Mapping the effector response space of antibody combinations

抗体是至关重要的，是免疫反应的中央调节器。他们特别多才多艺 由于它们既能以高亲和力结合靶又能引导靶向治疗剂， 免疫系统实际上，抗体包括广泛的批准的疗法， 疾病适应症，其中许多已知在很大程度上依赖于效应细胞（免疫） 反应IgG同种型的抗体与效应细胞上的Fcγ R相互作用， 通过多种细胞类型发挥作用（例如，巨噬细胞，单核细胞），并通过多种 过程，包括吞噬作用和杀死病变细胞。多种可能的设计 参数-恒定区组成、Fcγ R、细胞群和抗原结合， 组合-已经做出了精确的理解，测量和操纵效应器 实现一个难以捉摸的目标。我们提出的工作是围绕假设，两个IgG 可以引起不同的反应时，存在于组合从什么会建议， 对任何一个人的回应。使用抗体-Fc γR相互作用的计算模型，我们将 识别这种突发行为的预测案例。这些组合将被测试其 体外结合和效应子应答，然后在两种抗体靶向细胞杀伤模型中。 最后，我们将使用效应调控的计算模型来绘制人类和 小鼠IgG根据其效应子应答而相关。总的来说，这些努力将提供 设计更有效的抗体以靶向细胞杀伤为目标的关键信息 并提供现有治疗性抗体如何发挥作用的更清晰视图。

Antibodies are crucial, central regulators of the immune response. They are particularly versatile therapeutic agents due to their ability to both bind to a target with high affinity and direct the immune system. Indeed, antibodies comprise a broad range of approved therapies across disease indications, many of which are known to rely in large part on effector cell (immune) response. Antibodies of the IgG isotype interact with FcγRs on effector cells and elicit effector function through multiple cell types (e.g., macrophages, monocytes) and through multiple processes, including phagocytosis and killing of diseased cells. The many possible design parameters—constant region composition, FcγRs, cell populations, and antigen binding in combination—have made precisely understanding, measuring, and manipulating effector function an elusive goal. Our proposed work is centered around the hypothesis that two IgGs can elicit distinct responses when present in combination from what would be suggested by the response to either on its own. Using a computational model of antibody-FcγR interaction, we will identify predicted cases of this emergent behavior. These combinations will be tested for their binding and effector response in vitro and then in two models of antibody-targeted cell killing. Finally, we will use the computational model of effector regulation to map how human and mouse IgGs are related according to their effector response. In total, these efforts will provide critical information for designing more effective antibodies with the goal of targeted cell killing and provide a clearer view of how existing therapeutic antibodies function.