Marine Antibody-Drug Conjugates: Design Strategies and Research Progress

Abstract

Antibody-drug conjugates (ADCs), constructed with monoclonal antibodies (mAbs), linkers, and natural cytotoxins, are innovative drugs developed for oncotherapy. Owing to the distinctive advantages of both chemotherapy drugs and antibody drugs, ADCs have obtained enormous success during the past several years. The development of highly specific antibodies, novel marine toxins' applications, and innovative linker technologies all accelerate the rapid R&D of ADCs. Meanwhile, some challenges remain to be solved for future ADCs. For instance, varieties of site-specific conjugation have been proposed for solving the inhomogeneity of DARs (Drug Antibody Ratios). In this review, the usages of various natural toxins, especially marine cytotoxins, and the development strategies for ADCs in the past decade are summarized. Representative ADCs with marine cytotoxins in the pipeline are introduced and characterized with their new features, while perspective comments for future ADCs are proposed.

Keywords: antibody–drug conjugates; marine toxins; monoclonal antibody; targeted therapy.

Figure 1

The brief history and schematic diagram of ADCs.

Figure 2

Action mechanism of ADCs.

Figure 3

Three FDA-approved ADCs.

Figure 4

Schematic representation of miniaturization antibodies.

Figure 5

Schematic ThioBridge™.

Figure 6

Schematic c-Lock™/K-Lock™.

Figure 7

Schematic GlycoConnect™.

Figure 8

Schematic of antibody saccharides for conjugation and structures of fucose. Monosaccharide symbols used are as follows: triangle, fucose; rectangle, GlcNAc and mannose.

Figure 9

Structure of linker in ADCs.

Figure 10

Structures of the spacer and polarity parts: (a) three representative connections of the linker to the antibody; and (b) the polarity of the linker.

Figure 11

Schematic mechanism of a pyrophosphate ester linker.

Figure 12

Schematic 1,6-elimination reaction of the self-immolative spacer after cleavage of the linker.

Figure 13

Schematic a bioreversible linkage based on a quaternary ammonium.

Figure 14

Schematic of theoretical ADCs metabolism pathways.

Figure 15

Several representative cytotoxinic drugs used as payloads in ADCs.

Figure 16

Structures of several terrestrial payloads.

Figure 17

Structures of marine payloads.

Figure 18

Structures of several marine toxins.