Antibody-drug conjugates: Recent advances in linker chemistry

Abstract

Antibody-drug conjugates (ADCs) are gradually revolutionizing clinical cancer therapy. The antibody-drug conjugate linker molecule determines both the efficacy and the adverse effects, and so has a major influence on the fate of ADCs. An ideal linker should be stable in the circulatory system and release the cytotoxic payload specifically in the tumor. However, existing linkers often release payloads nonspecifically and inevitably lead to off-target toxicity. This defect is becoming an increasingly important factor that restricts the development of ADCs. The pursuit of ADCs with optimal therapeutic windows has resulted in remarkable progress in the discovery and development of novel linkers. The present review summarizes the advance of the chemical trigger, linker‒antibody attachment and linker‒payload attachment over the last 5 years, and describes the ADMET properties of ADCs. This work also helps clarify future developmental directions for the linkers.

Keywords: Antibody–drug conjugate; Chemical trigger; Linker; Linker‒antibody attachment; Linker‒payload attachment.

Graphical abstract

Figure 1

The general structure of an ADC and the roles of the chemical trigger, the linker‒antibody attachment and the linker‒payload attachment.

Figure 2

Structures of cathepsin-cleavable triggers. (A) The structure of the cBu-Cit-PABC-containing ADCs. Adapted with modification from Ref.  © 2017 American Association for Cancer Research. (B) The structure of CX-containing ADCs and catabolites expected from lysosomal proteolysis. Adapted with modification from Ref. 21 © 2016 American Association for Cancer Research.

Figure 3

Approved acid-cleavable linker-containing ADCs and the structure of silyl ether-containing ADC. Adapted with modification from Ref.  © 2019 Multidisciplinary Digital Publishing Institute.

Figure 4

Structures of GSH-cleavable triggers. (A) The structure and release mechanism of an ADC containing a disulfide linker and a disulfide-carbamate linker. Adapted with modification from Ref.  © 2017 Royal Society of Chemistry. (B) The structure and release mechanism of an ADC containing a disulfide-carbamate linker with a PBD-dimer. Adapted with modification from Ref.  © 2017 American Association for Cancer Research.

Figure 5

Structures of Fe(Ⅱ)-cleavable trigger. (A) The structure of the Fe(II)-reactive (TRX) linker-containing ADC. Adapted with modification from Ref.  © 2018 American Chemical Society. (B) Release mechanism of Fe(II)-cleavable linker-containing ADCs.

Figure 6

Structures of glycosidase- and sulfatase-cleavable triggers. (A) The structure of a β-glucuronidase-cleavable, linker-containing ADC. Adapted with modification from Ref.  © 2017 Elsevier. (B) Release mechanism of β-glucuronidase and β-glucuronidase-cleavable linker-containing ADCs. (C) The structure and release mechanism of sulfatase-cleavable linker-containing ADCs. Adapted with modification from Ref.  © 2020 The Royal Society of Chemistry.

Figure 7

Structures of a pyrophosphate-cleavable trigger and novel leaving group. (A) The structure and release mechanism of Val-Cit-PAB-pyrophosphate linker-containing ADCs. Adapted with modification from Ref.  © 2016 American Chemical Society. (B) The structure and release mechanism of pyrophosphate linker-containing ADCs. Adapted with modification from Ref.  © 2016 American Chemical Society. (C) The structure and release mechanism of Val-Ala-AHC cleavable linker-containing ADCs. Adapted with modification from Ref.  © 2020 Ivyspring International.

Figure 8

Structures of photo-responsive cleavable triggers. (A) The structure and release of NIR-cleavable linker-containing ADCs. Adapted with modification from Ref.  © 2015 WILEY. (B) The structure and release mechanism of UV-cleavable linker-containing ADCs. Adapted with modification from Ref.  © 2020 Elsevier. (C) The structure and release mechanism of PC4AP-UV cleavable linker-containing ADCs. Adapted with modification from Ref.  © 2019 The Royal Society of Chemistry.

Figure 9

The structures and release mechanism of biorthogonal-cleavable linker-containing ADCs. Adapted with modification from Ref.  © 2019 American Chemical Society.

Figure 10

Structures of non-cleavable linkers. (A) The structure of MD non-cleavable linker-containing ADCs. Adapted with modification from Ref.  © 2016 Nature Publishing Group. (B) The structure of noncleavable ADCs containing an alkyne, a triazole and a piperazine group, respectively. Adapted with modification from Ref.  © 2017 American Chemical Society. (C) The structure of noncleavable linker-MMAE-containing ADCs. Adapted with modification from Ref.  © 2020 Multidisciplinary Digital Publishing Institute.

Figure 11

Structures of the optimized maleimide attachment. (A) The structure and mechanism of optimized maleimide attachment by proximal amines and electron-withdrawing groups.(B) The structure and mechanism of optimized maleimide attachment by N-phenyl maleimide. Adapted with modification from Ref.  © 2017 Multidisciplinary Digital Publishing Institute.

Figure 12

Structures of novel linker‒antibody attachments. (A) “Re-bridge” strategy and the structure of BVP conjugation-containing ADCs. Adapted with modification from Ref.  © 2020 Elsevier. (B) The structure of N-methyl-N-phenylvinylsulfonamides attachment-containing ADCs. Adapted with modification from Ref.  © 2018 American Chemical Society. (C) The structure and synthesis of Lx® attachment-containing ADCs. Adapted with modification from Ref.  © 2016 American Association for Cancer Research.

Figure 13

Structures of novel linker‒payload attachments. (A) Structures of tertiary amine attachments. Adapted with modification from Ref.  © 2016 American Association for Cancer Research. (B) Structures of OHPAS attachments. Adapted with modification from Ref.  © 2019 American Chemical Society.

Figure 14

The structure of PSAR-β-glucuronidase cleavable linker-containing ADCs. Adapted with modification from Ref.  © 2019 Royal Society of Chemistry.

Figure 15

Effects on payload kinetics in tumors of linkers. (A) The structure of PBD-dimer-containing ADCs. Adapted with modification from Ref.  © 2016 American Society for Pharmacology and Experimental Therapeutics. (B) The structure and in vivo evaluation of PBD-dimer-containing ADCs. Adapted with modification from Ref.  © 2018 American Association for Cancer Research. (C) The structural optimization of MMAE-containing ADCs and the structure of DMx-containing ADCs. Adapted with modification from Ref.  © 2019 American Society for Pharmacology and Experimental Therapeutics.