Overview of 10 Types of Drug Conjugates

Conjugated drugs, especially antibody-drug conjugates (ADCs), have spurred enthusiasm for mergers and acquisitions between companies due to their clinical results and potential commercial value, drawing widespread attention within the industry. Technological advancements have also led to a convergence of new and traditional concepts in conjugated drug development, even challenging current ideas and technologies in this field. Today, beyond ADCs, the development of conjugated drugs includes radionuclide-drug conjugates (RDCs), small-molecule drug conjugates (SMDCs), peptide-drug conjugates (PDCs), immunostimulatory antibody-drug conjugates (ISACs), antibody fragment-drug conjugates (FDCs), antibody-cell conjugates (ACCs), virus-like drug conjugates (VDCs), antibody-oligonucleotide conjugates (AOCs), and antibody-biopolymer conjugates (ABCs). Furthermore, innovative formats such as antibody-degrading conjugates (ADeCs) and prodrug conjugates (Pro-DCs) continue to emerge.

What are Drug Conjugates?

Drug conjugate technology is an advanced drug delivery strategy that combines a drug with a carrier molecule to form a drug conjugate, enabling targeted delivery and controlled release of the drug. This technology has made significant breakthroughs in drug development and shows immense potential in clinical applications. By using specific linkers (often chemical chains) to connect targeting ligands with therapeutic molecules, drug conjugates are designed to deliver therapeutic agents specifically to disease sites. This approach can be summarized by the formula "Targeting Ligand-Linker-Therapeutic Molecule," and, depending on the type of targeting ligand, drug conjugates can be further categorized into types such as ADC, PDC, PDC, SMDC, polymer-drug conjugates, radionuclide-drug conjugates, and virus-like drug conjugates.

Fig. 1. Drug conjugates (Int J Mol Sci. 2023, 24(1): 829).

Chemical Structures of Drug Conjugates

The core concept of drug conjugate technology is to chemically link a drug with a carrier molecule to form a stable complex. This chemical bond may be a covalent, ionic, or other type of bond. The formation of a drug conjugate enables the drug to share the properties of the carrier, allowing targeted delivery to disease sites. Such targeted delivery enhances the drug concentration at the disease site while reducing distribution to healthy tissues, thus improving the drug's efficacy. Based on their chemical structure, drug conjugates can be classified as follows:

• Targeted Drug Conjugates (TDCs): These conjugates attach drugs to molecules targeting specific tumor cell surface structures, enabling selective tumor cell destruction. Common targeting molecules include antibodies, antibody fragments, and ligands. TDCs increase drug efficacy while reducing toxicity to normal cells by targeting specific molecular structures.
• Carrier Drug Conjugates (CDCs): These conjugates link drugs to carrier molecules, which aid in delivery and release of the drug. Common carriers include polymers, nanoparticles, and liposomes. CDCs enhance drug solubility, stability, and targeting, thereby improving therapeutic effects.
• Dual Drug Conjugates (DDCs): These conjugates connect two different drug molecules to achieve a synergistic therapeutic effect. Examples include combinations of antitumor drugs with immunomodulators or antiviral drugs with anti-inflammatory agents. DDCs enhance treatment efficacy through drug synergy and reduce the risk of resistance.

PEG linkers for Drug Conjugates

Polyethylene glycol (PEG) linkers are vital in drug conjugation, enhancing solubility, stability, and biodistribution. Their unique properties reduce drug immunogenicity and improve pharmacokinetics, enabling targeted delivery and minimizing damage to normal tissues. Additionally, PEG linkers prevent degradation, prolonging drug half-lives. BOC Sciences offers high-quality PEG linkers, including linear, branched, and functionalized variants, to meet diverse drug development needs, ensuring optimal outcomes in therapeutic applications.

Advantages of Drug Conjugates

• Drug conjugates offer highly selective targeting. By binding drugs to specific carrier molecules, drug conjugates can precisely target diseased cells or tissues, reducing the toxic effects on normal cells and thus minimizing adverse reactions and side effects. Selective targeting enables drug conjugates to work more effectively on diseased tissue, enhancing therapeutic outcomes.
• Drug conjugates can activate the release of drugs in targeted areas. They are often designed to release drugs under specific conditions, such as within tumor cells or unique physiological environments. This activation mechanism ensures that drugs are released at the intended time and place, maximizing efficacy. By controlling drug release, drug conjugates reduce degradation and excretion of the drug within the body, extending its action time.
• Drug conjugates can simultaneously carry multiple drugs. By combining different drugs, these conjugates can achieve multi-functional therapeutic effects. This approach allows for combination therapy, improving drug efficacy and reducing the occurrence of drug resistance. This multi-drug capability provides new strategies for treating complex diseases.
• Finally, drug conjugates exhibit favorable stability and pharmacokinetics. Chemical modifications or structural optimizations improve their stability and pharmacokinetic properties, extending their half-life in the body, enhancing bioavailability, and boosting therapeutic impact.

Types of Drug Conjugates

Currently, drug conjugates retain a uniform composition of "Targeting Ligand-Linker-Therapeutic Molecule." As technology advances, the diversity of targeting ligands, linkers, and therapeutic molecules has led to further specialization in the field, resulting in formats such as ADC, RDC, SMDC, ISAC, ADeC, PDC, FDC, VDC, AOC, and more. Among these, ADCs, RDCs, SMDCs, and ISACs are currently the most successful types, with several of them either on the market or showing promising clinical results.

Antibody-Drug Conjugates

Antibody-drug conjugates (ADCs) are currently the most successful type of conjugate drugs, with the highest number of approved drugs, as well as promising clinical benefits and commercial potential. The design concept of ADCs is to use the targeting ability of antibodies to deliver cytotoxic drugs directly to cancer cells, reducing systemic exposure and improving safety. ADCs are composed of three main components: an antibody (for targeted delivery), a linker (to connect the antibody and payload), and a payload (to kill tumor cells). ADCs are the most extensively researched conjugate drugs; however, as clinical data for drugs developed with advanced technologies increases, ADCs are facing significant challenges.

Fig. 2. ADC structure (Drug Discovery Today: Technologies. 2018, 30: 71-83).

First, it is commonly believed that antibody targets should exhibit good internalization capabilities and speed, but antibody immune-stimulating conjugates (ISACs) suggest that target protein internalization may not be necessary. Second, traditionally, antigens were required to be overexpressed with little or no expression in normal cells, but a subgroup analysis of Vidicitumumab at this year's ASCO conference showed nearly consistent benefits in both HER2-positive and HER2-low-expressing breast cancer, as well as similar findings for Enhertu in HER2-positive and HER2-low tumor types. Third, the range of payload types has expanded significantly, and they are not limited to cytotoxic agents. Immune stimulants and modulators (such as STING, TLR, and Treg agents), protein degraders (e.g., PROTACs), and oligonucleotides are also showing preliminary efficacy in clinical or preclinical studies. As of December 2023, 244 ADC drugs globally have entered clinical trial phases, with 15 approved for marketing, 2 under market application, 16 in phase III trials, and most others in early clinical stages. ADC drug targets are diverse, with HER2 and Trop2 currently being the most crowded targets, as they are both clinically validated. According to Frost & Sullivan, the global ADC market is projected to reach USD 20.7 billion by 2030.

Peptide-Drug Conjugates

The concept of peptide-drug conjugates (PDCs) is to link cell-targeting peptides with drug molecules, enhancing the drug's specificity by concentrating it in target tissues, thereby reducing its relative concentration in other tissues, increasing efficacy, and minimizing adverse effects. Peptides used in PDCs fall into two categories: cell-penetrating peptides (CPPs) and cell-targeting peptides (CTPs), both of which exhibit high affinity for receptors overexpressed on the surface of tumor cells. PDCs integrate the advantages of peptides, offering a low molecular weight (typically under 3 kD), biodegradability, and minimal immunogenicity.

Fig. 3. PDC structure (Int J Mol Sci. 2023, 24(1): 829).

By modifying the amino acid sequence of the peptide chain, PDCs can alter the conjugate's hydrophobicity and ionization properties, addressing challenges like poor solubility and delayed metabolism while enhancing cell penetration. This approach helps overcome the high failure rate associated with small-molecule drugs in clinical development due to suboptimal physicochemical properties. Additionally, the low molecular weight of PDCs makes them more amenable to purification via high-performance liquid chromatography (HPLC), which is also essential in pharmacokinetics.

Fragment-Drug Conjugates

Antikor Biopharma pioneered the development of fragment-drug conjugates (FDCs). Unlike ADCs, which use full monoclonal antibodies, FDCs link antibody fragments with cytotoxic drugs. Due to the smaller molecular weight of antibody fragments, FDCs demonstrate improved tumor penetration. Additionally, FDCs have a shorter half-life than ADCs, which helps reduce exposure in normal tissues and better controls toxic side effects. Antikor's OptiLink technology systematically analyzes and optimizes linkers between antibody fragments and toxins. By altering the chemical structure and length of linkers, and adding PEG polymers to the conjugate, this technology precisely adjusts the drug-to-antibody fragment ratio (DAR), druggability, efficacy, and safety of FDCs.

Immune-Stimulating Antibody Conjugates

Immune-stimulating antibody conjugate (ISAC) is composed of a tumor-targeting monoclonal antibody conjugated with an immune agonist via a non-cleavable linker. This design combines the antibody's precision in targeting tumors with the cytotoxic potential of the innate and adaptive immune systems in a single drug, achieving complete tumor regression and long-lasting anti-tumor immunity in various tumor models. Drugs utilizing this mechanism currently include Toll-like receptor (TLR) agonist ISACs such as SBT6050, SBT6290, and BDC-1001; STING agonist ISACs like XMT-2056; and Treg cell-modulating ISACs such as ADCT-301. However, many companies still categorize these agents as ADCs, likely because the external characteristics and underlying technology of ISACs and ADCs are quite similar.

Antibody-Biopolymer Conjugates

Kodiak Sciences, focusing on ophthalmic treatments, is developing an anti-VEGF macromolecular phosphorylcholine polymer conjugate, KSI-301, using its proprietary antibody biopolymer conjugate (ABC) technology platform. This conjugate is aimed at treating wet age-related macular degeneration, diabetic macular edema, and retinal vein occlusion, and is currently in Phase III clinical trials. By conjugating biopolymers with antibodies, Kodiak Sciences has extended the drug's half-life within the eye, significantly reducing injection frequency while enhancing therapeutic efficacy.

Small Molecule-Drug Conjugates

Small molecule-drug conjugates (SMDCs) have a composition similar to ADCs, comprising a targeting molecule, linker, and effector molecule (cytotoxic agent or E3 ligase). The key difference between SMDCs and ADCs lies in the targeting molecule: while ADCs use antibodies for targeting, SMDCs utilize small molecules. Compared to antibody drugs, SMDCs offer advantages in terms of synthesis control, cost-effectiveness, and ease of industrial production. Theoretically, SMDCs lack immunogenicity, making safety control easier to manage. SMDCs also show strong cell penetration in solid tumors, along with good stability both in vitro and in vivo.

Fig. 4. Structure of SMDC (Eur J Med Chem. 2019, 163: 883-895).

Currently, there are relatively few active SMDC products in development, with limited target diversity and none yet approved for market release. Nine products are in clinical research, focusing mainly on solid tumor indications. Besides Vintafolide, most of these are in early-stage development, with three in Phase II clinical trials and five in Phase I. These SMDCs are primarily being developed by smaller biotech firms such as Endocyte and Tarveda, with participation from global pharmaceutical giants like Merck, Novartis, and BMS.

Radioligand-Drug Conjugates (RDCs)

Radioligand-drug conjugates (RDCs) consist of a targeting agent, such as an antibody or small molecule, a linker, a chelator, and a cytotoxic or imaging agent (radioisotope). By leveraging the targeting action of antibodies or small molecules (including peptides), RDCs enable precise radiotherapy, delivering high-dose radiation to tumors while minimizing exposure to normal tissues, thereby reducing side effects. The primary distinction between RDCs and ADCs or SMDCs is in the payload: RDCs use radionuclides instead of small molecules. Different medical radionuclides can be used for imaging or therapeutic purposes, and some radionuclides possess both capabilities. Currently, very few RDC drugs have been approved globally, and there are limited ongoing clinical studies in this area. RDCs primarily target cancer indications, with substantial potential yet to be explored. They also hold promise for synergy with various anticancer drugs, enhancing treatment effectiveness in combination therapies. As international pharmaceutical leaders join the field and expand product pipelines, RDCs are anticipated to become a new and rapidly advancing sector in drug development.

Virus-Like Drug Conjugates

Virus-like drug conjugates (VDCs) couple a potent cytotoxic agent that can be activated by infrared light. Once activated, VDCs generate high levels of singlet oxygen, selectively destroying tumor cells, leading to acute necrosis of these cells. The death of immunogenic cells can activate the immune system to generate an antitumor response. This dual mechanism can be employed for the early treatment of primary lesions and can induce a lasting antitumor immune response to prevent distal metastasis of cancer cells. AU-011 is a leading candidate VDC therapy from Aura's pipeline for the first-line treatment of choroidal melanoma. It has received Fast Track designation and Orphan Drug status from the U.S. Food and Drug Administration and is currently in Phase II clinical trials.

Antibody-siRNA Conjugates

The scientific research utilizing antibodies to deliver siRNA dates back 15 years, when Professor Judy Lieberman's research group at Harvard University fused antibodies with protamine, a positively charged protein, to load negatively charged siRNA. As the technology matured, Genentech utilized Thiomab technology in 2015 to specifically couple and deliver siRNA, marking the first attempt to directly conjugate siRNA onto antibodies. This approach demonstrated intra-tumoral delivery and gene silencing effects in mouse tumor models.

Antibody-Oligonucleotide Conjugates

Antibody-oligonucleotide conjugates (AOCs) refer to the use of antibodies to deliver therapeutic oligonucleotides (such as siRNA and PMO) to specific cells or tissues, thereby reducing the amount of drug needed to treat diseases and addressing the challenges of targeting and delivering oligonucleotides. The conjugation of oligonucleotides with targeting ligands can also improve the pharmacokinetic properties of oligonucleotides (therapeutic RNA or DNA molecules) and expand their applications. Unlike aptamer drug conjugates (ApDCs), the goal of AOCs is to achieve targeted delivery of oligonucleotides. AstraZeneca has previously conducted research on related products. Technically, AOCs use antibodies as delivery vehicles, but small molecules (including peptides) and proteins (such as enzymes) can also fulfill similar functions. If further specified, drug products solely utilizing oligonucleotides as the payload can lead to various conceptual products. Avidity has also developed the AOC product AOC1001 based on this concept for the treatment of Myotonic Dystrophy Type 1 (DM1) and plans to initiate related clinical studies in the second half of 2021.

In Conclusion

As the technology of drug conjugates continues to advance, the selection of targeting ligands, effector molecules, and linkers will become increasingly diverse. Drug conjugate technology represents a drug delivery strategy with enormous potential. By coupling drugs with carrier molecules, drug conjugates can achieve targeted delivery and release of the drug, enhancing its efficacy while reducing side effects. With ongoing technological developments and improvements, we can expect to see more types of drug conjugates approved for clinical use in the future, and the next generation of drug conjugates will continue to bring new hope to patients.

BOC Sciences specializes in providing high-quality PEG linkers for drug conjugate development. Our extensive range includes linear, branched, and functionalized PEG linkers tailored to enhance solubility, stability, and targeting efficacy. With expertise in custom synthesis, we ensure that our linkers meet specific therapeutic requirements while adhering to cGMP and stringent quality control. We also offer technical support and consultation services to assist clients throughout the drug conjugate development process. BOC Sciences is committed to advancing innovative therapies through our PEG linker solutions.

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References

1. Heh, E. et al. Peptide Drug Conjugates and Their Role in Cancer Therapy. Int J Mol Sci. 2023, 24(1): 829.
2. Jackson, Paul J.M. et al. Use of pyrrolobenzodiazepines and related covalent-binding DNA-interactive molecules as ADC payloads: Is mechanism related to systemic toxicity? Drug Discovery Today: Technologies. 2018, 30: 71-83.
3. Zhuang, C. et al. Small molecule-drug conjugates: A novel strategy for cancer-targeted treatment. Eur J Med Chem. 2019, 163: 883-895.