Ala-Ala-Asn-PAB

Ala-Ala-Asn-PAB(2149584-00-7)藥理學：

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Ala-Ala-Asn-PAB(2149584-00-7)是抗體偶聯藥物 (ADCs) 的常用一種蛋白可降解 (cleavable) 的 ADC linker。

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Ala-Ala-Asn-PAB(2149584-00-7)參考文獻：

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1、MORAb-202, an Antibody-Drug Conjugate Utilizing Humanized Anti-human FRα
Farletuzumab and the Microtubule-targeting Agent Eribulin, has Potent Antitumor Activity Xin Cheng 1, Jing Li 2, Keigo Tanaka 3, Utpal Majumder 4, Andrew Z Milinichik 1, Arielle C Verdi 1, Christopher J Maddage 5, Katherine A Rybinski 5, Shawn Fernando 6, Danielle Fernando 6, Megan Kuc 6, Keiji Furuuchi 5, Frank Fang 2, Toshimitsu Uenaka 5, Luigi Grasso 7, Earl F Albone 8

Abstract Microtubule-targeting agents (MTA) have been investigated for many years as payloads for antibody-drug conjugates (ADC). In many cases, these ADCs have shown limited benefits due to lack of efficacy or significant toxicity, which has spurred continued investigation into novel MTA payloads for next-generation ADCs. In this study, we have developed ADCs using the MTA eribulin, a derivative of the macrocyclic polyether natural product halichondrin B, as a payload. Eribulin ADCs demonstrated in vitro potency and specificity using various linkers and two different conjugation approaches. MORAb-202 is an investigational agent that consists of the humanized anti-human folate receptor alpha (FRA) antibody farletuzumab conjugated via reduced interchain disulfide bonds to maleimido-PEG2-valine-citrulline-p-aminobenzylcarbamyl-eribulin at a drug-to-antibody ratio of 4.0. MORAb-202 displayed preferable biophysical properties and broad potency across a number of FRA-positive tumor cell lines as well as demonstrated improved specificity in vitro compared with farletuzumab conjugated with a number of other MTA payloads, including MMAE, MMAF, and the reducible maytansine linker-payload sulfo-SPDB-DM4. A single-dose administration of MORAb-202 in FRA-positive human tumor cell line xenograft and patient-derived tumor xenograft models elicited a robust and durable antitumor response. These data support further investigation of MORAb-202 as a potential new treatment modality for FRA-positive cancers, using the novel MTA eribulin as a payload.

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