Nanodelivery platform for antibody drugs targeting NHL

项目总结 治疗性单抗(MAbs)，如利妥昔单抗，已在治疗中产生显著改善 非霍奇金淋巴瘤(NHL)患者死亡率。然而，抗体的基本问题 治疗如抗体组织穿透力差，非特异性抗体传递，逃避抗体 识别和激发针对抗体的免疫反应仍然没有解决。我们已经开发出一种 用于大分子的纳米递送平台，通过该平台，单独的“货物”被封装在薄聚合物中 壳，被称为“纳米胶囊”。我们的平台具有很强的适应性，允许我们定制各种属性， 包括细胞表面亲和力、货物免疫原性、货物释放率、体内循环时间和 生物分布，通过改变纳米胶囊的表面化学。我们的纳米胶囊是惰性的，高度稳定， 和抗蛋白质吸附，这是增加血液循环时间和 消除货物的免疫原性。重要的是，我们的纳米胶囊不会因为它们的中性而进入细胞 表面电荷，但仍能有效进入中枢神经系统(CNS)，减轻癌症负担 人类Burkitt淋巴瘤异种移植小鼠的大脑和眼睛；这可能是因为视网膜是中枢神经系统的一部分。 这表明它们是理想的载体载体，用于细胞外将治疗性单抗输送到如下位置 如大脑和眼睛，那里的抗体穿透性极差。建议的最终目标是 研究是建立一个具有临床相关性的治疗性单抗药物的体内给药平台，从而使 有效地消除癌症，特别是那些已经转移到中枢神经系统或眼睛的癌症。

PROJECT SUMMARY Therapeutic monoclonal antibodies (mAbs), such as rituximab, have produced significant improvement in the mortality rates of patients with non-Hodgkin lymphoma (NHL). However, fundamental issues with antibody therapy such as poor tissue penetration of antibodies, non-specific antibody delivery, escape from antibody recognition, and eliciting of an immune response against antibodies, remain unsolved. We have developed a nanodelivery platform for macromolecules whereby an individual “cargo” is encapsulated within a thin polymer shell, termed a “nanocapsule”. Our platform is highly adaptable, allowing us to customize various properties, including cell surface affinity, cargo immunogenicity, cargo release rates, in vivo circulation times, and biodistribution, by altering the surface chemistry of the nanocapsules. Our nanocapsules are inert, highly stable, and resistant to protein adsorption, which are properties necessary for increased blood circulation times and elimination of cargo immunogenicity. Importantly, our nanocapsules do not enter into cells due to their neutral surface charge, but can still efficiently enter the central nervous system (CNS) and reduce cancer burden in the brain and eyes of human Burkitt lymphoma xenograft mice; this could be because the retina is part of the CNS. These indicate that they are ideal carrier vehicles for extracellular delivery of therapeutic mAbs to locations such as the brain and eyes, where penetration of antibodies is extremely poor. The ultimate goal of the proposed studies is to establish a clinically relevant in vivo delivery platform for therapeutic mAb drugs, thus enabling efficient elimination of cancers, especially those that have metastasized into the CNS or eyes.