Meyer Saskia, Nederend Maaike, Jansen J H Marco, Reiding Karli R, Jacobino Shamir R, Meeldijk Jan, Bovenschen Niels, Wuhrer Manfred, Valerius Thomas, Ubink Ruud, Boross Peter, Rouwendal Gerard, Leusen Jeanette H W
a Laboratory of Translational Immunology; UMC Utrecht ; Utrecht , The Netherlands.
b Center for Proteomics and Metabolomics; Leiden University Medical Center ; Leiden , The Netherlands.
MAbs. 2016;8(1):87-98. doi: 10.1080/19420862.2015.1106658. Epub 2015 Oct 14.
Antibody therapy is a validated treatment approach for several malignancies. All currently clinically applied therapeutic antibodies (Abs) are of the IgG isotype. However, not all patients respond to this therapy and relapses can occur. IgA represents an alternative isotype for antibody therapy that engages FcαRI expressing myeloid effector cells, such as neutrophils and monocytes. IgA Abs have been shown to effectively kill tumor cells both in vitro and in vivo. However, due to the short half-life of IgA Abs in mice, daily injections are required to reach an effect comparable to IgG Abs. The relatively long half-life of IgG Abs and serum albumin arises from their capability of interacting with the neonatal Fc receptor (FcRn). As IgA Abs lack a binding site for FcRn, we generated IgA Abs with the variable regions of the Her2-specific Ab trastuzumab and attached an albumin-binding domain (ABD) to the heavy or light chain (HCABD/LCABD) to extend their serum half-life. These modified Abs were able to bind albumin from different species in vitro. Furthermore, tumor cell lysis of IgA-Her2-LCABD Abs in vitro was similar to unmodified IgA-Her2 Abs. Pharmacokinetic studies in mice revealed that the serum exposure and half-life of the modified IgA-Her2 Abs was extended. In a xenograft mouse model, the modified IgA1 Abs exhibited a slightly, but significantly, improved anti-tumor response compared to the unmodified Ab. In conclusion, empowering IgA Abs with albumin-binding capacity results in in vitro and in vivo functional Abs with an enhanced exposure and prolonged half-life.
抗体疗法是几种恶性肿瘤的有效治疗方法。目前所有临床应用的治疗性抗体（Abs）均为IgG同种型。然而，并非所有患者都对这种疗法有反应，并且可能会发生复发。IgA是抗体疗法的另一种同种型，它可与表达FcαRI的髓样效应细胞（如中性粒细胞和单核细胞）结合。已证明IgA抗体在体外和体内均能有效杀死肿瘤细胞。然而，由于IgA抗体在小鼠体内的半衰期较短，需要每日注射才能达到与IgG抗体相当的效果。IgG抗体和血清白蛋白相对较长的半衰期源于它们与新生儿Fc受体（FcRn）相互作用的能力。由于IgA抗体缺乏与FcRn的结合位点，我们用Her2特异性抗体曲妥珠单抗的可变区生成了IgA抗体，并在重链或轻链上连接了白蛋白结合结构域（ABD）（HCABD/LCABD）以延长其血清半衰期。这些修饰的抗体能够在体外结合来自不同物种的白蛋白。此外，IgA-Her2-LCABD抗体在体外的肿瘤细胞裂解作用与未修饰的IgA-Her2抗体相似。小鼠的药代动力学研究表明，修饰后的IgA-Her2抗体的血清暴露量和半衰期延长。在异种移植小鼠模型中，与未修饰的抗体相比，修饰后的IgA1抗体表现出轻微但显著改善的抗肿瘤反应。总之，赋予IgA抗体白蛋白结合能力可产生在体外和体内具有增强暴露量和延长半衰期的功能性抗体。
