Studies of Hyper- IgM Syndrome

高 IgM 综合征的研究

• 批准号: 7732726
• 负责人: Ashish Jain
• 金额: $ 36.54万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7732726
• 关键词: Agonist; Antibodies; Antibody Therapy; Antigens; B-Lymphocytes; Biological; CD40 Ligand; CD8B1 gene; Candida; Class; Clinical Research; Clinical Trials; Clinical trial protocol document; Defect; Delayed Hypersensitivity; Development; Dose; Enrollment; Follicular Dendritic Cells; Goals; Half-Life; Human; Immune response; Immunoglobulin Class Switching; Immunoglobulin M; Immunoglobulin Switch Recombination; Immunologics; Investigation; Keyhole Limpet Hemocyanin; Lymphatic Diseases; Monoclonal Antibody HuM291; Mumps; Muromonab-CD3; Patients; Pharmaceutical Preparations; Phase; Phenotype; Pilot Projects; Population; Production; Reaction; Recombinant CD40-Ligand; Recombinants; Research Personnel; Risk; Safety; Schedule; Single-Gene Defect; Staining method; Stains; Staphylococcal Enterotoxin B; Structure of germinal center of lymph node; Syndrome; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Therapeutic; Time; Toxic effect; cytokine; design; in vivo; novel; pre-clinical; reconstitution

We previously conducted a clinical study to assess the therapeutic potential of recombinant human CD40 ligand in patients with XHM. We designed a one-center investigator-initiated Phase I/II clinical trial (protocol 00-I-0006) to assess safety of recombinant CD40L administration, and determine if it could restore the core immunologic defects of patients with XHM. Five patients were enrolled, and were treated on a dose escalation schedule for up to one year. We showed that administration of recombinant CD40 ligand is safe and can reconstitute deficient immune responses. Specifically, patients T cells demonstrate for the first time a capacity to synthesize IFN-γ and TNF-α when stimulated with anti- CD3, or SEB, or SEA. Studies of cytokine production by intracellular staining demonstrated that recombinant CD40L was able to prime both the CD4 and CD8 T cell populations. In addition, all patients developed positive delayed type hypersensitivity reactions to candida, and KLH, and one patient to mumps antigen. Patients on therapy also demonstrated the development of new adenopathy, improvement of primary follicle formation, expansion of both B and T cell populations in the lymphnodes, and the development of follicular dendritic cells. However, germinal center formation and immunoglobulin class switch recombination (CSR) in B cells was lacking. Further improvements in B cell terminal differentiation may require higher doses or a different class of drugs that offer greater half-life. Stimulated by these observations, we have initiated a a single center dose escalation pilot study with a fully human CD40 agonist antibody in XHM patients. Preliminary results indicate the anti- CD40 agonist antibody has significant biological activity in vivo. Human CD40 agonist antibody therapy may allow for less frequent dosing and a reduced risk of serious toxicity in study patients.

我们之前进行了一项临床研究，以评估重组人 CD40 配体对 XHM 患者的治疗潜力。 我们设计了一项由单中心研究者发起的 I/II 期临床试验（方案 00-I-0006），以评估重组 CD40L 给药的安全性，并确定其是否可以恢复 XHM 患者的核心免疫缺陷。五名患者入组，并按照剂量递增计划接受长达一年的治疗。 我们证明重组 CD40 配体的施用是安全的并且可以重建缺陷的免疫反应。 具体来说，当用抗CD3、SEB或SEA刺激时，患者T细胞首次表现出合成IFN-γ和TNF-α的能力。 通过细胞内染色对细胞因子产生的研究表明，重组 CD40L 能够启动 CD4 和 CD8 T 细胞群。 此外，所有患者均出现对念珠菌和KLH的阳性迟发型超敏反应，一名患者对腮腺炎抗原出现阳性迟发型超敏反应。接受治疗的患者还表现出新的腺病的发展、初级滤泡形成的改善、淋巴结中 B 和 T 细胞群的扩张以及滤泡树突细胞的发育。 然而，B 细胞中缺乏生发中心形成和免疫球蛋白类别转换重组 (CSR)。 B 细胞终末分化的进一步改善可能需要更高的剂量或提供更长半衰期的不同类别的药物。 受这些观察结果的刺激，我们在 XHM 患者中启动了一项单中心剂量递增试点研究，使用全人 CD40 激动剂抗体。初步结果表明抗CD40激动抗体具有显着的体内生物活性。 人 CD40 激动剂抗体疗法可以减少研究患者的给药频率并降低严重毒性的风险。