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Acid labile linkers are a critical component in antibody-drug conjugates (ADCs) for achieving precise drug release. These pH-sensitive cleavable linkers remain stable in plasma while rapidly cleaving in the acidic environment of tumor cells to release cytotoxic payloads. This mechanism improves the therapeutic index of ADCs and reduces off-target toxicity. This article systematically explores the definition, common chemical structures, mechanisms of action, and development challenges of acid labile linkers. It also discusses optimization strategies and clinical examples, providing ADC researchers with design and application references to support efficient and precise drug delivery.

ADC linkers are a critical component of antibody-drug conjugates (ADCs). They not only connect the antibody to the active drug but also directly influence the ADC’s in vivo stability, drug release efficiency, and therapeutic index. Selecting an appropriate linker requires a comprehensive evaluation of the drug’s chemical properties, the antibody structure, and the target tissue environment. Different types of linkers, such as cleavable and non-cleavable linkers, or functionalized specialized linkers, each offer advantages in drug release mechanisms, blood stability, and off-target toxicity control. This guide systematically analyzes the classification, design strategies, and optimization methods of ADC linkers, helping researchers understand the characteristics, application scenarios, and key considerations for each type, thereby enabling efficient and safe ADC development and enhancing the success rate of translational research and clinical applications.

ADC linkers are the key chemical structures in antibody–drug conjugates (ADCs) that connect monoclonal antibodies with cytotoxic drugs (payloads). They not only affect the stability of the drug in vivo but also determine the manner and timing of active payload release. According to different release mechanisms, ADC linkers can be divided into two major categories: cleavable and non-cleavable. Cleavable linkers can break under specific biochemical conditions inside target cells, enabling rapid drug release; non-cleavable linkers rely on antibody degradation to release the drug and maintain higher stability in circulation. Understanding the structural characteristics, release mechanisms, and clinical application differences of these two types of linkers is of great significance for optimizing ADC design, improving efficacy, and ensuring safety.

Ovarian cancer stands as one of the deadliest malignant tumors affecting the female reproductive system. Its asymptomatic early stages lead to most patients receiving diagnoses at advanced stages, which complicates treatment and worsens prognosis. Even though ovarian cancer treatment has seen successes through surgery and chemotherapy procedures, major clinical challenges still exist due to high recurrence rates and drug resistance. Antibody-Drug Conjugates (ADCs) have gained recognition as a promising targeted therapy in cancer research during recent years. It fuses monoclonal antibodies with cytotoxic medications to deliver targeted cancer treatment while protecting healthy tissues from damage. The article will analyze how ADCs are used to treat ovarian cancer along with their influence on patient outcomes and will examine potential future research paths.

In the past few decades, immunotherapy has emerged as a significant breakthrough in cancer treatment. By activating the body's immune system to recognize and attack cancer cells, immunotherapy has provided new hope for patients who do not respond to conventional treatments. Bispecific antibody-drug conjugates (Bispecific ADCs), a novel branch of immunotherapy, are gradually demonstrating their unique advantages and immense potential. This article will delve into the role of bispecific ADCs in modern immunotherapy, including their structure, mechanism of action, comparison with monoclonal antibodies, and their current clinical applications and future prospects.

The global medical community has been battling cancer as a significant challenge for many years. Traditional cancer treatments, including surgery, radiotherapy, and chemotherapy, provide some control over tumor development and spread. However, these treatment approaches frequently produce intense side effects and fail to effectively control advanced or resistant cancer types. Recent biotechnology advances have led to the development of Antibody-Drug Conjugates (ADCs) as cutting-edge targeted cancer treatments that show great promise. This article examines Trop-2 ADCs by exploring their exceptional benefits for cancer treatment alongside current research developments and potential future advancements.

Antibody-drug conjugates (ADC) are novel cancer treatments that deliver the specificity of monoclonal antibodies and the cytotoxicity of small molecules. It's a unique combination that lets ADCs give cancer cells lethal doses of chemotherapy, but without damaging healthy tissue, and reduces the systemic toxicity of traditional chemotherapy. In recent decades, ADCs have evolved, from their first design to the next generation of products that are set to revolutionise cancer treatment.

Antibody-Drug Conjugates (ADCs) are now a new and powerful therapy in contemporary medicine and the mainstay of cancer therapy and drug discovery. ADCs are able to combine the selective ability of monoclonal antibodies with the powerful cytotoxicity of small molecules to achieve targeted elimination of cancer cells with minimum disruption of healthy tissue. But as great as they are, the growth of the ADC market has been a very challenging process. In this article, the current scenario, market trends, prospects, and threats of the ADC market are discussed in detail to provide an in-depth insight to market players and interested parties.

Antibody-Drug Conjugates (ADCs) have emerged as an innovative therapeutic approach in cancer treatment in recent years. The basic principle behind ADCs is to link antibodies with cytotoxic drugs through a linker, allowing the drug to be selectively delivered to tumor cells, thus enhancing therapeutic efficacy and reducing toxicity to healthy cells. In the design of ADCs, the linker plays a critical role, determining the drug's selectivity, stability, and efficacy. The valine-citrulline (Val-Cit) linker has become a key focus in ADC research due to its advantages in stability and selective degradation.

In recent years, the development of various forms of conjugated drugs has flourished, with Antibody-Drug Conjugates (ADCs) leading the way in achieving significant success in cancer treatment. ADCs are a targeted therapy platform that combines monoclonal antibodies with cytotoxic drugs, designed to specifically recognize tumor cells through antibodies and deliver drugs precisely to the lesion site. SPDB (N-Succinimidyl 4-(2-pyridyldithio)butyrate) is a bifunctional chemical linker that facilitates stable drug conjugation and targeted release through its unique disulfide bond structure. Owing to its reduction sensitivity, stability, and broad chemical compatibility, SPDB has been widely employed in ADC research.

Antibody-Drug Conjugates (ADCs) are a class of emerging anticancer drugs that deliver highly cytotoxic molecules directly to cancer cells. To date, 15 ADC drugs have been approved for the market. ADCs are composed of monoclonal antibodies and cytotoxic drugs covalently linked via a linker. Research has shown that the linker plays a crucial role in ADC drugs, as its properties significantly impact the therapeutic indices, efficacy, and pharmacokinetics of these drugs. A stable linker can maintain the drug concentration in the bloodstream and prevent premature drug release before the cytotoxic agent reaches its target, resulting in minimal off-target effects and improved safety of the ADC drug.

Prostate cancer is one of the most common cancers among men worldwide, and its incidence is rising annually with the aging global population. While traditional treatments such as surgery, radiation therapy, and chemotherapy are effective in the early stages, their effectiveness significantly decreases for patients with advanced and drug-resistant prostate cancer. In recent years, Antibody-Drug Conjugates (ADCs) have emerged as a novel targeted therapy, becoming an important research direction in cancer treatment. ADCs combine the targeting characteristics of monoclonal antibodies with the toxic effects of chemotherapy drugs, allowing for more precise and effective treatment, especially showing promising clinical prospects in prostate cancer therapy.

Antibody-Drug Conjugates (ADCs) are targeted cancer therapies that combine monoclonal antibodies with cytotoxic payloads via chemical linkers. These therapies have been approved for the treatment of various cancers and are currently undergoing extensive clinical development for new structures. Brain cancer, particularly malignant types such as glioblastoma, is one of the most aggressive and recurrent forms of cancer. These cancers show significant resistance to conventional treatments such as radiotherapy and chemotherapy, making new therapeutic approaches urgently needed. ADCs' unique mechanism allows them to efficiently target tumor cells while minimizing damage to surrounding healthy tissues, which enhances their potential for brain cancer treatment.

In recent years, with the rapid development of molecular targeting, immunotherapy, and Antibody-Drug Conjugates (ADCs), clinical efficacy has been continuously updated, benefiting more and more cancer patients. Lung cancer treatment methods are evolving rapidly and are at the forefront of precise treatment for solid tumors. Therefore, the research progress of ADCs in the lung cancer field continues to attract industry attention. Currently, in the lung cancer field, ADC drug exploration targeting biomarkers such as TROP2, HER2, HER3, B7-H3, EGFR, and c-MET has already taken the lead. It is also worth noting that in addition to the progress of ADC monotherapy, studies on TROP2-targeted ADC drugs combined with immunotherapy are particularly abundant. Related results may further enrich the first-line treatment options for advanced non-small cell lung cancer.

Since 2000, with the FDA approval of Mylotarg™ for the treatment of acute myeloid leukemia (AML), Antibody-Drug Conjugates (ADCs) have gradually been introduced into oncology clinical practice. ADCs combine the precision of antibody-mediated targeting of tumor antigens with the potency of cytotoxic drugs, providing a targeted delivery vehicle for malignant tumors. In this way, ADCs offer a method to reduce off-target toxicity by limiting exposure of the active payload to normal tissues. As of December 31, 2023, there are 15 ADC drugs approved globally, mainly indicated for hematologic malignancies, breast cancer, gastric cancer, and other cancers.

The immune system is the body's most vital defense system, protecting against pathogens and maintaining overall health. Leveraging the immune system's functions to treat diseases is the foundation of immunotherapy. Examples of immunotherapy include the development of antiviral vaccines and the cultivation of antibodies for viruses like HPV and HSV. Among these, Antibody-Drug Conjugates (ADCs) have shown significant effectiveness in treating various cancers due to their precise targeting and powerful cytotoxic effects.

Maleimide linkers are an essential tool in bioconjugation, allowing for the covalent attachment of biomolecules such as antibodies, peptides, and proteins to various compounds like drugs, fluorophores, or other macromolecules. These linkers play a vital role in a range of biomedical applications, including the development of Antibody-Drug Conjugates (ADCs), imaging agents, and targeted therapies. Their unique chemical reactivity and stability have made them one of the most widely used linkers in the field of targeted drug delivery.

Biotinylation reagents have emerged as indispensable tools in various biochemical and molecular biology applications due to their highly efficient labeling capabilities. In the field of Antibody-Drug Conjugates (ADCs), these reagents are gaining attention for their potential to facilitate precise and targeted drug delivery. ADCs are complex biotherapeutic agents designed to selectively deliver cytotoxic drugs to cancer cells by linking a potent drug (payload) to an antibody via a chemical linker. Biotinylation reagents, known for their ability to covalently attach biotin to biomolecules like proteins and DNA, can significantly enhance the functionality of ADCs by improving their detection, purification, and even targeting strategies.

Antibody-drug conjugates (ADCs) represent a significant advancement in targeted cancer therapy, combining the specificity of monoclonal antibodies with the potent cytotoxic effects of chemotherapy. A critical component of these conjugates is the linker that connects the antibody to the cytotoxic payload. Among various linker types, disulfide linkers have garnered attention for their unique properties, which facilitate selective drug release in the tumor microenvironment. This article explores the chemical properties of disulfide linkers, their mechanisms of action within ADCs, and the various payloads that can be utilized to enhance therapeutic outcomes in cancer treatment.

Peptide linkers for antibody-drug conjugates (ADCs) are one of the important research directions in the field of cancer treatment. As a bridge connecting antibodies and cytotoxic drugs, peptide linkers are not only crucial for the stability and drug release of ADCs, they can also regulate the release rate, tissue distribution and efficacy of ADCs in vivo. Ideal peptide linkers should have stable chemical properties and the ability to break efficiently under specific conditions (such as acidic environment or enzymatic activity in target cells), thereby ensuring the release of drugs at specific sites. At present, a variety of optimized peptide linkers have been used in clinical and preclinical studies of ADC, some of which have significantly improved the therapeutic effect and safety of anticancer drugs. Research and development of new peptide linkers will continue to promote the development of ADC technology and bring new hope to cancer patients.

The unique properties of polyethylene glycol (PEG) make it an ideal linker material and are widely used in the research and development and application of various ADCs. PEG linkers can not only improve the water solubility and stability of ADC, but also prolong its half-life and reduce immunogenicity, thereby improving the pharmacokinetic properties and safety of drugs. In the future, the design and optimization of PEG linkers will further promote the development of ADC therapy and provide more effective options for the treatment of cancer and other diseases.

The 2024 JPMorgan Healthcare Conference highly praised the development of ADCs, considering it one of the fastest-growing pharmaceutical areas. According to the latest report from market intelligence company Evaluate, the trend of ADC expansion will continue in the next few years, and the value of the category will be close to $30 billion by 2028 (Fig. 1). ADCs will continue to attract investment from large pharmaceutical companies in the coming years. Evaluate said that in 2023, ADC-focused mergers and acquisitions and collaboration activities will total nearly $100 billion, more than three times the value of similar transactions in 2022 and more than nine times that in 2019. In addition to Pfizer's $43 billion acquisition of Seagen, large transactions centered on ADC assets include AbbVie's $10 billion acquisition of ImmunoGen (involving ADC asset Elahere) and Merck's potential total of $22 billion (with a $4 billion upfront payment) to purchase three ADC assets from Daiichi Sankyo. Bristol-Myers Squibb paid $800 million upfront to purchase SystImmune's bispecific ADC BL-B01D1 for non-small cell lung cancer.

Click chemistry is an efficient, selective and modular chemical reaction that is widely used in the field of biomedicine, and has shown great potential in the development of Antibody-Drug Conjugates (ADCs). ADCs are an innovative class of drugs that combine the targeting ability of antibodies with the cytotoxicity of small molecule drugs and are widely used in cancer treatment. However, the development of ADCs faces many challenges, one of which is how to establish a stable and effective connection between antibodies and drugs. This is where click chemistry comes into play.

Adcetris (Brentuximab Vedotin) is a targeted therapy for the treatment of certain types of lymphoma. Developed by Seattle Genetics and Takeda, this drug conforms to the technical principle of Antibody-Drug Conjugates (ADCs), combining the specificity of antibodies with the potency of chemotherapy drugs to form an efficient and precise treatment mechanism.

Elahere (mirvetuximab soravtansine-gynx) is an Antibody-Drug Conjugates (ADCs) that binds with high affinity to folate receptor α (FRα) expressed on the surface of tumor cells and promotes the internalization of the ADC/receptor complex through antigen-mediated endocytosis. Elahere is used to treat adult patients with platinum-resistant epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who are FRα-positive and have previously received 1-3 systemic treatment regimens. Elahere is the first therapy to show improvement in overall survival (OS) in patients with platinum-resistant ovarian cancer.

On April 22, 2020, the U.S. Food and Drug Administration (FDA) accelerated the approval of Trodelvy (sacituzumab govitecan-hziy) for adult patients with metastatic triple-negative breast cancer (mTNBC) who have previously received at least two therapies. Currently, it has been marketed in more than 30 countries including the United States, the European Union, Australia, Canada, China, and Singapore. It is the world's first Antibody-Drug Conjugates (ADCs) approved for the treatment of triple-negative breast cancer and the world's first TROP-2 ADC drug to be marketed.

Kadcyla, also known as Trastuzumab Emtansine, is a breakthrough drug for the treatment of breast cancer. This innovative drug is a targeted therapy that combines the efficacy of two well-known anticancer drugs, Trastuzumab and Emtansine, to specifically target and destroy cancer cells that overexpress human epidermal growth factor receptor 2 (HER2). This unique dual mechanism of action makes Kadcyla a key treatment option for patients with HER2-positive breast cancer.

Bioconjugation involves the attachment of one molecule to another molecule, often through a covalent bond, to produce a complex of two molecules linked together. The development of novel studies on particular targeted derivatized proteins, DNA, RNA, and carbohydrates frequently makes use of bioconjugation technology, such as ligand discovery, disease diagnosis, and efficient screening, and is a research field with broad prospects. At present, it mainly includes the development of mild, specific targeted derivatized proteins, DNA, RNA and carbohydrates and other antibody protein conjugates. New conjugates are usually used for ligand discovery and disease diagnosis.

Cytotoxicity refers to the ability of a substance to induce cell damage or death. In biology and medicine, cytotoxicity is often used to describe the toxic effects of various chemicals, drugs, or molecules on cells. When a substance exhibits cytotoxicity, it causes apoptosis (programmed cell death) or necrosis, ultimately impairing the function and viability of the affected cells. Substances that can cause cytotoxicity are known as cytotoxins. These can be manmade chemicals, natural substances made by living things (plants, animals, or bacteria), medications used to cure cancer (chemotherapy), or even immune system components that attack foreign or damaged cells. Cytotoxins can work in multiple ways, including rupturing cell membranes, interfering with intracellular functions like protein synthesis or DNA replication, or inducing an immune reaction directed against particular cells.

Camptothecin is a quinoline alkaloid isolated from the plant Camptotheca acuminata of the Davidiaceae family. It is a natural topoisomerase I inhibitor that forms a complex with topoisomerase I-DNA, thereby preventing DNA replication and RNA synthesis to produce anti-tumor effects. Camptothecin and its derivatives are a class of alkaloids with broad-spectrum anti-tumor activity, which have significant inhibitory effects on malignant tumors. Clinical drugs such as irinotecan and topotecan have been developed. The main defects of camptothecin anti-tumor drugs are low water solubility, poor structural stability, and strong toxic side effects. Therefore, the corresponding structural modification strategies are gradually iterated with the progress of drug development.

Antibody-Drug Conjugates (ADCs) are composed of antibodies and cytotoxic drugs linked through a linker. This type of drug accurately delivers drugs to the lesion by targeting antigens specifically expressed on the surface of tumor cells, releasing cytotoxic drugs with highly effective therapeutic effects inside the tumor, and ultimately specifically killing tumor cells. Therefore, ADC drugs have great clinical therapeutic value.

Microtubules are an essential component of the cytoskeleton present in all eukaryotic cells. These dynamic filamentous structures play crucial roles in various cellular processes, such as cell division, intracellular transport, and maintenance of cell shape. Microtubule inhibitors are a class of drugs that target and disrupt the normal dynamics of microtubules within cells. By interfering with the microtubule polymerization and depolymerization processes, these inhibitors can inhibit cell division and induce cell death. A well-known example of a microtubule inhibitor is paclitaxel, which stabilizes microtubules and prevents their disassembly. Another example is colchicine, which binds to tubulin and inhibits microtubule formation.

Doxorubicin (Dox) is an anthracycline cell growth inhibitor. It interacts with DNA by inserting and inhibiting macromolecule biosynthesis, preventing the recombination of the DNA double helix, thereby effectively inhibiting tumor growth. Currently, doxorubicin is widely used to treat hematological malignancies and solid tumors, including Antibody-Drug Conjugates (ADCs).

Antibody-Drug Conjugates (ADCs) stand out for their remarkable capacity to precisely ferry small molecule chemotherapeutic agents straight to malignant cells, evading any unintended repercussions in the systemic circulation. The US FDA has greenlit a total of 15 ADCs (refer to Table 1), with numerous others progressing through clinical trials. Despite the proven efficacy of ADC in tackling both solid and hematologic malignancies, the formidable adversaries of drug resistance and tumor heterogeneity loom large as primary culprits behind clinical setbacks. The intricate tapestry of tumor heterogeneity serves as the breeding ground for relapse, metastasis, and the insidious development of resistance against ADC and other therapeutic modalities. Diverse tumors, each harboring distinct sensitivities to drugs, fuel aggressive tumor proliferation, escalating recurrence rates, and diminishing survival prospects. To confront these formidable hurdles, most chemotherapy protocols embrace the synergy of multiple drugs. The simultaneous delivery of small molecules emerges as the linchpin in circumventing drug resistance, fostering either additive or synergistic effects, and elevating therapeutic outcomes. The advent of dual-toxin ADC heralds a promising amalgamation strategy.

Breast cancer is the leading cause of death among women worldwide. When breast cancer spreads to other parts of the body, the prognosis is poor. Currently, there is no treatment for metastatic breast cancer. Antibody-Drug Conjugates (ADCs) are new anti-cancer drugs composed of antibodies, linkers and cytotoxic agents. The monoclonal antibodies in the ADC target specific antigens, and the cytotoxic agent kills cancer cells without harming surrounding healthy cells. Ado-trastuzumab Emtansine (T-DM1), Fam-trastuzumab Deruxtecan (T-DXd) and Sacituzumab govitecan (SG) are FDA-approved ADCs for the treatment of breast cancer. T-DM1 and T-DXd target human epidermal growth factor receptor 2 (HER2), while SG targets trophoblast surface antigen 2 (TROP-2). Datopotamab deruxtecan (Dato-DXd) is an investigational ADC targeting TROP2. In the TROPION-Breast01 Phase III trial, the drug showed a clinically meaningful improvement in progression-free survival in breast cancer patients. Both TROP-2 and HER2 are involved in cancer cell proliferation. In addition to HER2 and TROP2, there are other proteins involved in tumor progression that could serve as important targets for ADCs.

Antibody-Drug Conjugates (ADCs) have emerged as a promising class of treatments in the evolving field of cancer treatment. ADCs combine the potency of cytotoxic drugs with the selectivity of monoclonal antibodies, providing a novel approach to targeted therapy. ADCs show great promise in the fight against cancer and have the potential to be game-changers for targeted therapies across a range of non-oncology indications.

The structure of Antibody-Drug Conjugates (ADCs) is composed of three basic components, namely, tumor-specific monoclonal antibodies (mAb), linkers, and cytotoxic drugs (toxin) which we usually call payloads or warheads. ADC drugs use the fine specificity of tumor-specific mAbs to deliver highly viable cytotoxic drugs to the tumor site, thereby exerting a tumor-killing effect. The tumor-killing effect and side effects of ADC drugs largely depend on the payload. An ideal payload drug needs to have the following four points: high cytotoxicity, small molecular weight, clear mechanism of action, and can be modified. There is currently no universal payload. Researchers in the field mainly consider the following points when developing payload: tumor type and microenvironment, expression level of target protein, ADC molecular design (coupling site, DAR value, etc.).

With the approval of many Antibody-Drug Conjugates (ADCs) drugs around the world since 2019, conjugate drugs have developed into one of the hottest tracks in the pharmaceutical industry. Not only the research and development of traditional ADCs continues to be hot, but various new drug conjugates (NDCs) are also blooming. In this article, we make statistics on the research and development pipeline of new conjugate drugs, in addition to ADC, including PDC, ARC, APC, AExC, AEC, ABC, ISAC, ACC, AOC, and ADeC. The specific research numbers are as follows:

Nanobodies are the smallest functional single-domain antibodies known to be able to stably bind to antigens, and have unique structural and functional advantages. The molecular weight of nanobodies is only 12-15 kDa, which retains the antigen binding ability of traditional antibodies. However, nanobodies have higher solubility and stability, and have unique advantages in biological function and biochemical characteristics. Therefore, nanobodies have shown good control effects in disease diagnosis, cancer and infectious diseases.

Antibody-Drug Conjugates (ADCs) are an emerging class of anti-cancer therapeutic drugs. This type of drug relies on the specificity of monoclonal antibodies to deliver cytotoxins to tumor sites, which can not only improve the efficacy of chemotherapy, but also reduce or eliminate the toxicity of cytotoxic molecules to non-target tissues and non-target cells. ADCs drugs are multi-domain molecules composed of monoclonal antibodies (mAbs), linkers and small molecule cytotoxins. mAbs can specifically bind to target antigens on the surface of tumor cells, while ADCs drugs enter tumor cells through internalization mediated by mAb recognition receptors, and subsequently release cytotoxins to exert cell killing effects.

After the Antibody-Drug Conjugates (ADCs) drug enters the blood circulation and binds to the target antigen receptor on the surface of tumor cells, the newly formed ADC-antigen complex is internalized and degraded by lysosomes, releasing the payload and inducing tumor cell death. Therefore, the payload is an important part of the ADC design. The activity and physicochemical properties of the payload directly affect the anti-tumor efficacy of ADC drugs. The mechanism of action of the payload is an important factor in determining the performance of the ADC. In addition, other properties of the ADC payload such as cytotoxicity, immunogenicity, stability during preparation and circulation, water solubility, and modifiability are also important.

Natural protein toxins can be divided into plant, bacterial and fungal protein toxin families based on their origin. Among them, plant protein toxins include toxins with double-stranded structures and single-stranded ribosome inactivating proteins. It generally has N-glycosidase activity and can catalyze the depurination of the conserved site of ribosomal 28S RNA, thereby inactivating the ribosomal 60S subunit. Bacterial protein toxins have structural diversity and can inactivate elongation factor 2 (EF-2) or activate G protein, causing cellular dysfunction. Toxins generally enter cells through receptor-mediated endocytosis and are transported and translocated by the retrosecretory pathway. Natural protein toxins have anti-tumor and anti-viral effects and have good clinical application prospects. One of these applications is the development of Antibody-Drug Conjugates (ADCs), which combine the specificity of antibodies with the cytotoxicity of protein toxins.

With the rapid development of Antibody-Drug Conjugates (ADCs), more and more companies have entered the field of ADC research and development, and various types of ADC technologies and branches have emerged. Bispecific antibody conjugates (BsAb ADCs) are one of the emerging new technologies. The high specificity of bispecific antibodies enables more precise targeting of tumor cells. On the other hand, promoting the coordinated endocytosis of the two targets through cross-linking can improve the efficiency of toxins entering tumor cells. Currently, bispecific ADCs are still in the early stages of development globally, with only a few products entering the clinical development stage, and all of them are in early clinical stages.

Compared with traditional cytotoxic drugs, antibody-drug conjugate (ADC) has the advantages of strong targeting and less toxic side effects, and has broad application prospects in the field of tumor treatment. As time goes by, ADC has received more and more attention. As an important class of drugs in the clinical research of cancer treatment, ADCs are combined with monoclonal antibodies through chemical bonds (linkers) through powerful small-molecule cytotoxins, which have a more complex structure than antibodies.

Degrader-antibody conjugates (DACs) are a new class of therapeutic agents that have garnered significant interest in recent years. DACs are composed of an antibody that targets a specific protein on the surface of cancer cells, and a small molecule degrader that binds to the targeted protein and induces its degradation. The goal of DACs is to selectively destroy cancer cells while sparing healthy cells, thereby improving the safety and efficacy of cancer therapy. Currently, there are several DACs in preclinical and clinical development. One of the most advanced DACs is ARV-471, which targets the estrogen receptor (ER) in breast cancer cells. ARV-471 has shown promising results in preclinical studies and is currently being evaluated in a Phase 1 clinical trial. Other DACs in development target a variety of cancer-associated proteins, including BCL-2, BRD4, and FLT3.

Currently clinically used ADCs rely in most cases on efficient internalization and intracellular lysosomal transport for bio-cleavage of the linker and thus release of the drug. In addition, the cleaved drug must escape from the lysosome to achieve its therapeutic effect. However, not all tumor antigens ensure efficient ADC treatment as described above, especially in solid tumors. Furthermore, currently internalized ADCs are also sensitive to acquired tumor resistance mechanisms.

Research on cancer treatment has made significant progress in the past few decades, and new anti-cancer drugs are constantly emerging. Microtubule inhibition is now one of the most important mechanisms of cytotoxic drugs in the current generation. Although tubulin stabilizers (e.g., Paclitaxel) and destabilizers (e.g., Vincine) have been clinically successful as stand-alone anticancer agents, they may cause systemic toxicity in many patients. To minimize the systemic toxicity, scientists combined tubulin inhibitors with antibodies to target tumors, a concept that eventually evolved into antibody-conjugated drugs known as "magic bullets".

There are both large and small ADC molecules. A variety of biological analysis methods and platforms are needed to analyze the diversity of ADCs. Conventional LC-MS/MS small-molecule assays are often used to analyze uncoupled payloads and DAR distributions over time, while ligand binding assays (LBA) and LC-MS/MS can also be used to analyze total antibodies (TAb) and total ADCs. The choice of analysis platform depends on the availability of key reagents, the required analytical sensitivity, and the different problems that need to be addressed at various stages of drug development. In this article, the classical LBA and LC-MS/MS methods for quantitative analysis of ADC components are briefly introduced.

Unlike the development of most small or large molecules, which typically measures only one part or the metabolite for pharmacokinetic analysis, multiple parts of ADCs need to be measured to characterize their PK properties. Therefore, a thorough understanding of the clinical pharmacology of ADCs is critical for selecting a safe and effective dose for patients.

Since 2000, the research and development of precision therapy represented by small molecule targeted drugs and antibodies has made great progress and become the main targeted therapy for tumors. However, since small molecules and antibody drugs can specifically target tumor signaling pathways or antigens on the surface of tumor cells, and the heterogeneity between tumor cells is strong, precision therapy is very important for precision therapy. Antibody-Drug Conjugates (ADCs) combine the dual advantages of small molecule and antibody drugs compared to antibody or small molecule drugs alone. Many ADCs have demonstrated impressive activity against treatment-refractory cancers, resulting in their approval for both hematologic malignancies and solid tumorindications.

ADC linkers play an important role in binding stability between cytotoxins and antibodies. The linkers in ADC can be roughly defined as a link between antibodies and cytotoxins, which can cause dissociation of antibodies and cytotoxins. Inappropriate release of cytotoxins from ADC leads to two outcomes: (i) the dissociation of cytotoxin before reaching the target position can damage healthy cells, (ii) the loss of excessive cytotoxins can make ADC drugs ineffective.

Tivdak (tisotumab vedotin) is a targeted Antibody-Drug Conjugates (ADCs) consisting of an antibody that specifically recognizes cervical cancer cells and a potent chemotherapy drug. Tivdak can deliver chemotherapy drugs directly into cancer cells, thereby killing cancer cells while reducing damage to normal cells. Currently, Tivdak is used to treat adult patients with recurrent or metastatic cervical cancer.

Antibody-Drug Conjugates (ADCs) consist of monoclonal antibodies targeting specific antigens and small molecule cytotoxic through linkers. It combines the powerful killing effects of traditional small molecule chemotherapy and tumor targeting of antibody drugs. The antigen recognition of ADCs leads to that entering into cells through endocytosis pathway.

The linker is not only the molecule part of the covalent link between the antibody and the small molecule payload, but also a key element with design properties in targeted drug therapy. The addition of the linker should not induce aggregation and needs to ensure acceptable PK characteristics, while limiting the premature release of the payload in plasma and enabling the effective release of active molecules at the targeted site. These linkers can be divided into cleavable linker and non-cleavable linker.

The design of clinically successful ADCs depends not only on the effectiveness of payloads and their junctions, the stability of linker and effective drug release, but also on the selection of antibodies and bioconjugation technologies. In the past 10 years, all FDA-approved ADCs have been in the form of heterogeneous mixtures of ADCs, with different amounts of drugs attached to different positions of monoclonal antibody. The conjugating sites have significant effects on ADC stability and pharmacokinetics. High DAR (drug-antibody ratio) often leads to rapid plasma clearance, while ADCs with low DAR show weaker activity. In ADC drugs, the presence of nude monoclonal antibody is an effective competitive inhibitor. Therefore, a large number of new conjugating strategies have been developed over the past decade to control the location and number of small molecule drugs while maintaining structural integrity and homogeneity.

ADC technology continues to advance, and its treatment window still has more room for improvement. ADC drugs are designed to improve chemotherapeutic drugs. Traditional chemotherapeutic drugs do not have the specificity of identifying tumors. Antibodies target cytotoxic drugs to cancer cells to increase the proportion of drug molecules reaching the tumor, thereby reducing the minimum effective dose of chemotherapeutics and increasing resistance. Receive the dose, broaden the treatment window. However, due to linkers and connection methods, the first and second-generation ADC drugs still have off-target toxicity and produce uneven antibody conjugates, making the therapeutic window still narrow. Now scientists have developed a variety of technologies to Optimize ADC drugs, such as antibody optimization to improve affinity, site-specific coupling technology to improve product uniformity, and new effector molecules to enhance molecular toxicity. The therapeutic window of ADC drugs has been greatly widened, the therapeutic index has risen, and the effect of ADC drugs has increased. And there are also obvious breakthroughs in the side killer effect and low expression targets.

Researchers from the University of Nottingham found that thapsigargin has novel antiviral properties and can effectively fight COVID-19 in preclinical studies. The study believes that the administration of the drug-thapsigargin-will help alleviates the future COVID-19 outbreak.

Maytansine is benzoansamacrolide originally isolated from the shrub Maytenus ovatus. It is a highly effective microtubule-targeting compound and is being widely studied as a cytotoxic component of antibody-drug conjugates.

Pyrrolobenzodiazepines (PBDs) are a class of anti-tumor antibiotics, including the naturally occurring anthramycins, siberomycins, chromanamycins, neomycins, and DC-81. They selectively bind to the 5'-purine-guanine-purine sequence DNA minor groove and form a covalent bond with the exocyclic amino group of the guanine base to exert their biological activity.

Monomethyl auristatin F (MMAF) is a synthetic anti-tumor drug that has been used as a cytotoxic payload molecule in at least six ADCs, and these ADCs have entered clinical trials.

Monomethyl auristatin E (MMAE, the commercial name is Vedotin) is a very effective anti-mitotic agent, which can inhibit cell division by preventing the polymerization of tubulin. It is a synthetic anti-tumor drug. Due to its high toxicity, it cannot be used as a medicine by itself. Instead, it is linked to monoclonal antibodies (MAB) that direct it to cancer cells.

Seattle Genetics and Genmab A/S announced the positive results from the innovaTV 204 Key Phase II study, which involves the use of Antibody-Drug Conjugates (ADCs) tisotumab vedotin for the treatment of cervical cancer. The results show that Tesotoma alone has significant efficacy as a monotherapy and can provide clinically meaningful and long-lasting objective effects.

ADC Therapeutics SA is a Swiss biotechnology company, dedicated to the development and commercialization of highly effective targeted antibody-drug conjugates (ADC) for the treatment of hematological malignancies and solid tumors. Recently, it announced that it has submitted a biologics license application (BLA) for Loncastuximab tesirine (Lonca, formerly known as ADCT-402) to the U.S. Food and Drug Administration (FDA) for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

Recently, the FDA has cleared an Investigational New Drug (IND) application allowing RemeGen, China-based biopharmaceutical company, to initiate a Phase II clinical trial of Disitamab Vedotin, to test the drug as a potential new treatment for human epidermal growth factor receptor 2 (HER2) positive metastatic or unresectable urothelial cancer.

Calicheamicin is a class of enediyne anti-tumor antibiotics derived from the bacteria of Micromonas Escherichia. It is extremely toxic to all cells, and the most famous of which is Calichemicin γ1. It was first separated from the chalky soil or "calichi pit" in Kerrville, Texas in the mid-1980s. In 2000, the immunoconjugate N-acetyl dimethyl hydrazide Calicheamicin was developed to target CD33 antigen and used as a targeted therapy for acute myeloid leukemia (AML) in non-solid tumor cancer.

Antibody-Drug Conjugates (ADCs) are promising drugs. Compared with conventional chemotherapy drugs, they have a wider therapeutic index (TI) because they can effectively and specifically deliver drugs to tumor cells expressing antigens.

The cytotoxic payload or warhead is an important part of ADC. It is activated after being released from ADC in the cytoplasm of tumor cells and can destroy tumor cells even at low doses.

Antibody-Drug Conjugates (ADCs) are a novel class of highly targeted biopharmaceutical drugs that conjugate a cytotoxic drug with a monoclonal antibody (mAb) through an applicable chemical linker (Fig. 1). Drug molecules are transported to target tissues via the specific targeting effect of antibodies, which can reduce the systemic side effects of drugs, expand the scope of drug treatment, and enhance the therapeutic potential of antibodies.

The development of oncology drugs can be traced back to the middle of the twentieth century. It has been discovered that nitrogen mustard destroys individual bone marrow and lymphatic tissues by targeting rapidly dividing cancer cells. Such drugs include folic acid and purine analogs (methotrexate and 6-mercaptopurine), microtubule polymerization inhibitors/promoters (vinca alkaloids and taxanes), and DNA disruptors (anthracyclines and nitrogen Mustard). Because early tumor drugs not only target cancer cells but also have killing effects on all dividing cells in the body, so patients have serious side effects, which greatly limits the efficacy and use of drugs. ADC drugs may achieve selective delivery of toxic compounds to specific cancer cells.