Novel Hybrid Compound of a Plinabulin Prodrug with an IgG Binding Peptide for Generating a Tumor Selective Noncovalent-Type Antibody-Drug Conjugate.
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) (Kd = 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.
Kyohei
K
Muguruma
Fumika
F
Yakushiji
Ryosuke
R
Kawamata
Daichi
D
Akiyama
Risako
R
Arima
Takuya
T
Shirasaka
Yamato
Y
Kikkawa
Akihiro
A
Taguchi
Kentaro
K
Takayama
Takeshi
T
Fukuhara
Tetsuro
T
Watabe
Department of Chemistry and Bioscience, Graduate School of Science and Engineering, Kagoshima University , Korimoto, Kagoshima, 890-0065, Japan.
Yuji
Y
Ito
Yoshio
Y
Hayashi
D000970:Antineoplastic Agents / Q000378:metabolism*; D054659:Diketopiperazines / Q000378:metabolism*; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000378:metabolism*; D061986:MCF-7 Cells; D011355:Prodrugs / Q000378:metabolism*; D012995:Solubility; D014867:Water / Q000737:chemistry
D000970:Antineoplastic Agents; D054659:Diketopiperazines; D018796:Immunoconjugates; D007074:Immunoglobulin G; C514351:NPI 2358; D011355:Prodrugs; D014867:Water