1 research outputs found
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) (<i>K</i><sub>d</sub> = 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