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Abstract：
Panitumumab, as a commercially available antibody, is an effective anticancer therapeutic against epidermal growth factor receptor (EGFR), although it exerts weak antibody-dependent cell-mediated cytotoxicity (ADCC) activity owing to its IgG2 nature. Here, we firstly engineered panitumumab by grafting its variable region into an IgG1 backbone. The engineered panitumumab (denoted as Pan) retained binding activity identical to the parental antibody while exhibiting stronger ADCC activity in vitro and more potent antitumor effect in vivo. To further enhance the target selectivity of Pan, we generated Pan-P by tethering an epitope-blocking peptide to Pan via a tumor-specific protease selective linker. Pan-P showed almost 40-fold weaker affinity compared with Pan, but functional activity was restored to a similar extent as Pan when Pan-P was selectively activated by urokinase-type plasminogen activator (uPA). More importantly, targeted localization of Pan-P was observed in tumor samples from colorectal cancer (CRC) patients and tumor-bearing nude mice, strongly indicating that specific activation also existed ex vivo and in vivo. Furthermore, Pan-P also exhibited effective in vivo antitumor potency similar to Pan. Taken together, our data evidence the enhanced antitumor potency and excellent target selectivity of Pan-P, suggesting its potential use for minimizing on-target toxicity in anti-EGFR therapy.
摘要：
帕尼单抗,作为一种市售的抗体，是一种有效的抗癌治疗表皮生长因子受体（EGFR），尽管由于其IgG2性质而发挥弱的抗体依赖性细胞介导的细胞毒性（ADCC）活性。这里,我们首先通过将其可变区移植到IgG1主链中来改造帕尼单抗。工程改造的帕尼单抗(表示为Pan)保持与亲本抗体相同的结合活性,同时在体外表现出更强的ADCC活性和在体内更有效的抗肿瘤作用。为了进一步增强Pan的目标选择性，我们通过肿瘤特异性蛋白酶选择性接头将表位阻断肽与Pan连接产生Pan-P。与Pan相比，Pan-P的亲和力弱了近40倍，但是当Pan-P被尿激酶型纤溶酶原激活剂（uPA）选择性激活时，功能活性恢复到与Pan相似的程度。更重要的是,在结直肠癌（CRC）患者和荷瘤裸鼠的肿瘤样本中观察到Pan-P的靶向定位，强烈表明特异性激活也存在于离体和体内。此外，Pan-P还表现出与Pan相似的有效体内抗肿瘤效力。一起来看,我们的数据证明了Pan-P的抗肿瘤效力和优异的靶标选择性，提示其在抗EGFR治疗中用于最小化靶毒性的潜在用途。
