PO.ET02.03 · 实验与分子治疗
一种首创的抗整合素α/β ADC在难治性实体瘤中的临床前疗效
Preclinical efficacy of a first-in-class anti-Integrin alpha/beta ADC in hard-to-treat solid tumors
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
整合素（ITG）α/β是一种异二聚体I型跨膜糖蛋白，由一个α整合素亚基和一个β整合素亚基组成。它介导细胞-细胞和细胞-细胞外基质（ECM）相互作用，并引发随后的信号级联，调控细胞黏附、运动、增殖、存活和基因表达。在多种实体瘤中已观察到ITGα/β的异常过表达，它支持癌症进展和转移，提示其可能作为一个潜在的治疗靶点。利用我们专有的活细胞免疫（LC-I）和高通量筛选（LC-HTS）平台，我们生成并开发了MAb51-31，一种抗ITGα/β单克隆抗体（mAb），它选择性识别ITGα/β的一个肿瘤限制性构象表位。MAb51-31与正常细胞或组织无交叉反应。MAb51-31的嵌合和人源化版本均对重组ITGα/β显示出高结合亲和力（K D ≈ 1.4 nM）。MAb51-31-cAb在每个Fc区经过两个点突变改造，通过MC-Vc-PAB连接子与MMAE偶联，生成MAb51-31-ADC（DAR4）。MAb51-31-ADC在体外展现出强效的抗增殖作用，其细胞毒性与其在各种实体瘤细胞系中的内化效率相关。在三阴性乳腺癌（TNBC）、非小细胞肺癌（NSCLC）、胃癌（GC）和其他实体瘤的细胞系来源异种移植（CDX）模型中，单次腹腔（i.p.）给予4、7或10 mg/kg的MAb51-31-ADC有效抑制了肿瘤生长，在治疗后24~30天内实现完全肿瘤消退。初步毒理学评估表明MAb51-31-ADC耐受性良好，未观察到明显的安全性问题。MAb51-31-ADC是一种有前景的实体瘤治疗候选药物，其对肿瘤特异性ITGα/β表位的选择性识别有可能实现强效抗肿瘤疗效并减少脱靶效应。正在进行的研究包括在胃肠道（GI）癌症的患者来源异种移植（PDX）模型中评估MAb51-31-ADC，以及对肿瘤样本中靶点表达的回顾性分析，以进一步支持其临床开发。
查看英文原文 English abstract
Integrin (ITG) alpha/beta is a heterodimeric type I transmembrane glycoprotein composed of one alpha and one beta integrin subunit. It mediates cell-cell and cell-extracellular matrix (ECM) interactions and elicits subsequent signaling cascades that regulate cell adhesion, motility, proliferation, survival, and gene expression. The aberrant overexpression of ITGalpha/beta has been observed across a variety of solid tumors, and it supports cancer progression and metastasis, suggesting that it may serve as a potential therapeutic target. Using our proprietary live-cell immunization (LC-I) and high-throughput screening (LC-HTS) platforms, we generated and developed MAb51-31, an anti-ITGalpha/beta monoclonal antibody (mAb), which selectively recognizes a tumor-restricted conformational epitope of ITGalpha/beta. MAb51-31 exhibited no cross-reactivity with normal cells or tissues. Both the chimeric and humanized versions of MAb51-31 displayed high binding affinity to recombinant ITGalpha/beta (K D ≈ 1.4 nM). MAb51-31-cAb, engineered with two point-mutations in each Fc region, was conjugated to MMAE via an MC-Vc-PAB linker to generate MAb51-31-ADC (DAR4). MAb51-31-ADC demonstrated potent antiproliferative effects in vitro , with cytotoxicity correlating with its internalization efficiency across various solid tumor cell lines. In cell line-derived xenograft (CDX) models of triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), gastric cancer (GC), and other solid tumors, a single intraperitoneal ( i.p .) dose of MAb51-31-ADC at 4, 7, or 10 mg/kg effectively inhibited tumor growth, resulting in complete tumor regression within 24~30 days post-treatment. Initial toxicology assessments indicated that MAb51-31-ADC was well tolerated, with no notable safety concerns observed. MAb51-31-ADC is a promising therapeutic candidate for treating solid tumors, with selective recognition of a tumor-specific ITGalpha/beta epitope potentially enabling strong antitumor efficacy and reduced off-target effects. Ongoing studies include evaluation of MAb51-31-ADC in patient-derived xenograft (PDX) models of gastrointestinal (GI) cancers, as well as retrospective analyses of target expression in tumor samples, to further support its clinical development.
利益披露 Disclosure
D. Li, None..
K. Zhao, None..
M. Q. Xu, None..
M. Lu, None.