Next-generation anti-CD20 rituximab antibody that is engineered to be resistant to the immuno-suppressive effect mediated by the tumor-shed antigen, CA125

下一代抗 CD20 利妥昔单抗抗体，经过改造可抵抗肿瘤脱落抗原 CA125 介导的免疫抑制作用

• 批准号: 10045037
• 负责人: Luigi Grasso
• 金额: $ 6.9万
• 依托单位: NAVROGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10045037
• 关键词: Address; Affinity; Antibodies; Antibody Affinity; Antibody-Dependent Enhancement; Antigens; B-Lymphocytes; Benchmarking; Binding; Binding Sites; Biological; Biology; Budgets; CA-125 Antigen; CD20 Antigens; Cancer Patient; Cell Survival; Cells; Clinical; Complement; Complement 1q; Complement component C1; Complement-Dependent Cytotoxicity; Disease-Free Survival; Effectiveness; Effector Cell; Engineering; Enzyme-Linked Immunosorbent Assay; FCGR3A gene; Fc Receptor; Fc domain; Flowcharts; Follicular Lymphoma; Funding; Future; Generations; Genetic Polymorphism; Goals; Human; Humoral Immunities; Immunoglobulin Variable Region; Immunoglobulins; Immunosuppression; Immunotherapy; In Vitro; Jurkat Cells; Knowledge; Lead; Libraries; Lymphoma cell; MS4A1 gene; Malignant - descriptor; Measures; Mediating; Medical; Methods; Modeling; Mutagenesis; Mutate; Mutation; N-terminal; NCAM1 gene; Names; Parents; Patients; Peptides; Pharmaceutical Preparations; Phase; Play; Preparation; Production; Productivity; Progression-Free Survivals; Protein Isoforms; Proteins; Raji Cell; Reading; Refractory; Reporting; Resistance; Risk; Role; Serum; Source; Technology; Testing; Therapeutic; Time; Tumor Antigens; Validation; Variant; anti-CD20; anti-cancer; antibody-dependent cell cytotoxicity; base; clinical effect; clinically relevant; cytotoxicity; cytotoxicity test; disorder control; experience; follow-up; immunogenicity; improved; in vivo; luminescence; mutant; neoplastic; next generation; nonlinear regression; novel; novel therapeutics; phase 3 study; prevent; response; rituximab; screening; tositumomab; tumor; tumor microenvironment

Follicular lymphoma (FL) is characterized by proliferation of neoplastic B cells, with 15,000 new cases/year in US. Standard therapy lines result in progressively shorter periods of FL disease-free survival. The median overall survival (OS) for FL has improved due to novel agents integrated into the FL therapeutic paradigm. Therefore, it is critical to advance novel drugs to achieve better disease control. CD20 is expressed on malignant FL cells and targeting CD20 plays a key role in the treatment of FL, with monoclonal anti-CD20 antibody rituximab having markedly improved the progression-free survival (PFS) and OS. Its mechanism of action includes antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Many reports have established CA125 as a tumor–microenvironment factor that can be detected elevated in serum of some cancer patients, including 37% of FL patients. Recent evidence show that CA125 dampens immunotherapy clinical effects: In a Phase III study, patients with low levels of serum CA-125 (sCA125) had superior PFS and OS when treated with farletuzumab, compared with farletuzumab-treated patients with high sCA125 levels. In another study testing amatuximab, patients with low sCA125 levels had superior PFS and OS as compared with patients with high sCA125 levels. Navrogen’s team discovered that sCA125 inhibits farletuzumab’s and amatuximab’s ADCC and CDC in vitro, as well as that sCA125 inhibits their engagement with Fc receptor and C1q. These effects are due to CA125 direct binding to farletuzumab and amatuximab, which alters their Fc domain. ADCC plays an important role in the clinical effect of rituximab as suggested by the analysis of Fc gamma RIIIa (CD16a) polymorphisms in FL patients. It is compelling to note that sCA125 levels correlated with responses to rituximab treatment in FL, with superior 5-year PFS in FL patients having low CA-125 levels. Navrogen’s team showed that rituximab’s ADCC and CDC is inhibited in vitro by sCA125 via its binding to rituximab. This mechanism by which CA125 inhibits rituximab activity represents a barrier to its full potential for the treatment of FL. The proposed 6-month plan aims at removing this barrier. The solution is to engineer an improved rituximab version that is CA125-refractory. CA125 binding site was narrowed down by the Navrogen’s team to heavy chain sequences which were mutated to generate a mutant antibody that has lost CA125 binding site becoming CA125-refractory. Similarly, this plan’s aim is to engineer a version of rituximab that is CA125-refractory, using a platform referred to as block-removed immunoglobulin technology, or BRITE. Aim 1 milestones include i) generation of rituximab BRITE library and its screening and ii) selection of rituximab variants that are CA125-refractory and retain CD20 binding (named NAV-006). Aim 2 milestone is to demonstrate NAV-006’s enhanced ADCC and CDC cytotoxicity in the presence of high levels of sCA125. Rituximab variant NAV-006 will be benchmarked against parent rituximab in terms of its enhanced ADCC and CDC cytotoxicity in the presence of high levels of CA125 (>100% more potent), binding affinity (if any loss, no greater than a factor of 5), and loss of CA125 interaction (>90%). Navrogen’s team experience with developing biological drugs and its knowledge of clinically relevant CA125 biology greatly mitigates the risks associated with achieving the specific objectives of this proposal.

滤泡性淋巴瘤（滤泡性淋巴瘤）以B细胞增生为特征，在美国每年有15000例新发病例。