Antibody-Drug Conjugates-Evolution and Perspectives

Abstract

Antineoplastic therapy is one of the main research themes of this century. Modern approaches have been implemented to target and heighten the effect of cytostatic drugs on tumors and diminish their general/unspecific toxicity. In this context, antibody-drug conjugates (ADCs) represent a promising and successful strategy. The aim of this review was to assess different aspects regarding ADCs. They were presented from a chemical and a pharmacological perspective and aspects like structure, conjugation and development particularities alongside effects, clinical trials, safety issues and perspectives and challenges for future use of these drugs were discussed. Representative examples include but are not limited to the following main structural components of ADCs: monoclonal antibodies (trastuzumab, brentuximab), linkers (pH-sensitive, reduction-sensitive, peptide-based, phosphate-based, and others), and payloads (doxorubicin, emtansine, ravtansine, calicheamicin). Regarding pharmacotherapy success, the high effectiveness expectation associated with ADC treatment is supported by the large number of ongoing clinical trials. Major aspects such as development strategies are first discussed, advantages and disadvantages, safety and efficacy, offering a retrospective insight on the subject. The second part of the review is prospective, focusing on various plans to overcome the previously identified difficulties.

Keywords: antibody–drug conjugates; cancer; clinical trials; cytotoxic payload; efficacy; linker; monoclonal antibody; safety; targeted therapy.

Figure 1

The evolution of ADCs in therapy [13].

Figure 2

Main components of (ADCs); 1—chemically cleavable linker; 2—enzymatically cleavable linker. Adapted from [11,25,26,27].

Figure 3

Hydrazone linker cleavage. 1—site of hydrolysis. Adapted from [31,33].

Figure 4

BR96—Doxorubicin ADC structure. 1—Site of hydrolysis; 2—(6-maleimidocaproyl) hydrazone linker (highlighted in green); 3—payload (doxorubicin) (red). Adapted from [26].

Figure 5

Cantuzumab ravtansine (huC242-SPDB-DM4) conjugate cleavage. 1—Site of first cleavage (proteolytic); 2—site of second cleavage (reduction of disulfide bond by cytoplasmatic glutathione); 3—payload (ravtansine, red). Adapted from [35,36,37].

Figure 6

Pyrophosphodiester linker cleavage in lysosome by pyrophosphatase and phosphatase. 1—Site of pyrophosphate cleavage (by pyrophosphatase); 2—site of phosphate cleavage (by phosphatase); 3—payload (dexamethasone) (red). Adapted from [31,39].

Figure 7

Val-Cit linker enzymatic cleavage by cathepsin B in lysosome. 1—Site of enzymatic cleavage; 2—Val-Cit linker (green); 3—payload (red). Adapted from [41].

Figure 8

β-Glucuronide linker enzymatic cleavage by β-glucuronidase in lysosome. 1—Site of enzymatic cleavage; 2—β-glucoronide-based linker (green); 3—payload (red). Adapted from [26].

Figure 9

Cytosolic/lysosomal degradation of ADCs with non-cleavable linkers. 1—MC; 2—thioether linker; 3—payload (red). Adapted from [46,47].

Figure 10

Structure of Trastuzumab emtansine. 1—Non-cleavable SMCC linker (blue); 2—payload (emtansine, red). Adapted from [49,50].

Figure 11

Chemical structures of maytansinoids. Adapted from [63,64].

Figure 12

Drug to Antibody Ratio (DAR) illustration. Adapted from [76].

Figure 13

Mirvetuximab soravtansine ADC structure. 1—Cleavable Sulfo-SPDB linker (green); 2—payload (ravtansine, red). Adapted from [54].