The clinical results and potential commercial value of drug conjugates, especially antibody drug conjugates (ADCs), have fueled the enthusiasm for M&A deals between companies and attracted widespread industry attention. Technological advances have also led to a collision of old and new concepts of drug conjugates, challenging even the current stage of drug conjugates concepts and technologies.
Nowadays, the development of drug conjugates has emerged with a dazzling variety of wild ideas, including, in addition to antibody drug conjugates (ADCs), radionuclide drug conjugates (RDC), small molecule-drug conjugates (SMDC), peptide-drug conjugates (PDC), immune-stimulating antibody conjugate (ISAC), antibody fragment-drug conjugates (FDC), antibody-cell conjugate (ACC), virus-like drug conjugates (VDC), antibody-oligonucleotide conjugates (AOC), antibody-biopolymer conjugates (ABC), etc. Furthermore, new technology forms such as antibody degraducer conjugates (ADeC) and pro-drug conjugates (Pro-DC) are still emerging. In this paper, we briefly introduce the technical features and representative project development progress of several types of drug conjugates for your reference.
Antibody drug conjugates (ADCs) are probably the most successful class of drug conjugates at this stage, with not only the largest number of drugs on the market, but also promising clinical benefits and commercial value. ADCs are designed to reduce systemic exposure and improve safety by bringing cytotoxic drugs around cancer cells based on antibody targeting. The drug consists of three main components: antibody (targeting), linker (links the antibody to the payload), payload (killing tumor cells).
ADCs are the most well-studied, but have been challenged the most as clinical confirmatory data increase for drugs based on more advanced technology development. First, the general consensus is that antibody targets should have good internalization and speed, but immune-stimulating antibody conjugates (ISACs) suggest that target protein endocytosis may not be required. Second, the traditional view is that antigens must be overexpressed and normal cells not or under-expressed, whereas subgroup analysis of disitamab vedotin at this year's ASCO meeting showed almost consistent benefit in HER2-positive and HER2-low expressing breast cancers, as well as benefit of Enhertu also in HER2-positive and HER2-low expressing tumor species. Third, the variety of effective molecules is already abundant and does not necessarily require cytotoxicity, drugs such as immune agonists and modulators (STING, TLR, Treg), proteolysis targeting chimeras (Protac), and oligonucleotides are also showing preliminary effectiveness in clinical or preclinical studies.
As of June 2021, a total of 12 ADCs have been approved for marketing worldwide, with one additional drug application for marketing, and more than 100 ADC programs in clinical development.
Although there are many ADC programs in development, the targets of these drugs are still highly concentrated, and the concentration of targets in China is consistent with the global level. This is a good indication that innovative targets are still extremely scarce after the resolution of coupling technologies, which may be one of the reasons for the dazzling variety of coupling drug technologies.
Radionuclide drug conjugates (RDC) is similar to ADC in that they use antibody or small molecule (including peptides) mediated location to precisely target cytotoxic/imaging factors (radionuclide radioisotope) to avoiding the potential hazards of systemic exposure. The difference is that the RDC payload is a radionuclide, which can be used for both diagnostic and therapeutic functions. The composition of RDC also differs slightly from that of ADC, requiring the addition of a specific functional group structure (Chelator) that chelates the toxin. In general, it still consists of a ligand-linker-payload.
Novartis is a leader in RDC drugs, having acquired Advanced Accelerator Applications for $3.9 billion in 2017 for its radionuclide drug conjugate Lutathera (lutetium Lu 177 dotatate), which was successfully launched and has also achieved notable commercialization success. The acquisition of Endocyte for $2.1 billion in October 2018 resulted in another acquisition of its small molecule targeted radiotherapy prostate cancer drug 177Lu-PSMA-617.
Small molecule-drug conjugates (SMDCs) are also usually composed of a target molecule, a linker and an effector molecule (cytotoxic, E3 ligase, etc.).
In fact, the current over-segmentation in the field of drug conjugates has led to crossover between different concept drugs as well. For example, peptide drug conjugates (PDCs), more often than not, still belong to the small molecule-drug conjugates. Like lutathera and 177Lu-PSMA-617, although they are classified as RDCs based on toxins, their targeted ligands all belong to the small molecule field. Recently, PEPAXTO was approved for marketing and Oncopeptides positioned it as a peptide drug conjugate, but its molecular structure is not the usual form of drug conjugates composition, or it may belong to pro-drug conjugate (Pro-DC) or pro-drug, which breaks down into Melphalan around cancer cells to achieve tumor-killing effect like alkylating agents.
The technical requirements of immune-stimulating antibody conjugate (ISAC) are very similar to those of ADC, except that loads of ISAC are innate immune agonists or modulators that enable the ability to convert cold tumors into immune hot tumors. Also, similar in function to the tumor microenvironment-activated drug conjugate (TMAC) in part, both achieve activation of immune killing and therapeutic sensitization by modulating immune stimulation and microenvironment.
Currently, drugs involved in such mechanisms mainly include the class of Toll-like receptor (TLR) agonist ISACs SBT6050, SBT6290, BDC-1001, STING agonist ISAC XMT-2056, and Treg cell regulatory ISAC ADCT-301, etc. However, many of these drugs are also defined as ADCs by the companies themselves, perhaps also because there are not too many differences between the two in terms of drug outward performance and technology.
On June 16, Debiopharm, a Swiss company, and Ubix Therapeutics, a Korean company, jointly announced a research collaboration to develop antibody degraducer conjugates (ADeC), combining their proprietary technology platforms Multilink™ and Degraducer®.
This collaboration has just begun and perhaps the drug in question has not yet been investigated. However, based on their platform technologies, it is predicted that the ADeC to be developed will be an ADC that replaces the payload with a degradation molecule, perhaps carrying other payloads as well for synergistic effects. ADeC aims to carry degradation molecules to the target site to avoid systemic exposure and even to overcome some problems of potential drugable of Protac molecules, such as physicochemical defects, specificity, PK, etc.
Antibody fragment drug conjugates (FDC), as the name implies, using smaller antibody fragments (single stranded scFv) to replace larger antibody molecules. It is generally believed that antibody fragments are relatively easy to discover and can use bioengineering to achieve higher DAR.
FDC and ADC are technically almost identical, but the use of smaller fragment antibodies is expected to improve tumor penetration and maximize efficacy of drugs. Small fragments and lack of fragment crystallizable (Fc) allow for rapid clearance in normal tissues and circulation with reducing toxicity.
Aptamer drug conjugate (ApDC) is a form of drug conjugates that uses a structured oligonucleotide sequence to target a corresponding molecule. Nucleic acid aptamers are known as “chemical antibodies” and have similar targeting and target binding properties to antibodies. Compared to antibodies, nucleic acid aptamers have many advantages, such as high stability, low immunogenicity, low production cost and easy chemical modification.
Since ApDCs use oligonucleotide sequences, they may differ from ADCs in terms of linker and coupling strategies, but they do not differ much from ADCs in terms of drug composition, action mechanism and payloads.
Virus-like drug conjugates (VDCs) are drug conjugates that employ viral capsids designed as non-infectious protein nanoparticles (virus-like particles, VLP) as efficient delivery payloads.
Aura uses VLP derived from human papillomavirus or HPV to selectively attach to the surface of modified heparan sulfate proteoglycan (HSPG) to achieve binding to solid tumor cells or metastases without binding to normal tissue. AU-001 is a VDC product of this mechanism. The virus-like component selectively binds HSPG, and the coupled infrared light-activated cytotoxic drugs are activated to selectively destroy tumor cells, leading to acute necrosis of tumor cells while activating the immune system to generate an anti-tumor response.
Antibody oligonucleotide conjugates (AOCs) refer to the use of antibodies to deliver therapeutic oligonucleotides (siRNA, PMO, etc.) to specific cells or tissues, thereby reducing the amount of drug needed to treat a patient's disease as well as solving the problem of non-targeting and oligonucleotide delivery. The coupling of oligonucleotides with targeting ligands can also improve the pharmacokinetic properties of oligonucleotides (therapeutic RNA or DNA molecules) and expand their applications. In contrast to ApDC, AOC aims to enable targeted delivery of oligonucleotides, and AstraZeneca has conducted studies on related products. In technology, AOC uses antibodies as delivery medium, and it is assumed that small molecules (including peptides), proteins (enzymes), etc. can also perform related functions. When subdivided, drugs with oligonucleotides alone as the load also give rise to a variety of conceptual products.
Avidity has developed the AOC product AOC1001 based on this concept for the treatment of myotonic dystrophy type 1 (DM1) disease, and plans to conduct related clinical studies in the second half of 2021.
To summarize, at this stage, drug conjugates still retain the same composition, that is the form of targeted ligand-linker-effector. As a result of technological advances and the boom in drug forms, more options for targeted ligands, linkers and effector molecules have been realized, resulting in the segmentation of the field and the emergence of numerous expressions of drug conjugates such as ADC, RDC, SMDC, ISAC, ADeC, PDC, FDC, VDC, AOC, etc. However, excessive segmentation has also caused confusion in product concepts, with different companies defining the same product differently, and the prosperity is dazzling.
Essentially, most drug conjugates take the targeted ligand to achieve the targeting purpose and different functional effector molecules to achieve the therapeutic value or clinical purpose. The product design concept continues the idea of ADCs, differing in the transformation of the three class of component (ligand-linker-effector). However, ADC, RDC, SMDC, and ISAC are still the most successful types of drug conjugates. There are already related drugs on the market or multiple clinical drugs in proof of concept, while other drug conjugates are still more in the conceptual or preclinical stage, and it remains to be observed whether the clinical value can be realized.