Depatuxizumab mafodotin (depatux-m, ABT-414) is a tumor-selective antibody drug conjugate (ADC) comprised of the anti-EGFR antibody ABT-806 and the monomethyl auristatin F (MMAF) warhead. Depatux-m has demonstrated promising clinical activity in glioblastoma multiforme (GBM) patients and is currently being evaluated in clinical trials in first-line and recurrent GBM disease settings. Depatux-m responses have been restricted to patients with amplified EGFR, highlighting the need for therapies with activity against tumors with nonamplified EGFR overexpression. In addition, depatux-m dosing has been limited by corneal side effects common to MMAF conjugates. We hypothesized that a monomethyl auristatin E (MMAE) ADC utilizing an EGFR-targeting antibody with increased affinity may have broader utility against tumors with more modest EGFR overexpression while mitigating the risk of corneal side effects. We describe here preclinical characterization of ABBV-221, an EGFR-targeting ADC comprised of an affinity-matured ABT-806 conjugated to MMAE. ABBV-221 binds to a similar EGFR epitope as depatux-m and retains tumor selectivity with increased binding to EGFR-positive tumor cells and greater in vitro potency. ABBV-221 displays increased tumor uptake and antitumor activity against wild-type EGFR-positive xenografts with a greatly reduced incidence of corneal side effects relative to depatux-m. ABBV-221 has similar activity as depatux-m against an EGFR-amplified GBM patient derived xenograft (PDX) model and is highly effective alone and in combination with standard-of-care temozolomide in an EGFRvIII-positive GBM xenograft model. Based on these results, ABBV-221 has advanced to a phase I clinical trial in patients with advanced solid tumors associated with elevated levels of EGFR. Mol Cancer Ther; 17(4); 795–805. ©2018 AACR.

中文翻译：

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ABBV-221 的表征，一种肿瘤选择性 EGFR 靶向抗体药物偶联物

Depatuxizumab mafodotin（depatux-m，ABT-414）是一种肿瘤选择性抗体药物偶联物（ADC），由抗EGFR抗体ABT-806和单甲基auristatin F（MMAF）弹头组成。Depatux-m 已在多形性胶质母细胞瘤 (GBM) 患者中显示出有希望的临床活性，目前正在一线和复发性 GBM 疾病环境中的临床试验中进行评估。Depatux-m 反应仅限于 EGFR 扩增的患者，强调需要对非扩增 EGFR 过表达的肿瘤具有活性的疗法。此外，depatux-m 剂量受到 MMAF 偶联物常见的角膜副作用的限制。我们假设，使用具有更高亲和力的 EGFR 靶向抗体的单甲基 auristatin E (MMAE) ADC 可能对具有更适度 EGFR 过度表达的肿瘤具有更广泛的效用，同时降低角膜副作用的风险。我们在此描述 ABBV-221 的临床前表征，这是一种靶向 EGFR 的 ADC，由结合到 MMAE 的亲和力成熟的 ABT-806 组成。ABBV-221 结合与 depatux-m 相似的 EGFR 表位，并保持肿瘤选择性，与 EGFR 阳性肿瘤细胞的结合增加，体外效力更强。ABBV-221 对野生型 EGFR 阳性异种移植物显示出增加的肿瘤吸收和抗肿瘤活性，相对于 depatux-m，角膜副作用的发生率大大降低。ABBV-221 对 EGFR 扩增的 GBM 患者衍生异种移植 (PDX) 模型具有与 depatux-m 相似的活性，并且在 EGFRvIII 阳性 GBM 异种移植模型中单独和与标准护理替莫唑胺联合使用时非常有效。基于这些结果，ABBV-221 已进入 I 期临床试验，用于治疗与 EGFR 水平升高相关的晚期实体瘤。摩尔癌症治疗; 17(4); 795-805。©2018 AACR。