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Review
. 2017 Aug 1;22(8):1281.
doi: 10.3390/molecules22081281.

Tubulin Inhibitor-Based Antibody-Drug Conjugates for Cancer Therapy

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Free PMC article
Review

Tubulin Inhibitor-Based Antibody-Drug Conjugates for Cancer Therapy

Hao Chen et al. Molecules. .
Free PMC article

Abstract

Antibody-drug conjugates (ADCs) are a class of highly potent biopharmaceutical drugs generated by conjugating cytotoxic drugs with specific monoclonal antibodies through appropriate linkers. Specific antibodies used to guide potent warheads to tumor tissues can effectively reduce undesired side effects of the cytotoxic drugs. An in-depth understanding of antibodies, linkers, conjugation strategies, cytotoxic drugs, and their molecular targets has led to the successful development of several approved ADCs. These ADCs are powerful therapeutics for cancer treatment, enabling wider therapeutic windows, improved pharmacokinetic/pharmacodynamic properties, and enhanced efficacy. Since tubulin inhibitors are one of the most successful cytotoxic drugs in the ADC armamentarium, this review focuses on the progress in tubulin inhibitor-based ADCs, as well as lessons learned from the unsuccessful ADCs containing tubulin inhibitors. This review should be helpful to facilitate future development of new generations of tubulin inhibitor-based ADCs for cancer therapy.

Keywords: antibody-drug conjugates; cytotoxic payloads; linker; monoclonal antibody; site-specific conjugation; tubulin inhibitors.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The general components of ADC. Selection principles of antibody, comparison between non-specific and specific conjugations, and descriptions on how the drug is released and its mechanism of action.
Figure 2
Figure 2
General mechanism of action of ADCs. The antibody of an ADC binds to tumor associated antigen. Upon binding, the ADC-antigen complex is internalized into the cancer cell. During the degradation of the complex, the released payload exerts its effects on the intracellular target leading to apoptosis.
Figure 3
Figure 3
Structure, polymerization and depolymerization of microtubules.
Figure 4
Figure 4
Classification of tubulin stabilizers and destabilizers arresting cell cycle at G2/M phase.
Figure 5
Figure 5
The chemical structures of tubulin inhibitors and their derivatives. Microtubule destabilizers: maytansine and its derivatives, dolastatin-10 and its derivatives, cryptopycin-1, cryptopycin-52, tubulysins D, hemiasterlin and its derivative (HTI-286), colchicine and CA4. Microtubule stabilizers: paclitaxel, discodermolide, taccalonolides A and B and their derivatives (taccalonolide AF and taccalonolide AJ), and taccalonolide AI-epoxide, laulimalide, and epothilones A and B.
Scheme 1
Scheme 1
Semi-synthesis of DM1, DM3 and DM4 from ansamitocin P-3.
Scheme 2
Scheme 2
(A) conjugation of DM1 to antibodies by maleimide linker to produce antibody-SMCC-DM1 ADCs. SMCC: N-succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate; (B) conjugation of maytansinoids (May: DM1, DM3 and DM4) to antibodies by disulfide linker to produce antibody–SPDB–May ADCs. SPDB: N-succinimidyl-4-(2-pyridyldithio)butanoate.
Scheme 3
Scheme 3
(A) antibody-SMCC-DM1 generates metabolite Lys-SMCC-DM1. SMCC: N-succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate; (B) metabolism of antibody-SPDB-DM4. SPDB: N-succinimidyl-4-(2-pyridyldithio)butanoate; (C) metabolism of antibody-SPDB-DM4.
Scheme 4
Scheme 4
(A) the chemical structure of mAb-PEG-Mal-DM1 and mAb-sulfo-SPDB-DM4. PEG4: hydrophilic tetraethylene glycol, sulfo-PDB: sulfo N-succinimidyl-4-(2-pyridyldithio)butanoate; (B) the tubulin inhibitor MMAF-based ADCs; (C) the hydrazone functionalities, β-glucuronide containing linkers, quaternary ammonium linkers or rebridged ado-trastuzumab-based ADCs using MMAE or MMAF as payload.
Scheme 5
Scheme 5
Metabolism and self-immolation of mc-Val-Cit-PABC-MMAE. mc: maleimidocaproyl. Val: valine. Cit: citrulline. MMAE: monomethylauristatin E.
Scheme 6
Scheme 6
(A) the tubulin inhibitor cryptophycins-based ADCs; (B) the tubulin inhibitor tubulysins-based ADCs containing quaternary ammonium linkers; (C) the tubulin inhibitor taxoid-based ADCs.

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