In recent years, with the continuous advancements in protein gene engineering and chemical conjugation technologies, the field of conjugated drugs has seen a blooming of diverse concepts, resulting in a trend where “everything can be conjugated.” A variety of emerging conjugated drug concepts have surfaced, sparking a new wave of research and development in this field.
Currently, the development of conjugated drugs has resulted in a dazzling array of ideas. In addition to ADCs (Antibody-Drug Conjugates), these include radionuclide conjugated drugs (RDC), small molecule drug conjugates (SMDC), peptide drug conjugates (PDC), antibody immune-stimulating conjugates (ISAC), antibody fragment drug conjugates (FDC), virus-like drug conjugates (VDC), antibody oligonucleotide conjugates (AOC), antibody-biopolymer conjugates (ABC), degradation-antibody conjugates (DAC), and more. This article briefly introduces some common types of conjugated drugs for reference.
Antibody-drug conjugates (ADCs)
Antibody-drug conjugates (ADCs) are arguably the most successful type of conjugated drug at present, not only with the highest number of approved drugs but also with clinical benefits and commercial potential that are highly anticipated. As of January 2025, a total of 17 ADCs have been approved globally, and more than 400 ADC candidates are in development, primarily targeting oncology, rare diseases, and hematological diseases. The design concept of ADCs is based on the targeted delivery of cytotoxic drugs to cancer cells via antibodies, reducing systemic exposure and improving safety. ADCs are typically composed of three parts: an antibody (targeting agent), a linker (connecting the antibody and the payload), and a cytotoxic payload (that kills tumor cells).
Peptide-Drug Conjugates (PDCs)
PDCs (Peptide-Drug Conjugates) consist of three components: peptides, cytotoxic drugs, and linkers. The peptides used in PDCs can be classified into cell-penetrating peptides (CPPs) and cell-targeting peptides (CTPs), which have high affinity for receptors overexpressed on tumor cell surfaces. The mechanism of action is that after the drug enters circulation, the peptide recognizes antigen epitopes on the tumor surface, and the tumor cells endocytose the cytotoxins. Once inside the cell, the linker releases the cytotoxin to kill the tumor cell.
Compared to ADCs, PDCs offer advantages such as smaller molecular weight, stronger tumor penetration, lower immunogenicity, large-scale synthesis using solid-phase peptide synthesis, lower production costs, and better pharmacokinetics.
Antibody fragment-drug conjugates (FDCs)
Antibody fragment-drug conjugates (FDCs), as the name suggests, replace larger antibody molecules with smaller antibody fragments (such as Fab, single-chain scFv, and nanobodies). Unlike ADCs, which use full monoclonal antibodies, FDCs conjugate antibody fragments with cytotoxic drugs. Due to their smaller size, FDCs offer better tissue penetration and lower immunogenicity compared to ADCs. Additionally, FDCs have a shorter half-life, which can reduce exposure to normal tissues and better control toxicity.
Immunostimulatory Antibody Conjugates (ISACs)
ISACs (Immunostimulatory Antibody Conjugates) have technical requirements similar to those of ADCs. However, ISACs consist of three parts: an antibody, a linker, and an agonist. The payload in ISACs is an innate immune agonist or modulator that can transform cold tumors into “hot” immune tumors. ISACs function as “spies” infiltrating the tumor, combining the precision of antibodies in targeting tumors with the tumor-killing potential of the immune system. This approach has shown complete tumor regression and lasting anti-tumor immunity in various tumor models, with the potential to convert cold tumors into immune-active tumors.
Currently, ISAC drugs in development include TLR (Toll-like receptor) agonist ISACs such as SBT6050, SBT6290, and BDC-1001; STING agonist ISACs like XMT-2056; and Treg cell modulating ISACs like ADCT-301. Overall, this novel ISAC approach demonstrates strong preclinical anti-tumor activity.
Small molecule-drug conjugates (SMDCs)
Small molecule-drug conjugates (SMDCs) are similar to ADCs, except that they use small molecule targeting ligands instead of antibodies. SMDCs consist of a small molecule targeting ligand (which is the most significant difference compared to ADCs), a linker, and a cytotoxic payload. The small molecule targeting ligand allows SMDCs to penetrate more easily and distribute more evenly into tumor tissues without accumulating in tumor or normal cells, and any off-target drugs are rapidly cleared from the body, reducing toxicity to normal cells. Furthermore, compared to antibody-based drugs, SMDCs are easier to synthesize, have lower production costs, and are less likely to have immunogenicity, making safety easier to control.
However, selecting appropriate small molecule ligands remains a challenge in SMDC development. These ligands are often derived from natural sources, such as folate derivatives targeting folate receptors or glutamyl urea derivatives targeting prostate-specific membrane antigens. The cytotoxic molecule is the core of SMDCs and is crucial for achieving clinical therapeutic value. The indications for SMDCs differ significantly from ADCs, with SMDCs focusing primarily on solid tumors, whereas ADCs are used for both solid and hematological cancers. SMDCs offer excellent cell penetration and stability in both in vitro and in vivo studies.
Currently, only a few SMDC products are active in the pipeline, and no SMDC product has been approved for marketing. Nine products are in clinical research, primarily targeting solid tumors. Except for Vintafolide, these products are still in early-stage development. Three are in phase II trials, and five are in phase I trials, with smaller biotech companies like Endocyte and Tarveda leading the development, while global pharmaceutical giants such as Merck, Novartis, and BMS are also involved.
Radionuclide Drug Conjugates (RDCs)
RDCs (Radionuclide Drug Conjugates) consist of an antibody or small molecule (which mediates targeting), a linker, a chelator, and a cytotoxic/imaging agent (radioactive isotope). RDCs are similar to ADCs in that they use antibodies or small molecules to mediate targeted delivery of cytotoxic or imaging agents (radioactive isotopes) to the tumor site, avoiding systemic exposure. The main difference is that the payload in RDCs is a radioactive isotope, which can be used for both diagnosis and therapy. RDCs also require a specific chelator functional group to be added to the toxin.
There are currently very few RDC drugs approved worldwide, and those in clinical trials are still limited. Most RDC drugs focus on oncology, and their therapeutic potential remains to be fully explored. RDCs have the potential for synergistic effects when combined with other anti-cancer drugs. With the involvement of international pharmaceutical giants and further product development, RDCs are expected to become a fast-growing field.
Aptamer-Drug Conjugates (ApDCs)
ApDCs (Aptamer-Drug Conjugates) replace the antibody in an ADC with an aptamer. The linker connects the aptamer to the drug, and the aptamer, as a recognition ligand, guides the drug to the disease site or regulates the biological function of a target biomarker. Aptamers are oligonucleotide sequences selected via Cell-SELEX, which can bind to various targets with high affinity and specificity. Compared to antibodies, aptamers offer several advantages:
- High screening efficiency (days to months);
- Aptamers can be used for antigens that are difficult to find corresponding antibodies for;
- Oligonucleotides are cost-effective to synthesize and have low batch-to-batch variability;
- Aptamers are easier to modify;
- They have better thermal and chemical stability;
- Smaller molecular weight and better tissue penetration;
- Almost no immunogenicity, avoiding immune-related side effects.
Antibody-oligonucleotide conjugates (AOCs)
Antibody-oligonucleotide conjugates (AOCs) use antibodies to deliver therapeutic oligonucleotides (such as siRNA, PMO) to specific cells or tissues, thereby reducing the amount of drug needed for treatment and solving issues related to oligonucleotide delivery. Conjugating oligonucleotides to targeting ligands can also improve the pharmacokinetics of therapeutic RNA or DNA molecules and expand their applications. Unlike ApDCs, AOCs are designed for targeted delivery of oligonucleotides. AstraZeneca has conducted research on related products. Technically, AOCs use antibodies as delivery media, and small molecules (including peptides) or proteins (such as enzymes) can also perform similar functions. Within this category, drugs that only use oligonucleotides as payloads can lead to various conceptual products.
Virus-like drug conjugates (VDCs)
Virus-like drug conjugates (VDCs) use virus-like particles (VLPs), which are non-infectious protein nanoparticles, as highly efficient delivery carriers. For example, Aura uses HPV-derived VLPs that selectively bind to modified heparan sulfate proteoglycans (HSPGs) on the surface of tumor cells, achieving targeted delivery to solid tumors while avoiding normal tissues. AU-011, a leading VDC candidate in Aura’s pipeline for choroidal melanoma, has received fast-track and orphan drug designations from the FDA and is currently in phase II clinical trials. AU-001, another VDC product, uses virus-like components that selectively bind to HSPGs, activating cytotoxic drugs upon infrared light activation to selectively destroy tumor cells, triggering an immune response for anti-tumor activity.
Kodiak Sciences, focusing on ophthalmic treatments, is developing KSI-301, an anti-VEGF large molecule phosphatidylserine-conjugated VDC drug candidate that targets retinal disease. The drug works by delivering payloads directly to the retinal target cells and is currently in phase III trials for the treatment of macular degeneration.
PROTAC
PROTAC stands for Proteolysis-Targeting Chimeras, a hybrid bifunctional small molecule compound that contains two different ligands: one is an E3 ubiquitin ligase ligand, and the other is a ligand that binds to the target protein in the cell. These two ligands are connected by a linker to form a “trimer” polymer—target protein ligand-Linker-E3 ligase ligand. PROTACs work by bringing the target protein closer to the intracellular E3 ubiquitin ligase, using the “ubiquitin-proteasome” pathway to specifically degrade the target protein. PROTACs can improve the druggability of traditionally undruggable targets. However, PROTACs have poor DMPK (drug metabolism and pharmacokinetics) properties, such as low oral bioavailability and/or rapid in vivo clearance, which pose significant obstacles to their development. Additionally, issues such as large molecular weight (700-1100 Da) and limited available E3 ligases further complicate the field.
Degrader-Antibody-Conjugate (DAC)
DAC (Degrader-Antibody-Conjugate) is a drug conjugate that is currently in the early stages of development. Its technological principle involves using a protein degrader as the payload, combining the tumor specificity of ADCs with the applicability of PROTAC molecules at low expression levels, thus enabling treatment of solid tumors.
Conclusion
In essence, most conjugated drugs aim to achieve targeted delivery through positioning ligands, with different functional effect molecules providing therapeutic value or clinical purposes. The product design concept follows the ADC model, with the difference being the variation in the three components (ligand-Linker-effect molecule). With technological advances and the proliferation of drug formats, there are now more choices for positioning ligands, linkers, and effect molecules. This has led to greater specialization within the field, resulting in the emergence of various forms of conjugated drugs, such as ADCs, RDCs, SMDCs, ISACs, DACs, PDCs, FDCs, VDCs, AOCs, and others.
Featured conjugates services at BOC Sciences
- Antibody-Drug Conjugates
- Antibody-Oligonucleotide Conjugates
- Peptide-Drug Conjugates
- Small Molecule-Drug Conjugates
- Peptide-Oligonucleotide Conjugates
- GalNAc-siRNA Conjugates
- Antibody-siRNA Conjugates
- Peptide-siRNA Conjugates
- Aptamer-Drug Conjugates
- Antibody-PNA Conjugates
- Targeted Protein Degradation Platform (PROTACs)
1. Image retrieved from Figure 1 “Drug conjugates are composed of 3 parts, carrier, linker and payload.,” Heh, Ethan, et al., 2023, used under [https://www.mdpi.com/openaccess).
2. Heh, Ethan, et al. “Peptide drug conjugates and their role in cancer therapy.” International Journal of Molecular Sciences 24.1 (2023): 829.