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抗体偶联药物 MORAb-202 在三阴性乳腺癌 PDx 模型中显示出持久的抗肿瘤疗效。

Antibody-drug conjugate MORAb-202 exhibits long-lasting antitumor efficacy in TNBC PDx models.

机构信息

Epochal Precision Anti-Cancer Therapeutics (EPAT), Eisai Inc, Exton, PA, USA.

Tsukuba Research Laboratory, Eisai, Co. Ltd, Tsukuba, Japan.

出版信息

Cancer Sci. 2021 Jun;112(6):2467-2480. doi: 10.1111/cas.14898. Epub 2021 May 1.

DOI:10.1111/cas.14898
PMID:33756060
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8177789/
Abstract

The antibody-drug conjugate (ADC) MORAb-202, consisting of farletuzumab paired with a cathepsin B-cleavable linker and eribulin, targets folate receptor alpha (FRA), which is frequently overexpressed in various tumor types. MORAb-202 was highly cytotoxic to FRA-positive cells in vitro, with limited off-target killing of FRA-negative cells. Furthermore, MORAb-202 showed a clear in vitro bystander cytotoxic effect in coculture with FRA-positive/negative cells. In vivo antitumor efficacy studies of MORAb-202 were conducted with a single administration of MORAb-202 in triple-negative breast cancer (TNBC) patient-derived xenograft (PDx) models expressing low and high levels of FRA. MORAb-202 exhibited durable efficacy proportional to tumor FRA expression. Toxicology studies (Q3Wx2) in nonhuman primates suggested that the major observed toxicity of MORAb-202 is hematologic toxicity. Overall, these findings support the concept that MORAb-202 represents a promising investigational ADC for the treatment of TNBC patients.

摘要

抗体药物偶联物（ADC）MORAb-202 由与组织蛋白酶 B 可切割接头偶联的 farletuzumab 组成，靶向叶酸受体-α（FRA），FRA 在多种肿瘤类型中经常过表达。MORAb-202 在体外对 FRA 阳性细胞具有高度细胞毒性，对 FRA 阴性细胞的非靶标杀伤有限。此外，MORAb-202 在与 FRA 阳性/阴性细胞共培养时显示出明显的体外旁观者细胞毒性作用。在表达低水平和高水平 FRA 的三阴性乳腺癌（TNBC）患者来源异种移植（PDx）模型中，单次给予 MORAb-202 进行了 MORAb-202 的体内抗肿瘤疗效研究。MORAb-202 表现出与肿瘤 FRA 表达成正比的持久疗效。在非人类灵长类动物中的毒理学研究（Q3Wx2）表明，MORAb-202 的主要观察到的毒性是血液学毒性。总体而言，这些发现支持了这样的概念，即 MORAb-202 代表了一种有前途的用于治疗 TNBC 患者的研究性 ADC。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62e7/8177789/1d1766d6c760/CAS-112-2467-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62e7/8177789/b8ec3101a7ee/CAS-112-2467-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62e7/8177789/1140be020efa/CAS-112-2467-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62e7/8177789/e584a9d4b0c9/CAS-112-2467-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62e7/8177789/ac1794c56af0/CAS-112-2467-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62e7/8177789/1d1766d6c760/CAS-112-2467-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62e7/8177789/b8ec3101a7ee/CAS-112-2467-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62e7/8177789/0152d71687a0/CAS-112-2467-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62e7/8177789/1140be020efa/CAS-112-2467-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62e7/8177789/e584a9d4b0c9/CAS-112-2467-g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62e7/8177789/1d1766d6c760/CAS-112-2467-g001.jpg

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