Development of Therapeutic CD59 inhibitor for treating B-cell malignancies

开发用于治疗 B 细胞恶性肿瘤的治疗性 CD59 抑制剂

• 批准号: 8438708
• 负责人: Xuebin Qin
• 金额: $ 11.91万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8438708
• 关键词: Adjuvant; Alleles; Amino Acids; Antibodies; Antigen Presentation; Antineoplastic Agents; B lymphoid malignancy; Binding; Biological; Blood Circulation; C-terminal; Cancer Patient; Cell Line; Cell surface; Cells; Chronic Lymphocytic Leukemia; Clinical Trials; Colon; Complement; Complement Membrane Attack Complex; Complement-Dependent Cytotoxicity; Computer Simulation; Docking; Epitopes; Erythrocytes; Gastric Adenoma; Half-Life; Hemolysis; Histocompatibility Antigens Class II; Human; Immune response; Immune system; Immunotherapy; In Vitro; Lead; Lymphoma; Major Histocompatibility Complex; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolic; Monoclonal Antibodies; Mutate; N-terminal; Non-Hodgkin' s Lymphoma; Outcomes Research; Parents; Patients; Peptides; Property; Publishing; Relapse; Resistance; Resistance development; Site; Site-Directed Mutagenesis; Solubility; Structure; T-Cell Receptor; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Therapeutic antibodies; Toxic effect; Transgenic Mice; Treatment Efficacy; Up-Regulation; Work; base; cancer cell; cancer therapy; cytotoxicity; genetic regulatory protein; human TACSTD1 protein; immunogenic; immunogenicity; improved; in vivo; inhibitor/antagonist; malignant breast neoplasm; novel; novel therapeutics; overexpression; pre-clinical; protein aminoacid sequence; public health relevance; rituximab; therapeutic development

DESCRIPTION (provided by applicant): Rituximab (RTX) and Ofatumumab (OFA) efficacies in cancer therapy depend in part on the induction of complement-dependent cytotoxicity (CDC). Human CD59 (hCD59) is a key complement regulator that restricts the formation of membrane attack complex (MAC), thereby inhibiting induction of CDC. hCD59 is highly expressed in B-cell malignancies such as non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) and up-regulation of hCD59 expression is an important determinant of the sensitivity of those cancer cells to RTX treatment. Therefore, it is imperative to develop a molecule capable of inhibiting hCD59 function in cancer cells and thus facilitate cancer immune therapy. However, targeted toxicity effect from antibody specific against hCD59 and less efficacy of C8 or C9 peptides limit them for therapeutic purposes. Recently, we have developed a specific and potent hCD59 inhibitor, ILYd4 (114AA), and demonstrated that 1) ILYd4 enhances CDC, thereby sensitizing RTX-resistant NHL cells and primary CLL to RTX or OFA treatment; 2) by itself ILYd4 does not adversely mediate in vivo hemolysis of hCD59-expressing erythrocytes; 3) the sensitivity to CDC effects mediated by RTX or OFA on RTX-resistant NHL cell lines and CLL cells negatively correlated with the level of CD59 on the cell surface; and 4) NHL cells overexpressing hCD59 were directly responsible for the resistance to RTX-mediated CDC. These results rationalize the use of ILYd4 as a lead biological candidate to develop a potential therapeutic adjuvant for RTX treatment of RTX-resistant NHL and CLL. Based on these results, we propose to develop marginally- or non- immunogenic, potent and stable ILYd4-derived peptides. We hypothesize that the optimized ILYd4-derived peptides will improve the physicochemical properties to enable parental administration, eliminate or reduce markedly immunogenicity, increase metabolic stability and half-life in circulation, and enhance therapeutic efficacy, thereby leading to effective ILYd4-related therapeutics that will function as an adjuvant to anti-cancer drugs such as OFA and RTX in B-cell malignancies that have relapsed after prior treatment with Ab-based therapies. Supportively, the availability of crystal structures of hCD59 and ILY enabled us to perform computational docking to identify potential interfaces between ILYd4 and hCD59 and predict nonfunctional and immunogenic epitopes. Recently, we generated a short form of ILYd4 by removing an immunogenic 21 AA residues in N-terminal region (ILYd4del21AA) and found that ILYd4del21AA had an anti-hCD59 activity at the level comparable to parental ILYd4. Therefore, we propose to develop active and deimmunized ILYd4del21AA and pegylate the deimmunized ILYd4del21AA, and to study the immunogenicity, the PK/PD, efficacy and toxicity profile in vivo. Successful outcome of this research will generate a novel therapeutic ILYd4 derivative for clinical trials that will test its efficacy as an adjuvantfor antibody-based cancer therapy such as RTX- or OFA-based B-cell malignancy therapy and provide the much needed means to overcome the devastating RTX- or OFA-resistant B-cell malignancies.

描述（由申请方提供）：利妥昔单抗（RTX）和奥法木单抗（OFA）在癌症治疗中的疗效部分取决于补体依赖性细胞毒性（CDC）的诱导。人CD 59（hCD 59）是一种关键的补体调节因子，其限制膜攻击复合物（MAC）的形成，从而抑制CDC的诱导。hCD 59在非霍奇金淋巴瘤（NHL）和慢性淋巴细胞白血病（CLL）等B细胞恶性肿瘤中高度表达，hCD 59表达的上调是这些癌细胞对RTX治疗敏感性的重要决定因素。因此，迫切需要开发能够抑制癌细胞中hCD 59功能的分子，从而促进癌症免疫治疗。然而，来自对hCD 59具有特异性的抗体的靶向毒性作用和C8或C9肽的较低功效限制了它们用于治疗目的。最近，我们开发了一种特异性和有效的hCD 59抑制剂ILYd 4（114 AA），并证明1）ILYd 4增强CDC，从而使RTX抗性NHL细胞和原发性CLL对RTX或OFA治疗敏感; 2）ILYd 4本身不会不利地介导表达hCD 59的红细胞的体内溶血;（3）RTX或OFA介导的CDC效应对耐RTX NHL细胞系和CLL细胞的敏感性与细胞表面CD 59水平呈负相关;（4）hCD 59过表达的NHL细胞对RTX介导的CDC产生抗性。这些结果使ILYd 4作为主要生物候选物的使用合理化，以开发用于RTX抗性NHL和CLL的RTX治疗的潜在治疗佐剂。基于这些结果，我们提出开发边缘免疫原性或非免疫原性的、有效且稳定的ILYd 4衍生肽。我们假设，优化的ILYd 4衍生肽将改善理化性质以使胃肠外给药成为可能，消除或显著降低免疫原性，增加代谢稳定性和循环中的半衰期，并增强治疗功效，从而产生将作为佐剂起作用的有效ILYd 4相关治疗剂 在先前用基于Ab的疗法治疗后复发的B细胞恶性肿瘤中的抗癌药物如OFA和RTX。支持性地，hCD 59和ILY的晶体结构的可用性使我们能够进行计算对接以鉴定ILYd 4和hCD 59之间的潜在界面并预测非功能性和免疫原性表位。最近，我们通过去除N-末端区域中的免疫原性21个AA残基产生了ILYd 4的短形式（ILYd 4del 21 AA），并且发现ILYd 4del 21 AA具有与亲本ILYd 4相当的水平的抗hCD 59活性。因此，我们建议开发活性和去免疫化的ILYd 4del 21 AA和聚乙二醇化去免疫化的ILYd 4del 21 AA，并在体内研究免疫原性、PK/PD、功效和毒性特征。这项研究的成功结果将产生 一种用于临床试验的新型治疗性ILYd 4衍生物，其将测试其作为基于抗体的癌症治疗（例如基于RTX或OFA的B细胞恶性肿瘤治疗）的化疗剂的功效，并提供急需的手段来克服毁灭性的RTX或OFA抗性B细胞恶性肿瘤。