PO.ET02.04 · 实验与分子治疗
TCX-201：一种靶向特定肿瘤相关碳水化合物抗原（TACA）的新型ADC，在实体瘤模型中具有优异的临床前疗效、PK和安全性特征
TCX-201, a novel ADC targeting a specific tumor-associated carbohydrate antigen (TACA) with excellent preclinical efficacy, PK and safety profile in solid tumor models
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摘要 Abstract
中文摘要
肿瘤相关碳水化合物抗原（TACA）是表达于癌细胞表面的确定寡糖结构。它们源自与恶性肿瘤相关的糖基化通路改变，从而导致过度产生或异常的结构，代表了一类尚未被探索的癌症治疗靶点。我们已针对其中几种难以靶向的抗原生成了特异性抗体，并获得了一种高亲和力、全人源化单克隆抗体（mAb）TCX-201，其针对其中一种TACA，该抗原在广泛的癌症适应证（包括各种胃肠道癌类型以及NSCLC）中高表达。经糖芯片、流式细胞术和免疫组织化学或免疫荧光评估，该mAb相较于现有基准物，对靶点显示出更优的内化、亲和力和特异性。通过可裂解连接子与MMAE（DAR 4）、Exatecan（DAR 8）和Deruxtecan（Dxd，DAR 8）偶联，构建了三种ADC变体，随后对其效力进行了分析。体外研究显示，对表达不同水平TACA的多种胰腺癌和结肠癌细胞系具有有效杀伤作用（例如HuP-T4（高表达，IC50为0.3 nM）、Capan-2（异质性表达，IC50为1.03 nM）、Colo-205（高表达，IC50为0.013 nM）、LS180（中等表达，IC50为4.7 nM））。此外，在每周静脉给药的不同异种移植模型中观察到所测载荷具有高疗效：Capan-2胰腺癌（在3和7 mg/kg MMAE下分别达到16%和6%的T/C，在7 mg/kg Dxd下达到27%的T/C）和Colo-205结直肠癌（在7 mg/kg MMAE下达到3%的T/C）。除CDX模型外，在PDAC和CRC模型上的PDX体外筛选显示，TCX-201 MMAE在5/8的PDAC PDX和2/5的CRC PDX中具有高效杀伤作用。这些结果，加上良好的PK和安全性特征，使该ADC成为治疗表达不同水平靶结构的各种实体瘤的首创分子。总之，我们的抗体代表了一种针对不同癌症适应证的新型有前景的治疗选择，并且可作为使用不同载荷的ADC有效应用。
查看英文原文 English abstract
Tumor-associated carbohydrate antigens (TACAs) are defined oligosaccharide structures that are expressed on the surface of cancer cells. They are derived from changes in glycosylation pathways associated with malignancy, which lead to overproduced or aberrant structures, and represent a still unexplored target class for cancer therapy. We have generated specific antibodies against several of these difficult to target antigens and obtained a high affinity, fully humanized monoclonal antibody (mAb), TCX-201, against one of these TACAs, highly expressed across a broad range of cancer indications, including various gastrointestinal cancer types as well as NSCLC. This mAb shows superior internalization, affinity, and specificity for the target compared to the available benchmark, as assessed by glycan array, flow cytometry, and immunohistochemistry or immunofluorescence. Three ADC-variants were created by conjugation with MMAE (DAR 4), Exatecan (DAR 8), and Deruxtecan (Dxd, DAR 8) via a cleavable linker and were subsequently analyzed regarding their potency. In vitro studies showed effective killing of various pancreatic and colon cancer cell lines expressing different levels of the TACA (e.g. HuP-T4 (high expressing, IC50 of 0.3 nM), Capan-2 (heterogeneous expression, IC50 of 1.03 nM), Colo-205 (high expressing, IC50 of 0.013 nM), LS180 (medium expressing, IC50 of 4.7 nM). Moreover, high efficacy was observed for the tested payloads in different xenograft models with weekly iv administration: Capan-2 pancreatic cancer (reaching T/C of 16% and 6% at 3 and 7 mg/kg MMAE, respectively and T/C of 27% with 7 mg/kg Dxd) and Colo-205 colorectal cancer reaching T/C of 3% with 7 mg/kg MMAE. In addition to CDX models, PDX in vitro screening on PDAC and CRC models showed highly effective killing in 5/8 PDAC PDX and 2/5 CRC PDX with TCX-201 MMAE. These results, coupled with a favorable PK and safety profile make this ADC a first-in-class molecule for the treatment of various solid tumors that express different levels of the target structure.In conclusion, our antibody represents a new promising treatment option for different cancer indications and can be effectively employed as an ADC using different payloads.
利益披露 Disclosure
M. Ocker, None..
F. Muraca, None..
S. Grunwald, None..
W. Winkler, None..
K. E. Soto, None..
C. Lange, None..
J. Engela, None..
P. Sondermann, None.