Studies of Hyper- IgM Syndrome

高 IgM 综合征的研究

• 批准号: 7964723
• 负责人: Ashish Jain
• 金额: $ 41.15万
• 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/7964723
• 关键词: Agonist; Antibodies; Antibody Therapy; Antigens; B-Lymphocytes; Biological; CD3 Antigens; CD40 Ligand; CD8B1 gene; Candida; 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; Mumps; 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.

我们先前进行了一项临床研究，以评估重组人CD 40配体在XHM患者中的治疗潜力。 我们设计了一个单中心的免疫启动的I/II期临床试验（方案00-I-0006），以评估重组CD 40 L给药的安全性，并确定它是否可以恢复XHM患者的核心免疫缺陷。入组了5例患者，并按剂量递增方案治疗长达1年。 我们表明，重组CD 40配体的管理是安全的，可以重建缺陷的免疫反应。 具体地，患者T细胞首次证明了当用抗CD 3或SEB或SEA刺激时合成IFN-γ和TNF-γ的能力。 通过细胞内染色的细胞因子产生的研究表明，重组CD 40 L能够引发CD 4和CD 8 T细胞群。 此外，所有患者均对念珠菌和KLH产生阳性迟发型超敏反应，1例患者对腮腺炎抗原产生阳性反应。接受治疗的患者还表现出新的腺病的发展，初级卵泡形成的改善，淋巴结中B和T细胞群的扩增，以及滤泡树突状细胞的发育。 然而，在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）。 进一步改善B细胞终末分化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。 在这些观察结果的刺激下，我们在XHM患者中启动了一项单中心剂量递增初步研究，使用全人CD 40激动剂抗体。初步结果表明，抗CD 40激动性抗体在体内具有显著的生物学活性。 人CD 40激动剂抗体治疗可降低研究患者的给药频率和严重毒性风险。