Quantifying ADC bystander payload penetration with cellular resolution using pharmacodynamic mapping.
Quantifying ADC bystander payload penetration with cellular resolution using pharmacodynamic mapping.
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使用药效学映射通过细胞分辨率定量ADC旁观者有效载荷穿透。
DOI：
10.1016/j.neo.2020.12.001
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Thurber GM
中科院分区：
文献类型：
--
作者：
Khera E;Cilliers C;Smith MD;Ganno ML;Lai KC;Keating TA;Kopp A;Nessler I;Abu-Yousif AO;Thurber GM
随着最近3种新的抗体药物偶联物（adc）被批准用于实体肿瘤，这类药物正在获得靶向治疗癌症的动力。尽管投入了大量资金，但仍有一些根本问题尚未完全了解。最近批准的三种adc含有显示旁观者效应的有效载荷，其中有效载荷可以从目标细胞扩散到邻近细胞。这些效应通常是用抗原阳性和阴性细胞的嵌合体来研究的。然而，这些有效载荷在肿瘤组织中扩散的距离并保持致死浓度尚不清楚。计算研究表明，除了靶向抗原阴性细胞外，旁观者效应部分补偿了肿瘤中ADC的异质性。然而，由于极有效载荷的低浓度，这种类型的研究在实验上具有挑战性。在这项工作中，我们使用了一系列的三维细胞培养和原代人类肿瘤异种移植研究来直接跟踪荧光标记的adc，并通过既定的药效学标记（γH2A）间接跟踪有效载荷。X)。使用正在进行临床评估的抗gcc ADC TAK-164，我们发现亲脂性dna烷基化有效载荷DGN549在gcc阳性肿瘤球体和原发人类肿瘤异种移植模型中穿透细胞靶层。渗透距离与模型预测相似，其中亲脂性导致适度的组织渗透，从而平衡改善的组织渗透与足够的细胞摄取，以避免显着的冲洗。这些结果有助于从机制上理解抗原异质性、旁观者效应和adc在肿瘤微环境中的异质性递送之间的相互作用，从而设计临床有效的治疗方法。
With the recent approval of 3 new antibody drug conjugates (ADCs) for solid tumors, this class of drugs is gaining momentum for the targeted treatment of cancer. Despite significant investment, there are still fundamental issues that are incompletely understood. Three of the recently approved ADCs contain payloads exhibiting bystander effects, where the payload can diffuse out of a targeted cell into adjacent cells. These effects are often studied using a mosaic of antigen positive and negative cells. However, the distance these payloads can diffuse in tumor tissue while maintaining a lethal concentration is unclear. Computational studies suggest bystander effects partially compensate for ADC heterogeneity in tumors in addition to targeting antigen negative cells. However, this type of study is challenging to conduct experimentally due to the low concentrations of extremely potent payloads. In this work, we use a series of 3-dimensional cell culture and primary human tumor xenograft studies to directly track fluorescently labeled ADCs and indirectly follow the payload via an established pharmacodynamic marker (γH2A. X). Using TAK-164, an anti-GCC ADC undergoing clinical evaluation, we show that the lipophilic DNA-alkylating payload, DGN549, penetrates beyond the cell targeted layer in GCC-positive tumor spheroids and primary human tumor xenograft models. The penetration distance is similar to model predictions, where the lipophilicity results in moderate tissue penetration, thereby balancing improved tissue penetration with sufficient cellular uptake to avoid significant washout. These results aid in mechanistic understanding of the interplay between antigen heterogeneity, bystander effects, and heterogeneous delivery of ADCs in the tumor microenvironment to design clinically effective therapeutics.
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影响因子：
56.9
作者：
Celeste, A;Petersen, S;Nussenzweig, A
通讯作者：
Nussenzweig, A
影响因子：
11.2
作者：
Erickson, HK;Park, PU;Blättler, WA
通讯作者：
Blättler, WA
影响因子：
7
作者：
Chen N;Li X;Chintala NK;Tano ZE;Adusumilli PS
通讯作者：
Adusumilli PS
影响因子：
10.9
作者：
D'Amico, Lucia;Menzel, Ulrike;Zippelius, Alfred
通讯作者：
Zippelius, Alfred
影响因子：
9.3
作者：
Ilovich, Ohad;Qutaish, Mohammed;Bradley, Daniel P.
通讯作者：
Bradley, Daniel P.