The Evolving Landscape of Antibody-Drug Conjugates: In Depth Analysis of Recent Research Progress

Abstract

Antibody-drug conjugates (ADCs) are targeted immunoconjugate constructs that integrate the potency of cytotoxic drugs with the selectivity of monoclonal antibodies, minimizing damage to healthy cells and reducing systemic toxicity. Their design allows for higher doses of the cytotoxic drug to be administered, potentially increasing efficacy. They are currently among the most promising drug classes in oncology, with efforts to expand their application for nononcological indications and in combination therapies. Here we provide a detailed overview of the recent advances in ADC research and consider future directions and challenges in promoting this promising platform to widespread therapeutic use. We examine data from the CAS Content Collection, the largest human-curated collection of published scientific information, and analyze the publication landscape of recent research to reveal the exploration trends in published documents and to provide insights into the scientific advances in the area. We also discuss the evolution of the key concepts in the field, the major technologies, and their development pipelines with company research focuses, disease targets, development stages, and publication and investment trends. A comprehensive concept map has been created based on the documents in the CAS Content Collection. We hope that this report can serve as a useful resource for understanding the current state of knowledge in the field of ADCs and the remaining challenges to fulfill their potential.

Figure 1

Structure and mechanism of action of ADCs. (A) Scheme of antibody structure including heavy chains, light chains, constant region, variable region, and antigen binding site. (B) Antitumor ADCs combine three key elements: a monoclonal antibody moiety that binds to an antigen preferentially expressed on the tumor cell surface, thereby ensuring specific binding to tumor cells; a covalent linker that warrants that the payload drug is not released in blood ahead of time, but is released within the tumor cell; and a cytotoxic payload that causes tumor cell apoptosis through targeting of key components such as DNA, microtubules. (C) ADC mechanism of action includes key sequential steps: binding to cell surface antigen; internalization of the ADC–antigen complex through endocytosis; lysosomal degradation; release of the cytotoxic payload within the cytoplasm; and interaction with target cell components. A fraction of the payload may be released in the extracellular environment and taken up by neighboring cells, known as the bystander effect.

Figure 2

Timeline of key events and discoveries in the antibody–drug conjugate research and development.^,−,−,−

Figure 3

Yearly growth of the number of documents (journal articles and patents) in the CAS Content Collection related to antibody–drug conjugate research and development.

Figure 4

Exemplary ADC linkers: (A) acid labile hydrazone linker; (B) enzyme cleavable Val-Cit linker; (C) glutathione-sensitive disulfide linker; (D) noncleavable maleimidomethyl cyclohexane-1-carboxylate (MCC) linker.

Figure 5

Top countries with respect to the number of ADC-related journal articles (blue) and patents (red).

Figure 6

(A) Top organizations publishing ADC-related journal articles. Top patent assignees of ADC-related patents from universities and (B) hospitals and (C) companies.

Figure 7

Top scientific journals with respect to the number of ADC-related (A) articles published and the (B) citations they received.

Figure 8

(A) Top patent offices receiving ADC-related patent applications. (B) Flow of ADC-related patent filings from different patent assignee locations (left) to various patent offices of filing (right). The abbreviations on the right indicate the patent offices of Hong Kong (HK), Australia (AU), Austria (AT), Argentina (AR), Taiwan (TW), Russian Federation (RU), Norway (NO), Colombia (CO), Portugal (PT), Costa Rica (CR), Cyprus (CY), Eurasian Patent Organization (EA), Philippines (PH), United States (US), World Intellectual Property Organization (WO), Israel (IL), Mexico (MX), Spain (ES), Canada (CA), European Patent Office (EP), Japan (JP), Brazil (BR), India (IN), South Korea (KR), Great Britain (GB), China (CN), Germany (DE), and France (FR).

Figure 9

Diseases explored in ADC-related publications: (A) cancers (Inset: Annual growth of the number of documents for the fastest growing solid and hematological cancers for the years 2018–2022); (B) other diseases.

Figure 10

Therapies explored in the ADC-related publications.

Figure 11

Drug delivery systems explored in the ADC-related publications.

Figure 12

ADC payloads explored in the scientific publications: (A) Number of publications exploring ADC payloads. (B) Trends in number of publications exploring ADC payloads during the years 2018–2022.

Figure 13

ADC target antigens explored in the scientific publications for solid tumors and hematological malignancies: (A) Number of publications exploring target antigens. (B) Trends in growth of publications exploring target antigens during the years 2018–2022.

Figure 14

ADC antibodies explored in the scientific publications: (A) Number of publications exploring ADC antibodies. (B) Trends in number of publications exploring ADC antibodies during the years 2018–2022.

Figure 15

Antibody-payload linker types explored in scientific publications.

Figure 16

Correlations between different concept pairings are shown as heat maps. ADC target antigens and (A) solid tumors and (B) hematological malignancies. (C) ADC antibodies and types of cancers and (D) ADC payloads and types of cancers (numbers represent percentage of documents related to the given disease). Darker shades correspond to a higher number.

Figure 17

(A) A word cloud of the most widely used ADC-related concepts in the CAS Content Collection. (B) Yearly growth in the number of documents (percentage) over the 2010–2022 period for ADC-related concepts.

Figure 18

ADC Concept Map. Size of the dot at each concept/topic corresponds to the number of documents (journals and patents) in the CAS Content Collection related to the given concept/topic.

Figure 19

Capital invested by global region for the period 2012–2022 in the antibody–drug conjugate field: (A) Venture capital investment. (B) Total capital investments.

Figure 20

Organizations conducting preclinical ADC research with the number of ADC candidates in their pipeline (left), target antigen (middle), and disease indication (right).

Figure 21

Number of ADC clinical trials by year.

Figure 22

(A) ADC clinical trial indications; (B) Percentage of ADC clinical trials in various phases for the treatment of solid tumors and hematological malignancies; (C) Percentage of ADC clinical trials in various statuses for the treatment of solid tumors and hematological malignancies.

Figure 23

Percentage of ADC clinical trials in various phases for the treatment of specific solid tumors and hematological malignancies.

Figure 24

Percentage of ADC clinical trials in various statuses for the treatment of specific solid tumors and hematological malignancies.