Antibody-Drug Conjugates (ADCs): current and future biopharmaceuticals

Abstract

Antibody-drug conjugates (ADCs) represent a novel class of biopharmaceuticals comprising monoclonal antibodies covalently conjugated to cytotoxic agents via engineered chemical linkers. This combination enables targeted delivery of cytotoxic agents to tumor site through recognizing target antigens by antibody while minimizing off-target effects on healthy tissues. Clinically, ADCs overcome the limitations of traditional chemotherapy, which lacks target specificity, and enhance the therapeutic efficacy of monoclonal antibodies, providing higher efficacy and fewer toxicity anti-tumor biopharmaceuticals. ADCs have ushered in a new era of targeted cancer therapy, with 15 drugs currently approved for clinical use. Additionally, ADCs are being investigated as potential therapeutic candidates for autoimmune diseases, persistent bacterial infections, and other challenging indications. Despite their therapeutic benefits, the development and application of ADCs face significant challenges, including antibody immunogenicity, linker instability, and inadequate control over the release of cytotoxic agent. How can ADCs be designed to be safer and more efficient? What is the future development direction of ADCs? This review provides a comprehensive overview of ADCs, summarizing the structural and functional characteristics of the three core components, antibody, linker, and payload. Furthermore, we systematically assess the advancements and challenges associated with the 15 approved ADCs in cancer therapy, while also exploring the future directions and ongoing challenges. We hope that this work will provide valuable insights into the design and optimization of next-generation ADCs for wider clinical applications.

Keywords: Antibody–drug conjugates; Clinical application; Cytotoxic agents; Linkers; Monoclonal antibody; Targeted therapy.

Fig. 1

The development of ADCs. a The development stages of ADCs. ADCs can be classified into four generations since the concept of “magic bullets” was proposed in 1906. b Key characteristics of approved ADCs. Currently, 15 ADCs are available on the market. Among them, 7 types of ADCs target tumor antigens of hematological malignancies (blue) and 8 target tumor antigens of solid tumor (brown). Thirteen of these ADCs belong to the IgG1 subclass (purple), and the remaining two belong to the IgG4 subclass (green). Linkers are categorized as either cleavable (curve lines) or non-cleavable (straight lines). Payloads include DNA-targeting agents (pentagram), pseudomonas aeruginosa exotoxin A (triangle), TOP 1 inhibitors (hexagon), tubulin binders (circular) and photosensitizers (square). The numbers associated with payloads represent the DAR

Fig. 2

The Mechanism of ADCs for anti-tumor through different approaches. ADCs couple highly specific mAbs to potent cytotoxic agents via chemical linkers. a The core mechanism of ADCs. ADC cytotoxicity involves a series of sequential processes: binding to cell-surface antigen, internalization of the ADC − antigen complex via endocytosis, subsequent lysosomal degradation, release of cytotoxic agents into the cytoplasm, and exertion of cytotoxic effects on target cells. b The bystander effect of ADCs. A portion of the payloads may be released into the extracellular environment and subsequently taken up by neighboring cells, including resistant or non-target cells. c Retention of mAb activity in ADCs. The mAbs in ADCs retain their ability to interfere with target function, inhibit downstream signaling pathway, and induce apoptosis. d Anti-tumor immunity effects of ADCs. ADC mAbs interact with immune effector cells to elicit ADCC, ADCP, and CDC effects. (by Fig Draw)

Fig. 3

Monoclonal antibodies in ADCs. a Upper: Key characteristics of monoclonal antibodies in ADCs. Lower: Human immunoglobulins (IgGs) include four subclasses (IgG1, IgG2, IgG3, and IgG4), which exhibit differences in their constant domain and hinge regions. Compared with IgG2 and IgG4, IgG1 demonstrates a comparable serum half-life but exhibits enhanced ADCC, ADCP, and CDC effects. b ZW49 is composed of an anti-HER2 biparatopic IgG1 antibody conjugated to a tubulin-binder auristatin payload (ZD02044) via a cleavable linker, with an average DAR of 2. c BL-B01D1 comprises a bispecific antibody against EGFR/HER3 conjugated to a novel TOP 1 inhibitor payload (Ed-04) via a cleavable linker, with an average DAR of 8. (by Fig Draw)

Fig. 4

Target antigens of ADCs. a Crystal structures of target antigens in marketed ADCs for treating hematological malignancies. b Crystal structures of target antigens in marketed ADCs for treating solid tumors. All crystal structures were obtained from the Protein Data Bank (PDB, https://www.rcsb.org/). c Distribution of target antigens among marketed ADCs, with HER2 being the most prominent target as it is recognized by three ADCs. d Distribution of target antigens among phase III ADCs, where HER2 remains the most highly focused target, accounting for eight out of 24 ADCs

Fig. 5

Classification of linkers in ADCs. Linkers of ADCs are classified into two categories: cleavable and non-cleavable linkers. Cleavable linkers consist of seven subtypes, which can be further divided into chemical cleavable and enzymatic cleavable linkers. In chemically cleavable linkers, the C-terminus of the hydrazone linker is conjugated to the cysteine residue of the antibody via an acetylbutyryl (AcBut) group, while its hydrazine terminus (NH-NH-R₃) is directly attached to the cytotoxic agent. For disulfide linkers, one sulfur atom originates from the cysteine residue of the antibody, whereas the other sulfur atom in the disulfide bridge stems from the thiol group of the cytotoxic agent. In Val-Cit and Val-Ala peptide linkers, the N-terminus (-NH₂) is covalently linked to antibody cysteine residues via a maleimide moiety, while the C-terminus (-COOH) is tethered to the cytotoxic agent through a PABC group. The N-terminus (-NH₂) of Gly-Gly-Phe-Gly is covalently conjugated to antibody cysteine residues via a maleimide moiety, while the C-terminus (-COOH) is connected to the cytotoxic agent through a PABC linker. In Glucosidase cleavable linkers, the C₁ hydroxyl group (-OH) is covalently attached to the PABC moiety, which cennects the cytotoxic agent to the antibody. The spacer serves as a crucial component of this linker type, meticulously engineered to ensure optimal length and flexibility for maintaining linker stability. Common spacer designs include alkyl chains, PEG, amino acid/peptide sequences, or aromatic moieties. In maleimidocaproyl linkers, the maleimide group facilitates site-specific conjugation to cysteine residues on the antibody and to the amino group of cytotoxic agents via the carboxyl group of the caproyl moiety. (http://pubchem.ncbi.nlm.nih.gov)

Fig. 6

“Bullets” for ADC payloads. a Characterization of payloads in ADCs. b Mechanism of tubulin binders in ADCs. Tubulin binders such as MMAE and MMAF inhibit tubulin polymerization, promote depolymerization, disrupt the dynamic equilibrium of microtubules, induce cell cycle arrest, and ultimately trigger apoptosis. c Mechanism of DNA-damaging agents in ADCs. DNA-damaging agents like calicheamicin and PBD inhibit DNA synthesis or cause structure disruption through mechanisms such as double-strand breaks, alkylation, and cross-linking, thereby inducing apoptosis. d Mechanism of Top1 inhibitors in ADCs. Top1 inhibitors such as DXd and SN-38 interfere with DNA transcription processes, leading to tumor cell apoptosis. e Mechanism of bacterial toxins in ADCs. The PE38 induces adenosine diphosphate (ADP) ribosylation, thereby blocking the elongation factor 2 (EF-2)-mediated peptide chain extension and inhibiting protein synthesis, which ultimately leads to cell apoptosis. f Mechanism of photosensitizers in ADCs. Near-infrared light irradiation activates the phototoxic properties of the photosensitizer IR700, enabling precise eradication of tumor cells. g Percentage distribution of marketed ADC payloads. Tubulin binders dominate this category, accounting for 53.3%. h Percentage distribution of phase III ADC payloads. Among these, Tubulin binders and Top1 inhibitors are the most prevalent payloads, representing 45.8% of the total

Fig. 7

Clinical applications of marketed ADCs. a ADCs for the treatment of hematological malignancies. Currently, Seven types of ADCs are available on the market for treating of six types of hematological malignancies, including acute myeloid leukemia, multiple myeloma, among others. b ADCs for the treatment of solid tumors. Eight types of ADCs are utilized in the treatment of solid tumors. Notably, disitamab vedotin is the most extensively used ADC for targeting HER2 in various cancers, such as breast cancer, gastric cancer, gastroesophageal junction cancer, lung cancer, and urothelial cancer