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Valency of HER2 Targeting Antibodies Influences Tumor Cell Internalization and Penetration
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2021-10-01 , DOI: 10.1158/1535-7163.mct-20-1097
Madeleine K Ramos 1 , Danielle Mandikian 1 , Lauren N Sermeño 1 , Anna King 1 , Alecia T Dent 1 , Jason Ho 1 , Sheila Ulufatu 1 , T Noelle Lombana 1 , Christoph Spiess 1 , Mary Ann T Go 1 , Shang-Fan Yu 1 , Amrita V Kamath 1 , Gregory Z Ferl 1 , C Andrew Boswell 1
Affiliation  

T-cell–dependent bispecific antibodies (TDB) have been a major advancement in the treatment of cancer, allowing for improved targeting and efficacy for large molecule therapeutics. TDBs are comprised of one arm targeting a surface antigen on a cancer cell and another targeting an engaging surface antigen on a cytotoxic T cell. To impart this function, the antibody must be in a bispecific format as opposed to the more conventional bivalent format. Through in vitro and in vivo studies, we sought to determine the impact of changing antibody valency on solid tumor distribution and catabolism. A bivalent anti-HER2 antibody exhibited higher catabolism than its full-length monovalent binding counterpart in vivo by both invasive tissue harvesting and noninvasive single photon emission computed tomography/X-ray computed tomography imaging despite similar systemic exposures for the two molecules. To determine what molecular factors drove in vivo distribution and uptake, we developed a mechanistic model for binding and catabolism of monovalent and bivalent HER2 antibodies in KPL4 cells. This model suggests that observed differences in cellular uptake of monovalent and bivalent antibodies are caused by the change in apparent affinity conferred by avidity as well as differences in internalization and degradation rates of receptor bound antibodies. To our knowledge, this is the first study to directly compare the targeting abilities of monovalent and bivalent full-length antibodies. These findings may inform diverse antibody therapeutic modalities, including T-cell–redirecting therapies and drug delivery strategies relying upon receptor internalization.

中文翻译:

HER2靶向抗体的效价影响肿瘤细胞内化和渗透

T 细胞依赖性双特异性抗体 (TDB) 在癌症治疗方面取得了重大进展,可以提高大分子治疗的靶向性和疗效。TDB 由一个臂组成,一个臂靶向癌细胞上的表面抗原,另一个臂靶向细胞毒性 T 细胞上的接合表面抗原。为了赋予这种功能,抗体必须是双特异性形式,而不是更传统的二价形式。通过体外和体内研究,我们试图确定改变抗体效价对实体瘤分布和分解代谢的影响。尽管两种分子的全身暴露相似,但通过侵入性组织采集和非侵入性单光子发射计算机断层扫描/X 射线计算机断层扫描成像,二价抗 HER2 抗体在体内表现出比其全长单价结合对应物更高的分解代谢。为了确定哪些分子因素推动了体内分布和摄取,我们开发了一种机制模型,用于 KPL4 细胞中单价和二价 HER2 抗体的结合和分解代谢。该模型表明,观察到的单价和二价抗体的细胞摄取差异是由亲合力赋予的表观亲和力的变化以及受体结合抗体的内化和降解速率的差异引起的。据我们所知,这是第一项直接比较单价和二价全长抗体靶向能力的研究。这些发现可能为不同的抗体治疗方式提供信息,包括 T 细胞重定向疗法和依赖于受体内化的药物递送策略。
更新日期:2021-10-04
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