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

项目摘要 一个可靠的联盟项目应该为神经母细胞瘤提供一种独特而令人信服的方法 并提供工具或组件，使其他成员的财团，使他们最好的 效果更好这里详细介绍的项目开始与选择和仔细 磷脂酰肌醇蛋白聚糖-2（Glypican-2）的十几种全人抗体的特征，磷脂酰肌醇蛋白聚糖-2是最有希望的抗原， 神经母细胞瘤，来自预先存在的杂交瘤原种。这些抗体，沿着着它们的全部 序列、结合亲和力、细胞内化、表位和（可能时）晶体结构， 将在第一年内提供给联合会成员，供其选择使用。 该项目将探索它们作为双双特异性抗体治疗中的组分的效用： 双特异性方法同时靶向两种癌抗原和两种T细胞受体，诱导T细胞活化。 细胞活化和共活化仅在表达两种抗原的癌细胞存在的情况下。的 双重目标战略应该允许更高水平的选择性交战和杀戮 这比迄今为止仅靶向单一癌抗原的疗法可能实现的效果更好，并且应该 它在神经母细胞瘤中被证明是有效，该方法可能在多种癌症中具有实用性。 免疫肿瘤学方法（如这种方法）发展的一个历史弱点是 动物模型几乎没有预测价值。因此，最好的 人源化小鼠模型，“MISTRG”小鼠，将用于开发这些分子 并在其他合作体成员的方法可能有用时测试这些方法。CIVO多功能 针阵列技术将用于简化与以下相关的组合挑战： 测试双特异性分子对;这项技术也将开放用于与 其他联盟成员。简而言之，该提案为财团提供了人类抗体， 针对经验证的神经母细胞瘤靶点，在人源化小鼠中获得最新技术水平， CIVO多针阵列装置，以便于测试治疗剂和双双特异性抗体 一种治疗方法，承诺高水平的T细胞杀伤和选择性， 适用于神经母细胞瘤以外的疾病。

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.