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: 8607165
• 负责人: Xuebin Qin
• 金额: $ 32.48万
• 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/8607165
• 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（由申请人提供）：利妥昔单抗（RTX）和Ofatumumab （OFA）在癌症治疗中的有效性部分依赖于补体依赖性细胞毒性（CDC）的诱导。人CD59 （hCD59）是一种关键的补体调节剂，它限制了膜攻击复合物（MAC）的形成，从而抑制了CDC的诱导。hCD59在非霍奇金淋巴瘤（NHL）和慢性淋巴细胞白血病（CLL）等b细胞恶性肿瘤中高表达，hCD59表达上调是这些癌细胞对RTX治疗敏感性的重要决定因素。因此，开发一种能够抑制hCD59在癌细胞中的功能，从而促进癌症免疫治疗的分子势在必行。然而，针对hCD59的抗体的靶向毒性作用和C8或C9肽的疗效较低限制了它们的治疗目的。最近，我们开发了一种特异性和有效的hCD59抑制剂ILYd4 (114AA)，并证明1)ILYd4增强CDC，从而使耐RTX的NHL细胞和原发性CLL对RTX或OFA治疗敏感；2) ILYd4本身不介导表达hcd59的红细胞的体内溶血；3) RTX或OFA对耐RTX NHL细胞株和CLL细胞介导的CDC效应的敏感性与细胞表面CD59水平呈负相关；4)过表达hCD59的NHL细胞对rtx介导的CDC产生耐药性是直接原因。这些结果为使用ILYd4作为主要生物学候选物开发RTX治疗耐药NHL和CLL的潜在治疗佐剂提供了合理的依据。基于这些结果，我们建议开发微免疫原性或非免疫原性、强效和稳定的ilyd4衍生肽。我们假设，优化后的ilyd4衍生肽将改善理化性质，使亲代给药，消除或显著降低免疫原性，增加代谢稳定性和循环半衰期，提高治疗效果，从而导致有效的ilyd4相关治疗药物，作为辅助药物