Trends in the Development of Antibody-Drug Conjugates for Cancer Therapy

Abstract

In cancer treatment, the first-generation, cytotoxic drugs, though effective against cancer cells, also harmed healthy ones. The second-generation targeted cancer cells precisely to inhibit their growth. Enter the third-generation, consisting of immuno-oncology drugs, designed to combat drug resistance and bolster the immune system's defenses. These advanced therapies operate by obstructing the uncontrolled growth and spread of cancer cells through the body, ultimately eliminating them effectively. Within the arsenal of cancer treatment, monoclonal antibodies offer several advantages, including inducing cancer cell apoptosis, precise targeting, prolonged presence in the body, and minimal side effects. A recent development in cancer therapy is Antibody-Drug Conjugates (ADCs), initially developed in the mid-20th century. The second generation of ADCs addressed this issue through innovative antibody modification techniques, such as DAR regulation, amino acid substitutions, incorporation of non-natural amino acids, and enzymatic drug attachment. Currently, a third generation of ADCs is in development. This study presents an overview of 12 available ADCs, reviews 71 recent research papers, and analyzes 128 clinical trial reports. The overarching objective is to gain insights into the prevailing trends in ADC research and development, with a particular focus on emerging frontiers like potential targets, linkers, and drug payloads within the realm of cancer treatment.

Keywords: antibody drug conjugates; conjugation; linker; monoclonal antibody; payload.

Figure 1

The structure and components of an ADC. ADC consist of a monoclonal antibody, a linker, and a cytotoxic payload. Antibody comprises two heavy chains and two light chains, containing four disulfide bonds within the heavy chains and one each in both the heavy and light chains. The linker-payload is connected to the external surface of the antibody, ensuring both easy attachment to the antibody and effortless detachment from the target cell.

Figure 2

The mode of action of ADC. The ADC attaches to the receptor located on the target cell, resulting in the formation of an ADC-antigen complex. This complex subsequently undergoes internalization by endocytosis, forming endosomes, and goes through maturation where it is degraded by lysosomes. Throughout this process, the activated payload binds to target DNA or microtubules, leading to cell death induction. Additionally, intracellular drugs have the potential to exit the cell and induce a bystander effect, resulting in cell death in neighboring cells.

Figure 3

Cleavable and Non-cleavable linkers. Cleavable linkers have the ability to break down in specific situations, like acidic environments, varying glutathione levels, or the influence of enzymes. This breakdown can happen within both endosomes and lysosomes. On the other hand, non-cleavable linkers are not susceptible to degradation in either endosomes or lysosomes, as the linker itself remains intact. Only the payload is liberated within the lysosome. In the figure, antibody are shown in blue, linker in green, and drug in red.

Figure 4

In the development of antibody-drug conjugates linkers play a crucial role. (a) Cleavable linkers include β-glucuronide linker, glutathione linkers, protease linkers, hydrazone linkers. (b) Non-cleavable linkers include SMCC, MC, PEG4Mal.

Figure 5

FDA-approved ADC. The majority of linkers utilized in ADCs are cleavable, although trastuzumab etansine used a noncleavable linker. The payloads used consisted of three types: a DNA-targeting agent (yellow), a tubulin-binding agent (red), and a topoisomerase 1 inhibitor (blue).

Figure 6

Diagram illustrating target antigens, linkers, payloads and diseases used in research articles. Among the 71 articles, the target antigen is HER2 in 20, EGFR in 5, B7-H3 in 5, TROP-2 in 4. As for the linker, 64 are cleavable, and 11 are non-cleavable, and 1 not-used linker. Regarding the payload, 30 articles focus on MMAE, 10 on DM1, and 9 on Topoisomerase 1 inhibitor. Additionally, there are 6 articles discussing DXd and 6 on PBD. The research covers various diseases in the following order: breast cancer with 29 articles, lung cancer with 18 articles, ovarian cancer with 12 articles, pancreatic cancer with 10 articles, colorectal cancer with 10 articles, stomach cancer with 6 articles, and melanoma with 6 articles.

Figure 6

Diagram illustrating target antigens, linkers, payloads and diseases used in research articles. Among the 71 articles, the target antigen is HER2 in 20, EGFR in 5, B7-H3 in 5, TROP-2 in 4. As for the linker, 64 are cleavable, and 11 are non-cleavable, and 1 not-used linker. Regarding the payload, 30 articles focus on MMAE, 10 on DM1, and 9 on Topoisomerase 1 inhibitor. Additionally, there are 6 articles discussing DXd and 6 on PBD. The research covers various diseases in the following order: breast cancer with 29 articles, lung cancer with 18 articles, ovarian cancer with 12 articles, pancreatic cancer with 10 articles, colorectal cancer with 10 articles, stomach cancer with 6 articles, and melanoma with 6 articles.

Figure 7

Diagram illustrating target antigens and clinical phases employed in clinical trials. Out of the 128 clinical investigations conducted, HER2 was the targeted antigen in 68 studies, while TROP-2 was the focus in 11 studies. Additionally, FRα was targeted in 8 studies, EGFR was targeted in 7 studies followed by c-MET in 4 studies. The remaining 30 studies targeted other antigens. In terms of clinical stages, 52 studies were categorized in phase 2, 25 in phase 1, 19 in both phases 1 and 2, 27 in phase 3, and 2 in the combined phases 2 and 3.

Figure 8

Diagram illustrating linkers and payloads used in clinical trials. The linker’s composition includes 77 instances of Val-Cit cleavable linker, 22 instances of tetrapeptide-based linker, 2 instances of SPDP linker, 1 instance of sulfo-SPDB linker, and 1 instance of glucuronide-trigger linker. Meanwhile, the non-cleavable linkers comprise 4 instances of SMCC linker and 13 instances of linkers with unknown attributes. Within the payload category, microtubule inhibitors consist of 70 cases of MMAE, 4 cases of eribulin, 4 cases of maytansinoid-DM4, 4 cases of MMAF, 4 case of maytansinoid-DM1, and 1 case of hemiasterlin. In relation to DNA damage reagents, there are 28 instances of topoisomerase I inhibitor, 1 instance of duocarmacin, and 7 instances of payloads with unknown characteristics.