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

Bioconjug Chem. 2016 Jul 20;27(7):1606-13. doi: 10.1021/acs.bioconjchem.6b00149. Epub 2016 Jul 7.


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.

MeSH terms

  • Antineoplastic Agents / metabolism*
  • Diketopiperazines / metabolism*
  • Humans
  • Immunoconjugates / chemistry
  • Immunoconjugates / metabolism*
  • Immunoconjugates / pharmacology*
  • Immunoglobulin G / metabolism*
  • MCF-7 Cells
  • Prodrugs / metabolism*
  • Solubility
  • Water / chemistry


  • Antineoplastic Agents
  • Diketopiperazines
  • Immunoconjugates
  • Immunoglobulin G
  • NPI 2358
  • Prodrugs
  • Water