Development and Evaluation of Competitive Inhibitors of Trastuzumab-HER2 Binding to Bypass the Binding-Site Barrier.
Development and Evaluation of Competitive Inhibitors of Trastuzumab-HER2 Binding to Bypass the Binding-Site Barrier.
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DOI：
10.3389/fphar.2022.837744
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发表时间：
2022
影响因子：
5.6
通讯作者：
Balthasar JP
中科院分区：
文献类型：
--
作者：
Bordeau BM;Abuqayyas L;Nguyen TD;Chen P;Balthasar JP
我们的团队已经开发并实验验证了一种策略，通过短暂抑制抗体-抗原结合来增加抗体在实体肿瘤中的渗透。在之前的工作中，我们证明了抗曲妥珠单抗1HE（一种抗曲妥珠单抗单域抗体，可短暂抑制曲妥珠单抗与HER2的结合）在HER2+异种移植小鼠中增加曲妥珠单抗的渗透，并增加了阿多曲妥珠单抗emtansine （T-DM1）的疗效。在目前的工作中，利用随机诱变和噬菌体展示开发了1HE变体，以优化基于曲妥珠单抗的治疗方法的肿瘤穿透性和疗效。为了指导合理选择特定的1HE突变体用于特定的曲妥珠单抗治疗，我们开发了一种机制药代动力学（PK）模型来预测曲妥珠单抗/T-DM1在肿瘤内的暴露。在模型中加入药效学（PD）成分来预测肿瘤内暴露于T-DM1与HER2+异种移植物相应治疗效果之间的关系。为了证明竞争抑制方法对免疫毒素的效用，重组免疫毒素特异性的PK参数被纳入模型结构。变体的解离半衰期从1.1 h（变体LG11）到107.9 h（变体HE10）不等。模拟预测，1HE联合给药可以增加T-DM1的肿瘤穿透，与1HE相比，曲妥珠单抗结合半衰期较长的抑制剂（15.5 h）进一步增加T-DM1的穿透，以牺牲T-DM1的总肿瘤摄取为代价。PK/PD模型准确预测了NCI-N87异种移植物对T-DM1或T-DM1与1HE联合治疗的反应。模型预测表明，曲妥珠单抗结合半衰期为51.1 h的1HE突变体HF9将是提高T-DM1疗效的最佳抑制剂，相对于T-DM1与1HE的中位生存时间有适度延长。模型模拟预测LG11联合给药将显著增加免疫毒素在所有肿瘤区域的渗透。我们期望在这项工作中开发的机制模型结构和广泛的抑制剂将能够优化曲妥珠单抗-细胞毒素在实体肿瘤中的渗透和功效。
Our group has developed and experimentally validated a strategy to increase antibody penetration in solid tumors through transient inhibition of antibody-antigen binding. In prior work, we demonstrated that 1HE, an anti-trastuzumab single domain antibody that transiently inhibits trastuzumab binding to HER2, increased the penetration of trastuzumab and increased the efficacy of ado-trastuzumab emtansine (T-DM1) in HER2+ xenograft bearing mice. In the present work, 1HE variants were developed using random mutagenesis and phage display to enable optimization of tumor penetration and efficacy of trastuzumab-based therapeutics. To guide the rational selection of a particular 1HE mutant for a specific trastuzumab-therapy, we developed a mechanistic pharmacokinetic (PK) model to predict within-tumor exposure of trastuzumab/T-DM1. A pharmacodynamic (PD) component was added to the model to predict the relationship between intratumor exposure to T-DM1 and the corresponding therapeutic effect in HER2+ xenografts. To demonstrate the utility of the competitive inhibition approach for immunotoxins, PK parameters specific for a recombinant immunotoxin were incorporated into the model structure. Dissociation half-lives for variants ranged from 1.1 h (for variant LG11) to 107.9 h (for variant HE10). Simulations predicted that 1HE co-administration can increase the tumor penetration of T-DM1, with inhibitors with longer trastuzumab binding half-lives relative to 1HE (15.5 h) further increasing T-DM1 penetration at the expense of total tumor uptake of T-DM1. The PK/PD model accurately predicted the response of NCI-N87 xenografts to treatment with T-DM1 or T-DM1 co-administered with 1HE. Model predictions indicate that the 1HE mutant HF9, with a trastuzumab binding half-life of 51.1 h, would be the optimal inhibitor for increasing T-DM1 efficacy with a modest extension in the median survival time relative to T-DM1 with 1HE. Model simulations predict that LG11 co-administration will dramatically increase immunotoxin penetration within all tumor regions. We expect that the mechanistic model structure and the wide range of inhibitors developed in this work will enable optimization of trastuzumab-cytotoxin penetration and efficacy in solid tumors.
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通过正电子发射断层扫描对肿瘤血管渗透性和血量进行量化。
影响因子：
12.4
作者：
Chen H;Tong X;Lang L;Jacobson O;Yung BC;Yang X;Bai R;Kiesewetter DO;Ma Y;Wu H;Niu G;Chen X
通讯作者：
Chen X
影响因子：
5.8
作者：
Alewine, Christine;Hassan, Raffit;Pastan, Ira
通讯作者：
Pastan, Ira
影响因子：
--
作者：
Cybulska, Magdalena;Olesinski, Tomasz;Ostrowski, Jerzy
通讯作者：
Ostrowski, Jerzy
影响因子：
7.3
作者：
FALLOWFIELD, ME
通讯作者：
FALLOWFIELD, ME
影响因子：
6.2
作者：
Hassan R;Alewine C;Mian I;Spreafico A;Siu LL;Gomez-Roca C;Delord JP;Italiano A;Lassen U;Soria JC;Bahleda R;Thomas A;Steinberg SM;Peer CJ;Figg WD;Niederfellner G;Méresse Naegelen V;Pastan I
通讯作者：
Pastan I