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: 9001317
• 负责人: Xuebin Qin
• 金额: $ 32.79万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 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 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9001317
• 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; Health; 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; immunogenic; immunogenicity; improved; in vivo; inhibitor/antagonist; malignant breast neoplasm; novel; novel therapeutics; overexpression; pre-clinical; protein aminoacid sequence; 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（由申请人提供）：利妥昔单抗（RTX）和Ofatumumab（OFA）在癌症治疗中的效率部分取决于诱导补体依赖性细胞毒性（CDC）。人CD59（HCD59）是限制膜攻击复合物（MAC）形成的关键补体调节剂，从而抑制了CDC的诱导。 HCD59在B细胞恶性肿瘤中高度表达，例如非霍奇金淋巴瘤（NHL）和慢性淋巴细胞性白血病（CLL），HCD59表达的上调是这些癌细胞对RTX治疗的敏感性的重要决定因素。因此，必须开发能够抑制癌细胞中HCD59功能的分子，从而促进癌症免疫治疗。但是，针对HCD59的抗体特异性的靶向毒性效应以及C8或C9肽的疗效限制了它们出于治疗目的。最近，我们开发了一种特异性且有效的HCD59抑制剂ILYD4（114AA），并证明1）ILYD4增强了CDC，从而使RTX耐药NHL细胞和初级CLL对RTX或RTX或OFA处理敏感； 2）iyd4本身不会对表达HCD59的红细胞的体内溶血进行不利的介导； 3）RTX或OFA对CDC效应的敏感性对RTX耐药的NHL细胞系和CLL细胞的敏感性与细胞表面上CD59的水平负相关； 4）过表达HCD59的NHL细胞直接导致对RTX介导的CDC的抗性。这些结果合理地将ILYD4用作主要生物学候选者，以开发潜在的治疗辅助治疗RTX治疗RTX耐药的NHL和CLL。基于这些结果，我们建议开发略微或非免疫原性，有效和稳定的ILYD4衍生肽。我们假设优化的ILYD4衍生的肽将提高物理化学特性，以使父母给药，消除或降低明显的免疫原性，提高代谢稳定性和循环中的半衰期，并提高治疗功效，从而导致有效的ILYD4与ILYD4与ILYD4相关的治疗疗法，从而有效 在B细胞恶性肿瘤中的抗癌药物（例如OFA和RTX）中，这些药物已先前治疗基于AB的疗法后已经复发。在支持方面，HCD59和ILY的晶体结构的可用性使我们能够执行计算对接，以识别ILYD4和HCD59之间的潜在接口，并预测非功能性和免疫原性表位。最近，我们通过除去N末端区域（ILYD4DEL21AA）的免疫原性21 AA残基产生了短形式的ILYD4，并发现ILYD4DEL21AA在与父母ILYD4相当的水平上具有抗HCD59活性。因此，我们建议开发主动和脱离Ilyd4del21aA并进行pegylate deimmunized Ilyd4del21aA，并研究体内的免疫原性，PK/PD，疗效和毒性特征。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ILYD4衍生物，该试验将测试其作为基于抗体的癌症疗法的功效，例如RTX-或OFA基于RTX或OFA的B细胞恶性疗法，并提供急需的手段来克服毁灭性的RTX或OFA耐药的B-B-Cell恶性肿瘤。