Laboratory of Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Infection, Immunity and Inflammation, Cochin Institute, Paris, France.
Université Paris Cité, Institut Cochin, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Paris, France.
Front Immunol. 2023 Feb 2;14:1037033. doi: 10.3389/fimmu.2023.1037033. eCollection 2023.
Recent advances in the development of therapeutic antibodies (Abs) have greatly improved the treatment of otherwise drug-resistant cancers and autoimmune diseases. Antibody activities are mediated by both their Fab and the Fc. However, therapeutic Abs base their protective mechanisms on Fc-mediated effector functions resulting in the activation of innate immune cells by FcRs. Therefore, Fc-bioengineering has been widely used to maximise the efficacy and convenience of therapeutic antibodies. Today, IgG remains the only commercially available therapeutic Abs, at the expense of other isotypes. Indeed, production, sampling, analysis and related studies are easier to perform with IgG than with IgA due to well-developed tools. However, interest in IgA is growing, despite a shorter serum half-life and a more difficult sampling and purification methods than IgG. Indeed, the paradigm that the effector functions of IgG surpass those of IgA has been experimentally challenged. Firstly, IgA has been shown to bind to its Fc receptor (FcR) on effector cells of innate immunity with greater efficiency than IgG, resulting in more robust IgA-mediated effector functions and better survival of treated animals. In addition, the two isotypes have been shown to act synergistically. From these results, new therapeutic formats of Abs are currently emerging, in particular chimeric Abs containing two tandemly expressed Fc, one from IgG (Fcγ) and one from IgA (Fcα). By binding both FcγR and FcαR on effector cells, these new chimeras showed improved effector functions that were translated . Furthermore, these chimeras retain an IgG-like half-life in the blood, which could improve Ab-based therapies, including in AIDS. This review provides the rationale, based on the biology of IgA and IgG, for the development of Fcγ and Fcα chimeras as therapeutic Abs, offering promising opportunities for HIV-1 infected patients. We will first describe the main features of the IgA- and IgG-specific Fc-mediated signalling pathways and their respective functional differences. We will then summarise the very promising results on Fcγ and Fcα containing chimeras in cancer treatment. Finally, we will discuss the impact of Fcα-Fcγ chimerism in prevention/treatment strategies against infectious diseases such as HIV-1.
近年来，治疗性抗体（Abs）的发展取得了重大进展，极大地改善了对其他耐药性癌症和自身免疫性疾病的治疗效果。抗体的活性由 Fab 和 Fc 介导。然而，治疗性 Abs 基于 Fc 介导的效应功能来保护机制，导致 FcR 激活先天免疫细胞。因此，Fc 生物工程已被广泛用于最大限度地提高治疗性抗体的疗效和便利性。如今，IgG 仍然是唯一商业化的治疗性 Abs，而其他同种型则不然。事实上，由于工具的开发，IgG 的生产、取样、分析和相关研究比 IgA 更容易进行。然而，尽管 IgA 的血清半衰期更短，取样和纯化方法比 IgG 更困难，但人们对 IgA 的兴趣正在增长。事实上，IgG 的效应功能优于 IgA 的范例已经在实验中受到挑战。首先，已经证明 IgA 比 IgG 更有效地与先天免疫效应细胞上的 Fc 受体（FcR）结合，导致更强大的 IgA 介导的效应功能和治疗动物的更好生存。此外，这两种同种型已被证明具有协同作用。基于这些结果，目前正在出现新的 Abs 治疗形式，特别是包含两个串联表达的 Fc 的嵌合 Abs，一个来自 IgG（Fcγ），一个来自 IgA（Fcα）。通过结合效应细胞上的 FcγR 和 FcαR，这些新嵌合体显示出改善的效应功能，并且这些功能已经得到了翻译。此外，这些嵌合体在血液中的半衰期类似于 IgG，这可以改善基于 Abs 的治疗方法，包括艾滋病。本综述基于 IgA 和 IgG 的生物学，为开发 Fcγ 和 Fcα 嵌合体作为治疗性 Abs 提供了原理，为 HIV-1 感染患者提供了有前途的机会。我们将首先描述 IgA 和 IgG 特异性 Fc 介导的信号通路的主要特征及其各自的功能差异。然后，我们将总结癌症治疗中含有 Fcγ 和 Fcα 的嵌合体的非常有前途的结果。最后，我们将讨论 Fcα-Fcγ 嵌合在预防/治疗 HIV-1 等传染病策略中的影响。
