PO.ET01.01 · 实验与分子治疗
一款同类首创的抗SLC3A2 ADC在难治性实体瘤和血液系统恶性肿瘤中的临床前疗效
Preclinical efficacy of a first-in-class anti-SLC3A2 ADC in hard-to-treat solid and hematologic malignancies
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
SLC3A2（CD98重链、CD98hc或4F2hc）是一种II型跨膜糖蛋白，主要作为异二聚体氨基酸转运蛋白（HATs）的重链组分发挥功能。SLC3A2的异常过表达与多种癌症相关，如肺癌、乳腺癌、结直肠癌（CRC）、胰腺癌（PDAC）以及各类血液系统恶性肿瘤。我们利用自主研发的活细胞免疫（LC-I）和高通量筛选（LC-HTS）平台，开发了MAb52-4.2，这是一种抗SLC3A2单克隆抗体，能够选择性识别SLC3A2的一个肿瘤相关构象表位，该表位在癌细胞系中表达水平显著升高，且与正常细胞或组织几乎无交叉反应。MAb52-4.2的嵌合型和人源化型均能以低个位数纳摩尔级的高亲和力与重组SLC3A2-ECD结合。含两个Fc点突变的MAb52-4.2 cAb通过MC-Vc-PAB连接子与MMAE偶联，制备出MAb52-4.2-ADC（DAR4）。MAb52-4.2-ADC在体外表现出强效的抗增殖作用，其细胞毒性与多种癌细胞系中靶点的丰度及抗体内化效率相关。单次腹腔（i.p.）给药4、7或10 mg/kg的MAb52-4.2-ADC，在三阴性乳腺癌（TNBC）、非小细胞肺癌（NSCLC）、胃癌（GC）及其他肿瘤类型的细胞系来源异种移植（CDX）小鼠模型中有效抑制了肿瘤生长，皮下接种的肿瘤在治疗后24~30天内完全消退。初步毒理学研究表明MAb52-4.2-ADC未引发任何安全性担忧。这些发现支持将MAb52-4.2-ADC作为治疗实体瘤和血液系统恶性肿瘤的有前景的候选疗法，并有望缓解毒性方面的担忧。为支持进一步临床研究，正在开展的研究包括在患者来源异种移植（PDX）胃肠道（GI）癌模型中评估MAb52-4.2-ADC，以及对其靶点在临床肿瘤样本中表达情况的回顾性分析。
查看英文原文 English abstract
SLC3A2 (CD98 heavy chain, CD98hc, or 4F2hc) is a type II transmembrane glycoprotein that functions primarily as the heavy chain component of heterodimeric amino acid transporters (HATs). The aberrant overexpression of SLC3A2 has been linked to many types of cancer, such as lung cancer, breast cancer, colorectal cancer (CRC), pancreatic cancer (PDAC), and various types of hematologic malignancies. Using our proprietary live-cell immunization (LC-I) and high-throughput screening (LC-HTS) platforms, we developed MAb52-4.2, an anti-SLC3A2 monoclonal antibody that selectively recognizes a tumor-associated conformational epitope of SLC3A2, which significantly elevated expression levels in cancer cell lines, and exhibits minimal or no cross-reactivity with normal cells or tissues. Both the chimeric and humanized versions of MAb52-4.2 bound to recombinant SLC3A2-ECD with high affinities in the low single-digit nanomolar range. MAb52-4.2 cAb, containing two Fc point-mutations, was conjugated to MMAE through an MC-Vc-PAB linker to produce MAb52-4.2-ADC (DAR4). MAb52-4.2-ADC demonstrated potent antiproliferative effects in vitro , with cytotoxicity correlating with the target abundance and antibody internalization efficiency across a variety of cancer cell lines. A single intraperitoneal ( i.p .) dose of MAb52-4.2-ADC at 4, 7, or 10 mg/kg effectively inhibited tumor growth in cell line-derived xenograft (CDX) mouse models of triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), gastric cancer (GC), and other tumor types, with subcutaneously inoculated tumors completely regressing within 24~30 days post-treatment. Preliminary toxicology studies indicated that MAb52-4.2-ADC did not raise any safety concerns. These findings support MAb52-4.2-ADC as a promising therapeutic candidate for treating solid and hematologic malignancies, and potentially mitigating toxicity concerns. Ongoing studies aiming to support further clinical investigation include MAb52-4.2-ADC in patient-derived xenograft (PDX) gastrointestinal (GI) cancer models, along with retrospective analyses of its target expression in clinical tumor samples.
利益披露 Disclosure
D. Li, None..
K. Zhao, None..
M. Q. Xu, None..
M. Lu, None.