Antibody-drug conjugates: Recent advances in payloads

Abstract

Antibody‒drug conjugates (ADCs), which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing, show great clinical therapeutic value. The ADCs' payloads play a key role in determining the efficacy of ADC drugs and thus have attracted great attention in the field. An ideal ADC payload should possess sufficient toxicity, low immunogenicity, high stability, and modifiable functional groups. Common ADC payloads include tubulin inhibitors and DNA damaging agents, with tubulin inhibitors accounting for more than half of the ADC drugs in clinical development. However, due to clinical limitations of traditional ADC payloads, such as inadequate efficacy and the development of acquired drug resistance, novel highly efficient payloads with diverse targets and reduced side effects are being developed. This perspective summarizes the recent research advances of traditional and novel ADC payloads with main focuses on the structure-activity relationship studies, co-crystal structures, and designing strategies, and further discusses the future research directions of ADC payloads. This review also aims to provide valuable references and future directions for the development of novel ADC payloads that will have high efficacy, low toxicity, adequate stability, and abilities to overcome drug resistance.

Keywords: Antibody‒drug conjugates; DNA damaging agents; Dual payloads; PROTACs; RNA targeting agents; Tubulin inhibitors.

Graphical abstract

Figure 1

Key structures and mechanisms of action of ADCs. (A) The general mechanism of action of ADCs; (B) The mechanism of DNA inhibitors as ADC payloads; (C) The mechanism of Splicing inhibitors as ADC payloads; (D) The mechanism of tubulin inhibitors as ADC payloads; (E) The mechanism of PROTAC molecules as ADC payloads; (F) The mechanism of Bcl-xL inhibitors and proteasome inhibitors as ADC payloads; (G) The mechanism of NAMPT inhibitors as ADC payloads; (H) The mechanism of NIR-PIT ADC.

Figure 2

Milestones in the development of ADCs payloads.

Figure 3

Design and SAR analysis of maytansinoids. (A) Chemical structures of maytansinoids 1–5; (B) Binding mode of maytansine (1) in complex with tubulin (PDB code 4TV8); (C) Binding mode of compound 5 in complex with tubulin (PDB code 5SBA).

Figure 4-1

Design and SAR analysis of auristatin analogs. (A) Chemical structures of auristatin analogs 7–10, 21–24; (B) Binding mode of compound 10 in complex with tubulin (PDB code 4X1I).

Figure 4-2

Chemical structures of auristatin analogs 11–20.

Figure 5

Design and SAR analysis of eribulin analogs. (A) Chemical structures of eribulin analogs 25–27; (B) Binding mode of eribulin 26 in complex with tubulin (PDB code 5JH7).

Figure 6

Design and SAR analysis of tubulysin analogs. (A) Chemical structures of tubulysin analogs 28–34; (B) Binding mode of compound 30 in complex with tubulin (PDB code 6Y4N).

Figure 7

Design and SAR analysis of cryptophycin analogs. (A) Chemical structures of cryptophycin analogs 35–40; (B) Binding mode of cryptophycin-52 (36) in complex with tubulin (PDB code 7M20).

Figure 8

Design and SAR analysis of EG5 inhibitors. (A) Chemical structures of EG5 inhibitors 41–45; (B) Binding mode of ispinesib (41) in complex with EG5 (PDB code 4AP0).

Figure 9

Design and SAR analysis of enediyne. (A) Chemical structures of enediyne 46–52; (B) Binding mode of calicheamicin γ^I₁ (46) in complex with DNA (PDB code 2PIK).

Figure 10

Design and SAR analysis of Topoisomerase I inhibitors. (A) Binding mode of Topotecan (53) in complex with TOPO I-DNA (PDB code 1K4T); (B) Chemical structures of Topoisomerase I inhibitors 53–60.

Figure 11

Design and SAR analysis of PBD analogs 61–72.

Figure 12

Design and SAR analysis of duocarmycins analogs. (A) Chemical structures of duocarmycins analogs 73–80; (B) Binding mode of Duocarmycins A (73) in complex with DNA (PDB code 1DSM).

Figure 13

Design and SAR analysis of thailanstatin analogs 81–87.

Figure 14

Design and SAR analysis of amatoxins. (A) Chemical structures of amatoxins 88, 89; (B) Binding mode of α-Amanitin (88) in complex with RNA (PDB code 3CQZ).

Figure 15

Design and SAR analysis of TLR agonists 90–92.

Figure 16

Design and SAR analysis of STING agonists. (A) Chemical structures of STING agonists 93–96; (B) Binding mode of CDN (93) in complex with STING (PDB code 6A05).

Figure 17

Design and SAR analysis of glucocorticoid receptor modulators (GRMs). (A) Chemical structures of GRMs 97–102; (B) Binding mode of compound 97 in complex with GR (PDB code 4UDC); (C) Binding mode of compound 98 in complex with GR (PDB code 4UDD).

Figure 18

Design and SAR analysis of Bcl-xL inhibitors. (A) Chemical structures of Bcl-xL inhibitors 103, 104; (B) Binding mode of ABT-737 (103) in complex with Bcl-xL (PDB code 2YXJ).

Figure 19

Design and SAR analysis of NAMPT inhibitors. (A) Chemical structures of NAMPT inhibitors 105–113; (B) Binding mode of A-1293201 (106) in complex with NAMPT (PDB code 5U2M).

Figure 20

Design of carmaphycins analogs 114–122.

Figure 21

Chemical structures of PROTAC molecules 123–127.

Figure 22

Design and analysis of IRDye700DX (128). (A) Chemical structures of IRDye700DX (128); (B) The mechanism of NIR-PIT ADC.

Figure 23

The mode pattern of dual-payloads drug ADC (The red and green shapes mean different payloads).

Figure 24

Key structures and mechanisms of action of PDCs. (A) The general mechanism of action of PDCs; (B) Chemical structures of the common PDC payloads.