Combinations of Synergistic Bispecific Human Antibodies: A Novel Strategy for the Treatment of Neuroblastoma

协同双特异性人类抗体的组合：治疗神经母细胞瘤的新策略

• 批准号: 10228852
• 负责人: JAMES M OLSON
• 金额: $ 17.6万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228852
• 关键词: Address; Affect; Affinity; Animal Model; Antibodies; Antibody Therapy; Antibody-drug conjugates; Antigen Targeting; Antigens; Architecture; Binding; Biological Assay; Biological Models; Biological Products; Bispecific Antibodies; Bite; CD28 gene; CD3 Antigens; Cell Death; Cell Surface Proteins; Cells; Child; Childhood Brain Neoplasm; Childhood Solid Neoplasm; Clinic; Clinical; Crystallization; Developing Countries; Development; Devices; Engineering; Epitopes; FDA approved; Glypican; Harvest; Human; Hybridomas; Immune system; Immunooncology; Immunotherapeutic agent; Infusion procedures; Investigational Drugs; Lead; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of brain; Modality; Molecular; Mus; Needles; Nerve; Neuroblastoma; Normal tissue morphology; Oncology; Opioid; Pain; Paint; Patients; Pediatric Oncologist; Predictive Value; Proteins; Resistance; Science; Signal Transduction; Solid; Specificity; Structure; System; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic antibodies; Tissues; Toxic effect; Tumor Antigens; Up-Regulation; Work; cancer cell; cell killing; chimeric antigen receptor T cells; combinatorial; design; high risk; humanized mouse; improved outcome; in vivo; innovation; leukemia; member; mouse model; neuroblastoma cell; novel; novel strategies; programmed cell death ligand 1; receptor; reconstitution; sialogangliosides; stem; stem cells; success; targeted agent; targeted treatment; therapeutic evaluation; tool; treatment strategy; tumor

PROJECT SUMMARY A solid Consortium project should contribute a unique and compelling approach to neuroblastoma and supply tools or components that enable other members of the Consortium to make their best work even better. The project detailed here commences with the selection and careful characterization of a dozen fully human antibodies to Glypican-2, the most promising antigen in neuroblastoma, from a pre-existing hybridoma stock. These antibodies, along with their full sequences, binding affinities, cellular internalization, epitope, and (where possible) crystal structures, will be made available to Consortium members within the first year for use in their modality of choice. This project will explore their utility as components in double bispecific antibody therapy: this double bispecific approach targets two cancer antigens and two T cell receptors simultaneously, inducing T cell activation and co-activation only in the presence of cancer cells expressing both antigens. The double targeting strategy should allow for a much higher level of selective engagement and killing than has heretofore been possible with therapies that target only a single cancer antigen, and should it prove effective in neuroblastoma the approach is likely to have utility in a wide variety of cancers. One historical weakness for the development of immuno-oncology approaches such as this one is that the animal models have had very little predictive value. For this reason, the best of the humanized mouse models, “MISTRG” mice, will be used both for the development of these molecules and for testing the other consortium members’ approaches, where they could be useful. CIVO multi- needle array technology will be employed to simplify the combinatorial challenge associated with testing pairs of bispecific molecules; this technology will also be open for use collaboratively with the other Consortium members. In short, the proposal provides the Consortium with human antibodies against a validated neuroblastoma target, access to the current state-of-the-art in humanized mice, a CIVO multi-needle array device to facilitate testing therapeutics, and a double bispecific antibody therapeutic approach that promises a high level of T cell killing and selectivity and a likely broad applicability beyond neuroblastoma.

项目概要 一个可靠的联盟项目应该为神经母细胞瘤提供独特且引人注目的方法 并提供工具或组件，使联盟的其他成员能够发挥最大作用 工作得更好。这里详述的项目从选择和仔细开始 十几种针对 Glypican-2（最有希望的抗原）的全人类抗体的表征 神经母细胞瘤，来自预先存在的杂交瘤细胞。这些抗体及其完整的 序列、结合亲和力、细胞内化、表位和（如果可能）晶体结构， 将在第一年内提供给联盟成员，供他们选择的方式使用。 该项目将探索它们作为双双特异性抗体疗法的组成部分的效用：这种双抗体 双特异性方法同时针对两种癌症抗原和两种 T 细胞受体，诱导 T 仅在表达两种抗原的癌细胞存在的情况下，细胞激活和共激活。这 双重目标战略应该允许更高水平的选择性交战和杀戮 迄今为止，仅针对单一癌症抗原的疗法是可能的，并且应该 它被证明对神经母细胞瘤有效，该方法可能适用于多种癌症。 像这样的免疫肿瘤学方法的发展的一个历史弱点是 动物模型的预测价值非常小。出于这个原因，最好的 人源化小鼠模型“MSTRG”小鼠将用于这些分子的开发 并测试其他联盟成员的方法，看看它们可能有用。 CIVO 多 将采用针阵列技术来简化与相关的组合挑战 测试双特异性分子对；该技术也将开放供与 其他财团成员。简而言之，该提案为联盟提供了人类抗体 针对经过验证的神经母细胞瘤靶标，获得人源化小鼠中当前最先进的技术， CIVO 多针阵列装置，便于测试治疗方法，以及双双特异性抗体 有望实现高水平 T 细胞杀伤和选择性以及可能广泛应用的治疗方法 神经母细胞瘤以外的适用性。