Chemotherapy is one of the most widely used cancer therapies; however, chemotherapy often causes serious side effects. Antibody-drug conjugates (ADCs) are promising emergent cancer therapies that combine the effective killing power of small molecule cytotoxins and the highly specific targeting ability of monoclonal antibodies (mAbs). Thus, ADCs precisely deliver cytotoxins to tumor cells, while minimally affecting normal cells. ADCs have become a hot spot for anticancer drug development [1,2].
The first-generation ADC, gemtuzumab ozogamicin, was approved by the U.S. Food and Drug Administration (FDA) in 2000. Since then, multiple ADCs have been approved worldwide, and more than 100 ADC candidates have entered the clinical phase. These new anticancer drugs are leading the way to a new cancer therapy phase.
Table.1 Currently approved ADCs on the market.
Key Components of ADCs
An ADC consists of a target-specific mAb, a cytotoxic payload, and a chemically synthesized linker that covalently links the toxin and the antibody. The mAb binds to specific antigens on the surface of tumor cells, and ADCs are internalized into tumor cells during the formation of antibody-antigen complexes. ADCs are typically transported from the endosome to the lysosome, where the linker is cleaved and the small molecule cytotoxins are released, leading to tumor cell death [3]. Overall, ADC development requires consideration of the target antigens, antibodies, cytotoxic payload, and linker (Figure 1).
Figure 1. The general mechanism of action for antibody-drug conjugates (ADCs).
Target Antigens
Target antigens should be non-secretory, expressed mainly on the tumor cell surface and expressed at low levels in normal tissues. In addition, target antigens should be internalized after binding to the corresponding antibodies to facilitate the entry of ADC-antigen complexes into tumor cells to release cytotoxic payloads via an appropriate intracellular translocation route [4].
At present, the target antigens for approved ADC drugs are specific proteins overexpressed in tumor cells, including HER2, Trop2, Nectin4, and EGFR in solid tumors, and CD19, CD22, CD33, CD30, BCMA, and CD79 in hematologic malignancies. Emerging targets, such as EpCAM, CD70, CD25, CD166, and others, are under development and showing promising results [5]. Sino Biological is at the forefront of the ADC therapy field, providing quality products for ADC target antigens.
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Figure 2. High-quality target antigen products. (a) Well-established targets: EGFR, HER2, and CD22. (b) Emerging targets: CD70, CD166, and CD25.
Antibodies
Immunoglobulins (IgGs) and their derivatives are commonly used in clinical studies. IgG1, IgG2, and IgG4 are mainly used for ADCs because of their specificity, affinity for the target antigen, and long circulating half-life. In addition, the antibodies should possess effective internalization ability and low immunogenicity[6].
In early ADC drug development, predominantly mouse antibodies were used. However, these antibodies elicited a significant immune response, resulting in reduced therapeutic efficacy. With the advent of recombinant technology, mouse antibodies have been replaced with chimeric and humanized antibodies. Currently, ADCs increasingly use fully humanized antibodies with significantly lower immunogenicity [7].
Sino Biological provides high-quality mAb humanization servicesusing complementarity-determining region (CDR) grafting technology and computer-aided molecular modeling. In addition, Sino Biological possesses the high-throughput and scale-up capabilities to produce highly efficient antibodies in HEK293 and CHO cells in as fast as 2 weeks, with over 1000 Abs expression per batch.
Figure 3. The process of antibody humanization and complementarity-determining region (CDR) grafting technology.
Cytotoxic Payload
Cytotoxins should have high toxicity, low immunogenicity, and high stability. In addition, the cytotoxin should have a modifiable functional group or a site where a functional group can be introduced to link the mAb. The most commonly used cytotoxins for ADC drugs on the market or in clinical trials are microtubule protein inhibitors or DNA-damaging agents [8]. Additionally, the drug-antibody ratio (DAR), i.e. the number of drug molecules attached to the antibody by the linker, is a key factor in ADC development. A low DAR may reduce ADC efficacy, while a high DAR may cause instability, leading to off-target toxicity [8,9].
Linker
The linker ensures that the cytotoxic payload remains firmly attached to the antibody in the plasma during circulation, avoiding premature release that would damage normal tissues or cells and ensuring the effective release within the target tumor cells. Linkers can be classified as cleavable and non-cleavable. Cleavable linkers take advantage of the environmental differences between the circulation and tumor cells to accurately release free cytotoxins. Non-cleavable linkers depend on lysosomal degradation of the entire antibody-linker structure, which results in the retention of charged amino acids in the payload [10,11].
Challenges and Perspectives
Many challenges remain in ADC development. The biggest challenge is the toxic effects of ADCs, including neutropenia, thrombocytopenia, leukopenia, anemia, and gastrointestinal effects [4]. Another challenge is tumor resistance to ADCs, as evidenced by reduced antigen expression levels, altered intracellular transport pathways, and payload resistance. In addition, payload release is a challenge. The ADCs are much larger than traditional cytotoxic drugs, and the efficiency of cytotoxin penetration into tumors is limited.
To overcome these challenges, future ADC development should focus on the following: improvements in ADC design to reduce toxicity, including payload platforms, linkers, and coupling strategies; use of two cytotoxic agents as payloads to reduce ADC resistance; and enhancing ADC internalization and lysosomal delivery through bispecific antibodies to improve antitumor specificity. Sino Biological utilizes an optimized mammalian cell expression platform to provide fast and efficient bispecific antibody expression services for clients worldwide [12].
Figure 4. Sino Biological bispecific antibody production service highlights.
ADC therapy has benefited many cancer patients. In the future, the therapeutic efficacy of ADC will be improved by reducing ADC toxicity and drug resistance. Sino Biological will continue to be at the forefront of the ADC therapy field, providing researchers and pharmaceutical companies with high-quality products and one-stop services.
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Source
- Fu Z, Li S, Han S, Shi C, Zhang Y. Antibody drug conjugate: the "biological missile" for targeted cancer therapy. Signal Transduct. Target Ther. 7(1), 93 (2022).
- Schwach J, Abdellatif M, Stengl A. More than toxins-current prospects in designing the next generation of antibody drug conjugates Front. Biosci. Apr 26;28(4):79 (2023).
- Tang H, Liu Y, Yu Z, et al. The analysis of key factors related to ADCs structural design. Front. Pharmacol. 10,373 (2019).
- Zhao P, Zhang Y, Li W, Jeanty C, Xiang G, Dong Y. Recent advances of antibody drug conjugates for clinical applications. Acta. Pharm. Sin. B. 10(9),1589-1600 (2020).
- Hafeez U, Parakh S, Gan HK, Scott AM. Antibody-drug conjugates for cancer therapy. Molecules. 25(20), 4764 (2020).
- Zhang X, Huang AC, Chen F, et al. Novel development strategies and challenges for anti-Her2 antibody-drug conjugates. Antib. Ther. 5(1),18-29 (2022).
- Khongorzul P, Ling CJ, Khan FU, Ihsan AU, Zhang J. Antibody-drug conjugates: a comprehensive review. Mol. Cancer Res. 18(1), 3-19 (2020).
- Abuhelwa Z, Alloghbi A, Nagasaka M. A comprehensive review on antibody-drug conjugates (ADCs) in the treatment landscape of non-small cell lung cancer (NSCLC). Cancer. Treat. Rev. 106, 102393 (2022).
- Sheyi R, de la Torre BG, Albericio F. Linkers: an assurance for controlled delivery of antibody-drug conjugate. Pharmaceutics. 14(2), 396 (2022).
- Tong JTW, Harris PWR, Brimble MA, Kavianinia I. An insight into FDA approved antibody-drug conjugates for cancer therapy. Molecules. 26(19), 5847 (2021)
- Ungaro A, Tucci M, Audisio A, et al. Antibody-drug conjugates in urothelial carcinoma: a new therapeutic opportunity moves from bench to bedside. Cells. 11(5), 803 (2022).
- Yu J, Fang T, Yun C, Liu X, Cai X. Antibody-drug conjugates targeting the human epidermal growth factor receptor family in cancers. Front Mol. Biosci. 9, 847835 (2022).
FAQs
What is an antibody drug conjugate for cancer therapy? ›
Antibody drug conjugates (ADCs) are drugs designed to target specific cancer cells and release a toxic drug into the cancer cell. Antibody drug conjugates work like a “smart bomb” directed against cancer cells.
Are antibody drug conjugates an emerging modality for the treatment of cancer? ›Antibody-drug conjugates (ADCs) offer promise as a therapeutic modality that can potentially reduce the toxicities and poor therapeutic indices caused by the lack of specificity of conventional anticancer therapies.
Are antibody drug conjugates considered chemotherapy? ›Antibody-drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. As of 2019, some 56 pharmaceutical companies were developing ADCs.
How many antibody drug conjugates have been approved by the FDA? ›Among the 14 approved ADC drugs, 5 of them use MMAE/MMAF as the payloads. In contrast, the inhibitor of tubulin polymerization blocks the polymerization of tubulin dimer to form mature microtubules.
How does antibody therapy work for cancer? ›For example, some monoclonal antibodies mark cancer cells so that the immune system will better recognize and destroy them. An example is rituximab, which binds to a protein called CD20 on B cells and some types of cancer cells, causing the immune system to kill them.
How do antibody drug conjugates work? ›A substance made up of a monoclonal antibody chemically linked to a drug. The monoclonal antibody binds to specific proteins or receptors found on certain types of cells, including cancer cells. The linked drug enters these cells and kills them without harming other cells.
How do new antibody therapies fight cancer? ›Monoclonal antibodies (MABs) are a type of targeted drug therapy. These drugs recognise and find specific proteins on cancer cells. There are many different MABs to treat cancer. They work in different ways to kill the cancer cell or stop it from growing.
What is the new monoclonal antibody treatment for cancer? ›Monoclonal antibody therapy is a form of targeted treatment that uses lab-created antibodies that find and kill specific cancer cells. Physicians who treat cancer (oncologists) also use monoclonal antibody therapy to boost the immune system's ability to defend against cancer.
What is an example of an antibody drug conjugate? ›One example is trastuzumab emtansine (Kadcyla®), an antibody–drug conjugate incorporating the HER2-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1.
Why do antibody drug conjugates fail? ›Early ADCs encountered major obstacles including, low blood residency time, low penetration capacity to tumor microenvironment, low payload potency, immunogenicity, unusual off-target toxicity, drug resistance, and the lack of stable linkage in blood circulation.
How many approved ADCs are there? ›
Currently, there are two FDA approved HER-targeting ADCs: Kadcyla, approved in 2013, and Enhertu, approved in 2019. Disitamab vedotin is approved in China and under investigation in multiple Phase 2 trials worldwide. Table 1 highlights the key features of selected HER2 ADCs.
What are the benefits of antibody drug conjugates? ›The advantages of ADCs are the increase of the cell-killing potential of monoclonal antibodies; the higher tumor selectivity, the increase of drug tolerability and limited systemic exposure (compared to standard chemotherapeutic bioactive compounds) (Haddish-Berhane et al., 2013.
What ADC is approved in 2023? ›2023 ADC Catalysts
In early April 2023, Merck & Co., Inc.'s PD-1 inhibitor Keytruda won US approval for use in combination with Seagen Inc. 's ADC Padcev for the treatment of first-line urothelial carcinoma in an industry first.
Coronavirus (COVID-19) Update: FDA Limits Use of Certain Monoclonal Antibodies to Treat COVID-19 Due to the Omicron Variant.
Who is the largest antibody supplier? ›Abnova is the world's largest antibody manufacturer. We have the capacity of generating 300 mouse monoclonal antibodies and 200 rabbit polyclonal antibodies per month. Rather than the traditional method of antibody production, Abnova is taking a genomic/proteomic approach for the antibody development.
Which cancers are treated with monoclonal antibodies? ›Because they're targeting specific receptors in the cells, these monoclonal antibodies are referred to as targeted therapies. An example is trastuzumab (Herceptin), which is used to treat HER2-positive breast cancer and stomach cancer.
How long have monoclonal antibodies been used for cancer? ›Soon after the discovery of hybridomas, research into the use of mAbs to treat cancer began. Anti-melanoma mAbs were shown to suppress the growth of human melanomas in nude mice and in 1980 the first human trial of mAb therapy against cancer was conducted in a lymphoma patient [7,8].
How much does monoclonal antibody treatment for cancer cost? ›Results: The average annual price of a mAb was $96,731, exceeding $100,000 for 34 mAb-indication combinations. Oncology and hematology mAbs represented 40% of the mAb-indication combinations approved, yet they accounted for more than 85% of those priced $100,000 or higher.
What are the three main components of an antibody drug conjugate? ›The key components of antibody-drug conjugates include a monoclonal antibody, a stable linker, and a cytotoxic agent to target a variety of cancers.
What are ADCs in oncology? ›Unlike conventional chemotherapy treatments, which can damage healthy cells, antibody drug conjugates (ADCs) are targeted medicines that deliver chemotherapy agents to cancer cells. 1 ADCs deliver the chemotherapy via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.
What do antibody-drug conjugates target? ›
Antibody–drug conjugates (ADCs) are complex targeted agents composed by a cytotoxic drug hanging on an antibody scaffold. Upon binding with the cell surface antigen targeted by the specific antibody, the ADC is internalized by the tumor cell and processed by the endo-lysosomal system.
What are the disadvantages of monoclonal antibodies? ›Despite their many advantages, a drawback of monoclonal antibodies is that they are more time-consuming and expensive to produce than polyclonals. If a monoclonal has not yet been developed, researchers may consider using an existing polyclonal antibody, then switching to a monoclonal if one becomes available.
What is the success rate of monoclonal antibodies for cancer? ›In a study involving 48 patients with chronic or small lymphocytic leukaemia, rituximab therapy resulted in an overall response rate of 58%, with 9% complete responses (21). Similar success has been reported for treatment of follicular lymphoma (22) and diffuse large B-cell lymphoma (23).
What are the FDA approved monoclonal antibodies for cancer? ›The Food and Drug Administration (FDA) has, to date, approved nivolumab, pembrolizumab, ramucirumab, nivolumab/ipilimumab, atezolizumab/bevacizumab, as well as tremelimumab/durvalumab, as first- or second-line monoclonal antibodies (mAbs) for unresectable HCC.
Why are monoclonal antibodies not widely used? ›The interactions in the human body has resulted in unwanted side effects. This means they are not as widely used by doctors as originally thought. Monoclonal antibodies are also very expensive to produce.
Is monoclonal antibodies safe? ›Monoclonal antibody therapy for COVID-19 is well tolerated with minimal risks. Injection site reactions and infusion-related reactions are the most commonly reported adverse events. Monoclonal antibody therapy is not indicated in severe cases requiring hospitalization.
How long do monoclonal antibodies stay in your system? ›But though these antibodies mimic the infection-fighting work of the immune system, they don't last forever – typically, a monoclonal antibody will stick around for a number of weeks or months.
What are the side effects of antibody drug conjugate? ›The most common AEs affecting at least 20% of patients treated with BV across all clinical trials were neutropenia, anemia, peripheral sensory neuropathy, nausea, fatigue, constipation, diarrhea, vomiting, and pyrexia.
What does conjugate a drug mean? ›(KON-jih-gut) A compound formed by chemically joining two or more different substances. For example, an antibody-drug conjugate is made up of a monoclonal antibody that is chemically linked to a drug. Some conjugates are used to treat cancer.
What is the first approved antibody drug conjugate? ›This construct was the first FDA-approved antibody-drug conjugate (ADC) and was marketed as Mylotarg. It was retracted in 2010; however, calicheamicin ADCs have now been re- evaluated as therapeutic.
What are the problems with ADCs? ›
One of the major challenges of ADCs is off-target toxicity, which is caused by the premature release of cytotoxic small molecules into the bloodstream.
How long do conjugated antibodies last? ›In most cases, storage at 4°C upon receiving the antibody is acceptable for one to two weeks. It is essential to follow the recommendations on the datasheet.
What does it mean when an antibody is conjugated? ›What Are Conjugated Antibodies? A conjugated antibody is a polyclonal or monoclonal antibody that has a molecule attached which can be used to create a detectable signal. Detection can be visualized by color-generation, fluorescence, or other signals.
What is the most successful ADC? ›Kadcyla (ado-trastuzumab emtansine, T-DM1), a second-generation antibody-drug conjugate (ADC), is the most commercially successful ADC.
What is the promise of ADCs? ›Novel and Promising ADCs
The antibody binds to an antigen on a cancer cell, triggering endocytosis, and the drug is released from the linker, allowing selective delivery of the treatment to the cancer cells. ADCs also induce antitumor immunity and can trigger a bystander effect on neighboring cancer cells.
The FDA regulates ADCs as biologics rather than as conventional chemically synthesized drugs. ADCs, therefore, are approved through a Biologics License Application (BLA) instead of the typical New Drug Application (NDA) for small-molecule drugs.
How does treatment with an ADC differ from traditional chemotherapy? ›ADCs are able to allow for much stronger doses of drugs than traditional chemotherapy because ADCs have less of an impact on healthy cells by carrying their payloads directly to the cancerous cells.
Is ADC an immunotherapy? ›ADCs interact with cancer and immune cells by eliciting mechanisms such as immunogenic cell death, antibody-dependent cell-mediated cytotoxicity and dendritic cell activation, ultimately providing potential synergism with immunotherapy.
What is the future of ADC? ›ADCs have been widely used for cancer treatments, exhibiting both high efficacy and favorable tolerability. By the end of December 2021, twelve ADCs have been approved by the FDA (Table 1), and it is estimated that the global sales of ADCs will exceed $16.4 billion by 2026 [13].
What new drugs are coming out 2023? ›| No. | Drug Name | Active Ingredient |
|---|---|---|
| 11. | Zynyz | retifanlimab-dlwr |
| 10. | Daybue | trofinetide |
| 9. | Zavzpret | zavegepant |
| 8. | Skyclarys | omaveloxolone |
What was the first FDA-approved ADC? ›
Monoclonal Antibodies and the rise of ADCs
The first FDA-approved ADC (Food and drug administration approval) was gemtuzumab ozogamicin in 2000, for the treatment of acute myeloid leukemia.
Antibody-drug conjugates(ADCs) are an important class of highly potent biopharmaceutical drugs designed as a targeted therapy for the treatment of people with cancer.
What are drug conjugates in oncology? ›Antibody–drug conjugates (ADCs) are complex targeted agents composed by a cytotoxic drug hanging on an antibody scaffold. Upon binding with the cell surface antigen targeted by the specific antibody, the ADC is internalized by the tumor cell and processed by the endo-lysosomal system.
What is the use of monoclonal and conjugated monoclonal antibodies in cancer therapy? ›Chemotherapeutic monoclonal antibodies may be conjugated to other forms of cancer therapy and this facilitates greater efficacy. More importantly, conjugation provides targeted attack at cancer cells and therefore reduced widespread systemic toxicities to normal cells.
What are examples of monoclonal antibodies for cancer? ›Examples of MABS that work in this way include: rituximab (Mabthera) – a treatment for chronic lymphocytic leukaemia (CLL) and some types of non Hodgkin lymphoma. cetuximab (Erbitux) – a treatment for advanced bowel cancer and head and neck cancer. trastuzumab (Herceptin) – used to treat breast cancer and stomach ...
What is a conjugated monoclonal antibody? ›Conjugated monoclonal antibodies — also known as labeled, loaded or tagged antibodies — are radioactive particles that are combined with a chemotherapy drug. These monoclonal antibodies deliver the therapy directly to cells that need it the most and decreases damage to normal cells within the body.