PO.ET01.06 · 实验与分子治疗
在膀胱、肺和乳腺实体瘤中开发差异化Trop2 ADC的理论依据
Rationale for the development of a differentiated Trop2 ADC in solid tumors of the bladder, lung, and breast
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：Trop2是一种跨膜蛋白，在多种实体瘤癌症中过表达，是一个已验证的靶点。Trop2 ADC已在美国、中国或日本获批用于TNBC、Her2阴性HR阳性转移性乳腺癌以及二线EGFR突变NSCLC。PH1是一种靶向剪接体的独特免疫调节载荷，已被用作平台以生成Trop2 PH1 ADC及其他具有差异化临床前疗效和安全性特征的管线ADC 1,2,3。在对Akari的Trop2 ADC项目进行了大量表征和降风险后，临床候选药物AKTX-101正推进IND申报支持研究。
结果：此前进行了一项75个细胞系的筛选，Trop2 PH1 ADC在8种实体瘤适应症的体外实验中表现出个位数纳摩尔（nM）级IC50效力 2。在后续实验中，AKTX-101与首创的已获批Trop2 ADC一并测试，并在这些模型中与标准治疗靶向疗法进行比较，以确定AKTX-101临床开发的优势细分领域（表1）。由于AKTX-101在所有测试的尿路上皮模型中（5/5）均表现出nM级IC50效力，且鉴于PH1载荷已知与抗PD-1协同，因此在一个过表达人Trop2的尿路上皮癌同基因MB49小鼠模型中，测试了该ADC联合或不联合检查点抑制剂的效果。先给予ADC后给予mPD-1的序贯给药显示出协同作用，而同时给药则与相加性抗肿瘤疗效相关。
结论：我们的结果支持AKTX-101在膀胱癌及其他实体瘤细分领域的临床开发。这些细分领域将在计划中的转化研究中进一步探索。
参考文献：
1. Mitra SK. 951 一种新型剪接靶向ADC载荷驱动免疫激活、与检查点抑制剂协同并具有超越细胞毒性的增强治疗潜力。Journal for ImmunoTherapy of Cancer. 2025; 13:.
2. Cancer Res (2023) 83 (7_Supplement): 6297 3. AACR; Cancer Res 2021;81(13_Suppl): 摘要号1832
表1：
表1：AKTX-101 vs SOC，其中a=Enfortumab vedotin，b=Daraxonrasib，c=Trastuzumab deruxtecan 适应症 驱动突变 细胞系 指标 AKTX-101 标准治疗 膀胱 FGFR3融合 RT112/84 IC50 (nM) 0.30 19.47 a RT112/84 最大杀伤(%) 93.6 94.3 a 膀胱 FGFR3融合 RT4 IC50 (nM) 1.10 68.76 a RT4 最大杀伤(%) 83.5 53.7 a 膀胱 FGFR3融合 SW-780 IC50 (nM) 0.26 61.76 a SW-780 最大杀伤(%) 87.0 61.9 a 肺 Kras G12V NCI-H441 IC50 (nM) 0.43 13.12 b NCI-H441 最大杀伤(%) 69.8 56.4 b 肺 BRAF G466V NCI-H1666 IC50 (nM) 0.07 NCI-H1666 最大杀伤(%) 90.0 肺 SMARCA4缺失 NCI-H2126 IC50 (nM) 0.43 NCI-H2126 最大杀伤(%) 75.1 乳腺 对Top1药物敏感性不同，Her2扩增 HCC 1954 IC50 (nM) 0.39 3.06 c HCC 1954 最大杀伤(%) 80.2 52.5 c 乳腺 曲妥珠单抗耐药，Her2扩增，HR阴性，PIK3CA、TP53突变 JIMT-1 IC50 (nM) 0.35 N.A. c JIMT-1 最大杀伤(%) 89.6 11.8 c
查看英文原文 English abstract
Background: Trop2 is a transmembrane protein that is overexpressed in several solid tumor cancers and is a validated target. Trop2 ADCs are approved in TNBC, Her2- HR+ metastatic breast cancer, and 2 nd line EGFR-mutated NSCLC in US, China, or Japan. PH1 is a unique immunomodulatory payload targeting the spliceosome and has been used as a platform to generate a Trop2 PH1 ADC and other pipeline ADCs with differentiated preclinical efficacy and safety profiles 1,2, 3 . Following significant characterization and derisking of the Akari Trop2 ADC program, the clinical candidate, AKTX-101, is progressing for IND-enabling studies.
Results: Previously, a 75-cell line screen was performed and Trop2 PH1 ADC demonstrated single digit nanomolar (nM) IC50 potency in 8 solid tumor indications in vitro 2 . In follow-up experiments, AKTX-101 was tested alongside first-in-class approved Trop2 ADCs and compared with Standard-of-care targeted therapy in these models to identify an advantageous niche for the clinical development of AKTX-101 (Table 1). As AKTX-101 exhibited nM IC50 potency in all urothelial models tested (5/5), and since the PH1 payload is known to synergize with anti-PD-1, the ADC was tested plus/ minus checkpoint inhibitor in a syngeneic MB49 mouse model of urothelial cancer overexpressing human Trop2. Sequential dosing of ADC followed by mPD-1 demonstrated synergy whereas concomitant dosing was associated with additive anti-tumor efficacy.
Conclusion: Our results support the clinical development of AKTX-101 in bladder cancer and in other solid tumor niches. These niches will be explored further in planned translational studies.
References:
1. Mitra SK. 951 A novel splicing-targeted ADC payload drives immune activation, synergy with checkpoint inhibitors, and enhanced therapeutic potential beyond cytotoxicity. Journal for ImmunoTherapy of Cancer. 2025; 13:.
2. Cancer Res (2023) 83 (7_Supplement): 6297 3. AACR; Cancer Res 2021;81(13_Suppl): Abstract nr 1832
Table 1:
Table 1: AKTX-101 vs SOC, where a=Enfortumab vedotin, b= Daraxonrasib, c=Trastuzumab deruxtecan Indication Driver mutation Cell line Metric AKTX-101 Standard of care Bladder FGFR3 fusions RT112/84 IC50 (nM) 0.30 19.47 a RT112/84 Maximum kill (%) 93.6 94.3 a Bladder FGFR3 fusions RT4 IC50 (nM) 1.10 68.76 a RT4 Maximum kill (%) 83.5 53.7 a Bladder FGFR3 fusions SW-780 IC50 (nM) 0.26 61.76 a SW-780 Maximum kill (%) 87.0 61.9 a Lung Kras G12V NCI-H441 IC50 (nM) 0.43 13.12 b NCI-H441 Maximum kill (%) 69.8 56.4 b Lung BRAF G466V NCI-H1666 IC50 (nM) 0.07 NCI-H1666 Maximum kill (%) 90.0 Lung SMARCA4 deletion NCI-H2126 IC50 (nM) 0.43 NCI-H2126 Maximum kill (%) 75.1 Breast Different sensitivity to Top1 agents, Her2 amplification HCC 1954 IC50 (nM) 0.39 3.06 c HCC 1954 Maximum kill (%) 80.2 52.5 c Breast Trastuzumab resistant, Her2 amplification, HR- negative, PIK3CA, TP53 mutations JIMT-1 IC50 (nM) 0.35 N.A. c JIMT-1 Maximum kill (%) 89.6 11.8 c
利益披露 Disclosure
S. K. Mitra,
Akari Therapeutics Employment, Stock, Stock Option, Patent, Other Intellectual Property.
Mereo BioPharma Stock Option, Patent, Other Intellectual Property, Former employee of Oncomed Pharmaceuticals.
Exelixis Stock, Publicly traded stock.
Abbvie Stock, Publicly traded stock.
AstraZeneca Stock, Publicly traded stock.
Gilead Stock, Publicly traded stock.
Amgen Stock, Publicly traded stock.
Daiichi Sankyo Stock, Publicly traded stock.
GlaxoSmithkline Stock, Publicly traded stock.
Bristol Myers Squibb Stock, Publicly traded stock.
Merck & Co Stock, Publicly traded stock.
Pfizer Stock, Publicly traded stock.
Lexicon Pharma Stock, Publicly traded stock.
Ajinomoto Stock, Publicly traded stock.
Cardinal Health Stock, Publicly traded stock.
M. Abuhay,
Akari Therapeutics Employment, Stock, Stock Option, Other Intellectual Property.
M. Do,
Akari Therapeutics Stock, Stock Option, Ex-employee of Peak Bio that merged with Akari Therapeutics.