尽管它的不良事件是众所周知的，大大增加了患者的发病率和死亡率。因此，迫切需要为自身免疫性疾病患者开发新的治疗方法。理想情况下，这些细胞应该是致病的，或者是针对致病的、自身抗原特异性的B和/或T细胞(靶向治疗)。这种靶向治疗最近在天疱疮的临床前小鼠模型中得到了描述，天疱疮是一种自身免疫性皮肤起泡疾病，其特征是由抗Dsg3的自身抗体引起。总之，基于嵌合抗原受体(CAR)技术，获得了表达天疱疮自身抗原Dsg3与CD137-CD3zeta信号域融合的嵌合自身抗体受体(CAAR)的人T细胞。这些Dsg3CAAR-T细胞在体外对表达抗Dsg3BCR的细胞具有特异性的细胞毒作用，在体内扩增、持续存在并特异性地消除Dsg3特异性的B细胞。因此，Dsg3CAAR-T细胞阻止了由注射产生抗Dsg3抗体的淋巴瘤细胞诱导的小鼠实验性天疱疮的诱导。然而，CAAR-T细胞的疗效仍有待于在治疗实验环境中进行评估。此外，考虑到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。为了解决这一翻译差距，我们的目标是开发能够特异性消除自身反应性B细胞的双特异性T细胞结合蛋白(BITE)。我们将设计由抗鼠CD3融合到鼠II型胶原(COL7)免疫优势片段(抗CD3xCOL7)的咬合组成的咬合。抗CD3xCOL7抗体的治疗效果将在我们已建立的免疫诱导获得性大疱性表皮松解症(EBA)小鼠模型中进行评估。该模型的优势在于COL7自身抗体的存在与临床疾病表现之间的因果关系。我们预计，抗CD3xCOL7的咬合将对免疫诱导的EBA产生完全和持久的治愈。证实我们的假设将为自身免疫疾病的治疗开辟新的途径，自身免疫反应和临床表现之间存在明确的致病联系。

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.