AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL, 60064-6099, USA.
Formerly AbbVie, Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL, 60064, USA.
BMC Cancer. 2021 Jun 9;21(1):681. doi: 10.1186/s12885-021-08403-5.
Prolactin receptor (PRLR) is an attractive antibody therapeutic target with expression across a broad population of breast cancers. Antibody efficacy, however, may be limited to subtypes with either PRLR overexpression and/or those where estradiol no longer functions as a mitogen and are, therefore, reliant on PRLR signaling for growth. In contrast a potent PRLR antibody-drug conjugate (ADC) may provide improved therapeutic outcomes extending beyond either PRLR overexpressing or estradiol-insensitive breast cancer populations.
We derived a novel ADC targeting PRLR, ABBV-176, that delivers a pyrrolobenzodiazepine (PBD) dimer cytotoxin, an emerging class of warheads with enhanced potency and broader anticancer activity than the clinically validated auristatin or maytansine derivatives. This agent was tested in vitro and in vivo cell lines and patient derived xenograft models.
In both in vitro and in vivo assays, ABBV-176 exhibits potent cytotoxicity against multiple cell line and patient-derived xenograft breast tumor models, including triple negative and low PRLR expressing models insensitive to monomethyl auristatin (MMAE) based PRLR ADCs. ABBV-176, which cross links DNA and causes DNA breaks by virtue of its PBD warhead, also demonstrates enhanced anti-tumor activity in several breast cancer models when combined with a poly-ADP ribose polymerase (PARP) inhibitor, a potentiator of DNA damage.
Collectively the efficacy and safety profile of ABBV-176 suggest it may be an effective therapy across a broad range of breast cancers and other cancer types where PRLR is expressed with the potential to combine with other therapeutics including PARP inhibitors.
催乳素受体（PRLR）是一种有吸引力的抗体治疗靶点，在广泛的乳腺癌人群中表达。然而，抗体的疗效可能仅限于那些 PRLR 过表达和/或雌激素不再作为有丝分裂原的亚型，因此依赖于 PRLR 信号来生长。相比之下，一种有效的 PRLR 抗体药物偶联物（ADC）可能会提供更好的治疗效果，超出 PRLR 过表达或雌激素不敏感的乳腺癌人群。
我们开发了一种新型的靶向 PRLR 的 ADC，ABBV-176，它携带吡咯苯并二氮杂卓（PBD）二聚体细胞毒素，这是一种新兴的弹头类别，与临床验证的奥瑞他汀或美坦辛衍生物相比，具有更强的效力和更广泛的抗癌活性。该药物在体外和体内细胞系和患者来源的异种移植模型中进行了测试。
在体外和体内测定中，ABBV-176 对多种细胞系和患者来源的异种移植乳腺癌模型表现出强大的细胞毒性，包括三阴性和低 PRLR 表达的模型，这些模型对基于单甲基奥瑞他汀（MMAE）的 PRLR ADC 不敏感。ABBV-176 通过其 PBD 弹头交联 DNA 并导致 DNA 断裂，当与聚 ADP 核糖聚合酶（PARP）抑制剂联合使用时，在几种乳腺癌模型中也表现出增强的抗肿瘤活性，PARP 抑制剂是 DNA 损伤的增效剂。
ABBV-176 的疗效和安全性概况表明，它可能是一种有效的治疗方法，适用于广泛的乳腺癌和其他表达 PRLR 的癌症类型，具有与其他治疗方法（包括 PARP 抑制剂）联合使用的潜力。
