Novel Hybrid Compound of a Plinabulin Prodrug with an IgG Binding Peptide for Generating a Tumor Selective Noncovalent-Type Antibody–Drug Conjugate

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• 作者：Kyohei Muguruma ; Fumika Yakushiji ; Ryosuke Kawamata ; Daichi Akiyama ; Risako Arima ; Takuya Shirasaka ; Yamato Kikkawa ; Akihiro Taguchi ; Kentaro Takayama ; Takeshi Fukuhara ; Tetsuro Watabe ; Yuji Ito ; Yoshio Hayashi
• 刊名：Bioconjugate Chemistry
• 出版年：2016
• 出版时间：July 20, 2016
• 年：2016
• 卷：27
• 期：7
• 页码：1606-1613
• 全文大小：341K
• 年卷期：0
• ISSN：1520-4812

文摘

Although several approaches for making antibody–drug conjugates (ADC) have been developed, it has yet to be reported that an antibody binding peptide such as Z33 from protein A is utilized as the pivotal unit to generate the noncovalent-type ADC (NC-ADC). Herein we aim to establish a novel probe for NC-ADC by synthesizing the Z33-conjugated antitumor agent, plinabulin. Due to the different solubility of two components, including hydrophobic plinabulin and hydrophilic Z33, an innovative method with a solid-supported disulfide coupling reagent is required for the synthesis of the target compounds with prominent efficiency (29% isolated yield). We demonstrate that the synthesized hybrid exhibits a binding affinity against the anti-HER2 antibody (Herceptin) and the anti-CD71 antibody (6E1) (K_d = 46.6 ± 0.5 nM and 4.5 ± 0.56 μM, respectively) in the surface plasmon resonance (SPR) assay. In the cell-based assays, the hybrid provides a significant cytotoxicity in the presence of Herceptin against HER2 overexpressing SKBR-3 cells, but not against HER2 low-expressing MCF-7 cells. Further, it is noteworthy that the hybrid in combination with Herceptin induces cytotoxicity against Herceptin-resistant SKBR-3 (SKBR-3HR) cells. Similar results are obtained with the 6E1 antibody, suggesting that the synthesized hybrid can be widely applicable for NC-ADC using the antibody of interest. In summary, a series of evidence presented here strongly indicate that NC-ADCs have high potential for the next generation of antitumor agents.