Kristina M J Aertker, Minu Ravindra Pilvankar, Tobias M Prass, Michaela Blech, Fabian Higel, Srinath Kasturirangan
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引用次数: 0
摘要
能够识别两种不同表位或抗原的双特异性抗体(BsAbs)通过靶向多种途径为各种疾病提供了有前景的治疗方案。单克隆抗体(mAbs)良好的药代动力学(PK)特性至关重要,因为它们直接影响患者的安全性和疗效。对于许多 mAb 疗法来说,新生 Fc 受体(FcRn)相互作用的优化和不利分子特性的消除已使 PK 特性得到改善。然而,许多 BsAbs 表现出不利的 PK 特性,这阻碍了它们作为药物的开发。在本报告中,我们对三种 IgG1-scFv BsAbs 不同 PK 特性的分子决定因素进行了研究。我们的研究表明,高水平的非特异性相互作用、等电点(pI)升高以及带正电荷的斑块数量增加导致了 IgG1-scFv 的快速清除。FcRn层析结果显示了IgG1-scFv特有的特异性scFv-FcRn相互作用,分子动力学(MD)模拟进一步证实了这一点。这些相互作用可能会稳定 BsAb 与 FcRn 在生理 pH 值下的相互作用,进而破坏 FcRn 介导的 BsAb 循环。除了经验观察之外,我们还评估了硅学特性的影响,包括 Fab 和 scFv 之间的 pI 差异以及偶极矩与疏水矩(RM)之比,以及它们与观察到的清除率之间的相关性。这些发现突出表明,与免疫球蛋白 G(IgG)1 抗体相比,BsAbs 的结构更加复杂,因此它们的 PK 特性可能受新的决定因素制约。
Exploring molecular determinants and pharmacokinetic properties of IgG1-scFv bispecific antibodies.
Bispecific antibodies (BsAbs) capable of recognizing two distinct epitopes or antigens offer promising therapeutic options for various diseases by targeting multiple pathways. The favorable pharmacokinetic (PK) properties of monoclonal antibodies (mAbs) are crucial, as they directly influence patient safety and therapeutic efficacy. For numerous mAb therapeutics, optimization of neonatal Fc receptor (FcRn) interactions and elimination of unfavorable molecular properties have led to improved PK properties. However, many BsAbs exhibit unfavorable PK, which has precluded their development as drugs. In this report, we present studies on the molecular determinants underlying the distinct PK profiles of three IgG1-scFv BsAbs. Our study indicated that high levels of nonspecific interactions, elevated isoelectric point (pI), and increased number of positively charged patches contributed to the fast clearance of IgG1-scFv. FcRn chromatography results revealed specific scFv-FcRn interactions that are unique to the IgG1-scFv, which was further supported by molecular dynamics (MD) simulation. These interactions likely stabilize the BsAb FcRn interaction at physiological pH, which in turn could disrupt FcRn-mediated BsAb recycling. In addition to the empirical observations, we also evaluated the impact of in silico properties, including pI differential between the Fab and scFv and the ratio of dipole moment to hydrophobic moment (RM) and their correlation with the observed clearance. These findings highlight that the PK properties of BsAbs may be governed by novel determinants, owing to their increased structural complexity compared to immunoglobulin G (IgG) 1 antibodies.
期刊介绍:
mAbs is a multi-disciplinary journal dedicated to the art and science of antibody research and development. The journal has a strong scientific and medical focus, but also strives to serve a broader readership. The articles are thus of interest to scientists, clinical researchers, and physicians, as well as the wider mAb community, including our readers involved in technology transfer, legal issues, investment, strategic planning and the regulation of therapeutics.