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- 1. Tel: 1-631-504-6093 Email: info@bocsci.com Address: 45-16 Ramsey Road, Shirley, NY 11967, USA Biomissiles-ADC Drugs Antibody–Drug Conjugates for Targeted Cancer Therapy
- 2. TABLE OF CONTENTS 01 What is Antibody-drug Conjugates (ADCs) 02 The History of ADCs and Next-generation ADCs 03 Clinical Therapeutic Potential of ADC Drugs 04 ADC Drug Characteristics 05 ADC Drug Technologies
- 3. What is Antibody-drug Conjugates (ADCs)? • Antibody, the precise guidance component of ADCs that brings cytotoxic molecules to tumor cells. • Cytotoxin, is the critical factor contributing to ADCs' activities and tumor cells' inhibitions. • Linker, requires high stability in the blood circulation so to effectively release small-molecule toxins after reaching the target cell surface or entering the cell.
- 4. The History of ADCs and Next-generation ADCs First-generation ADC Second-generation ADC Third-generation ADC Representative Products Technical Characteristics Mylotarg® (Pfizer, 2000) Adcetris® (Seattle，2011) Kadcyla® (Roche，2013) Polivy® (Roche, 2019) Enhertu® (Astrazeneca, 2019) • Low specificity antigen • Weakly toxic payload • Unstable linker • Enhanced antigen specificity • DAR based on random coupling strategy has heterogeneity • More stable linker • Site-specific conjugation with homogeneous ADC • More potent cytotoxin Nat Rev Drug Discov
- 5. Clinical Therapeutic Potential of ADC Drugs mAbs, 13:1 1951427.
- 6. ADC Drugs Characteristics Specific Binding ADCC Effects Inhibit Downstream Signaling Pathways Bystander Effects Antibody-drug conjugates specifically bind cancer cell antigens through targeted antibodies. Antibody-drug conjugates enhance antibody- dependent cell-mediated cyto-toxicity (ADCC). Antibody-drug conjugates inhibit the downstream signal transduction of antigen receptors. The bystander effect can kill adjacent cancer cells because drugs released by ADCs within cancer cells are permeable or transmembrane. Int. J. Mol. Sci. 2016, 17, 561.
- 7. ADC Drugs Technologies ADC Drugs Mechanism of Action Target Selection Affects ADC Drug Therapeutic Windows Antibody Selection Affects ADC Drug Endocytosis Efficiency Linker Selection Affects ADC Stability And Efficiency Toxin Selection Affects ADC Drug Potency Conjugation Method Selection Affects ADC Drug Uniformity ADC Drugs Resistance Mechanism
- 8. ADC Drugs Mechanism of Action Int. J. Mol. Sci. 2016, 17, 561. A General Mechanism of Action of ADCs Step 1: ADC binds to its target cell-surface antigen receptor Step 2: Form an ADC-antigen complex, leading to endocytosis of the complex Step 3: Cytotoxic payload is released inside the cell Step 4: Released payload binds to its target Step 5: Leading to cell death Structure of Antibody-drug Conjugates A general structure of an ADC contains a humanized/human monoclonal antibody (mAb), a cleavable/non-cleavable chemical linker, and a cytotoxic payload. The linker is covalently linked to the mAb at the conjugation site.
- 9. Target Selection of ADCs Target Selection Affects ADC Drug Therapeutic Windows Lung cancer Rectal Cancer Breast Cancer Uterine cancer Since the action mechanism of ADC drugs and the existing therapeutic effects are different, requirements for the target characteristics are special： • Tumor specific • Abundantly expressed on the surface of tumor cells • Antigen should be non-secreted • Antigens can be efficiently internalized
- 10. Antibody Selection of ADCs Antibody Selection Affects ADC Drug Endocytosis Efficiency a) Size of the monoclonal antibody b) Antibody modifications c) ADC internalization Molecules 2021, 26, 2943. mAbs, 13:1, 1951427.
- 11. Cleavable linker: The linker may be cleavable. Non-cleavable linker: The non-cleavable linker maintains the coupling integrity of antibody and chemical drug throughout the entire drug action process. Linker Selection of ADCs Linker Selection Affects ADC Drug Stability And Efficiency Nat Rev Drug Discov
- 12. Cytotoxin Selection of ADCs Cytotoxin Selection Affects ADC Drug Potency Requirements for ADC Linked Toxins Include: • Sufficient water solubility and stability in serum • Toxins require functional groups that can be conjugated to linkers • Toxins must be insensitive to enzymatic degradation reactions of lysosomes • Toxins with reduced aggregation effects Tubulin inhibitors
- 13. Conjugation Method Selection of ADCs Conjugation Method Selection Affects ADC Drug Uniformity
- 14. ADC Drugs Resistance Mechanism Pharmacology & Therapeutics. 2018; 181: 126-142.
- 15. Tel: 1-631-504-6093 Email: info@bocsci.com Address: 45-16 Ramsey Road, Shirley, NY 11967, USA
Notas del editor
- Over the past half-century, cancer management has improved significantly along with the advancement of chemotherapy. Chemotherapy using cytotoxic agents is a major treatment option, in addition to surgical removal, radiation, targeted therapies using small molecules or monoclonal antibodies, and, more recently, immunotherapy. Chemotherapy has been refined by screening and developing small molecules that can cause cell death selectively to cancer cells through inhibiting microtubule function, DNA synthesis, or protein function. In particular, antibody-drug conjugates (ADCs), humanized or human monoclonal antibodies conjugated with cytotoxic small molecules through chemical linkers, could potentially make a fundamental change in the way cancer chemotherapy is designed and administered. This platform enables targeting cancer cells and selective delivery of highly cytotoxic drugs, resulting in a broad therapeutic window. Indeed, successful clinical outcomes using ADCs have inspired scientists in the biomedical research community further to advance this new platform toward next-generation cancer therapeutics.
- In this video, we review the molecular aspects of ADCs, the history and next-generation ADCs, the clinical pipeline of ADCs, ADC drug characteristics, and the technical requirements for successful ADC construction.
- Antibody-drug Conjugate (ADC) is a chemotherapeutic drug with strong cytotoxicity. It possesses both the powerful lethality of small molecule drugs and the highly targeting capability of pure monoclonal antibodies; thus, it has become a hot issue in the research and development of tumor-targeted therapy. The targeting capability of ADC originates from the antibody, while the relevant toxicity originates from the payload. After the antibody binds to the cancer cell surface antigen, it mediates ADC to enter cells through endocytosis and is transported into lysosomes through the endosome. ADC linkers or antibodies in lysosomes degrade and release small molecule drugs that further exert cytotoxicity and kill tumor cells.
- Antibody-drug conjugates (ADCs) have made considerable progress in the past decade. Among the first-generation ADC drugs, anti-cancer drugs such as mitomycin C, idarubicin, anthracyclines, N-acetyl melphalan, adriamycin, vinca alkaloids, and methotrexate are mainly conjugated to the mouse monoclonal antibody via a non-cleavable linker. However, the first-generation ADC drugs possess strong immunogenicity and unstable linkers. It often early toxins release in the plasma leading to severe toxic reactions. Additionally, the cytotoxins of the first-generation ADC are considered ineffective in killing tumor cells. After nearly 10 years of the rapid development of monoclonal antibody drugs and the continuous discovery of more effective anti-cancer small molecule drugs, the second-generation ADC drugs were evaluated with better CMC characteristics than the first generation. Representatives of second-generation drugs include Brentuximab vedotin, Ado-trastuzumab emtansine, and Inotuzumab Ozogamicin. However, second-generation ADC drugs have a narrow therapeutic window, mainly due to their low off-target toxicity and competition with antibodies that do not bind small molecule drugs to tumor targets. Thus, the key to third-generation ADC drugs is site-specific binding that can ensure a clear DAR. Through the specific binding of small molecule drugs and monoclonal antibodies, the stability and pharmacokinetics of the drugs are significantly improved, and relative drug activity and binding activity to cells at lower antigen levels are enhanced as well. In addition, antibody optimization, linkers, and small molecule drugs can significantly improve the therapeutic effect of ADC drugs.
- There are currently 82 novel ADCs within 150 active clinical trials registered with clinicaltrials.gov for cancer patients. Most ADCs are currently under investigation in phase 1 trials, while a small percentage has advanced to phase 3. Of the 150 ongoing trials, more than 80% of cases evaluate ADC safety and efficacy in solid tumors, whereas less than 20% are trials for hematological malignancies. There are 43 disclosed targets organized here by the number of ADCs designed to recognize them. Most of these targets are under close investigation by a single ADC, while some are being investigated by various ADCs. Of these 82 novel ADCs, most employ tubulin disrupting payloads, followed by DNA-damaging molecules, topoisomerase I inhibitors, and finally, unique payloads, such as TLR agonists, a BCL2-xL inhibitor, and an RNA polymerase II inhibitor. Many payloads remain undisclosed. Most ADCs under clinical investigation either utilize the conventional cysteine conjugation strategy or site-specific conjugation platforms, while few conjugates to surface lysines. Many techniques remain undisclosed as well.
- ADC drugs have the following characteristics: 1. Specific Binding: Antibody-drug conjugates specifically bind cancer cell antigens through targeted antibodies. Then, ADC drug enters the cancer cell through antigen-mediated endocytosis. Subsequently, highly active cytotoxic drugs are released into the cell through special environments (such as lysosomes or low pH) and finally achieve specific killing of cancer cells. 2. Antibody-dependent cell-mediated cytotoxicity Effects: Antibody-drug conjugates enhance antibody-dependent cell-mediated cytotoxicity. The antibody Fab segment of this drug binds to antigens of virus-infected cells or tumor cells. Then, the antibody Fc segment binds to the FcR of killer cells, such as NK cells and macrophages, thereby mediating the direct killing of cancer cells by killer cells. 3. Inhibit Downstream Signaling Pathways: The antibody component of the antibody-drug conjugate specifically binds to the antigen target of cancer cells and inhibits downstream signal transduction of antigen receptors to induce apoptosis of cancer cells. For example, the antibody component of the ADC drug Kadcyla can bind to HER2 receptor in cancer cells, which inhibits the formation of heterodimers between HER2 and HER1, HER3 or HER4, thereby inhibiting cell growth signaling pathways. 4. Bystander Effects: Drugs released by antibody-drug conjugates within cancer cells are permeable or transmembrane, and they are able to kill adjacent cancer cells, known as the bystander effect. The expression of antigens in solid tumor cells is often heterogeneous, so antibody-drug conjugates may not effectively kill adjacent antigen-negative cancer cells directly. When antibody-drug conjugates release cytotoxins outside cancer cells or inside target cells, the released small-molecule drugs can kill not only antigen-positive cancer cells, but also other nearby cancer cells through the bystander effect. At the same time, the bystander effect of such drugs also destroys the environment for tumor growth, such as tumor stromal cells and tumor blood vessels and further inhibiting cancer cell growth.
- As mentioned above, the ADC consists of three parts, each of which can affect the final efficacy and safety of the overall molecule. In order for ADC drugs to efficiently pass through intracellular biological processes and exert relative cytotoxic effects, it is necessary to comprehensively consider antigen targets, antibodies, cytotoxic molecules, linkers, and coupling methods when constructing ADCs.
- The primary advantages of ADCs are that they can act as prodrugs during systemic circulation and finally release the free drugs to the target tumor cells. Relying on highly targeted tumor antigen recognition and effective internalization, ADCs recognize and bind to a specific tumor antigen on the cell surface, then internalization of ADCs is conducted through endocytosis. Once they enter tumor cells, ADCs are transferred to the endosomes or lysosomes, which digest potential linkers or antibodies, thus releasing active cytotoxic drugs. Meanwhile, technical obstacles are presented in each step of ADC targeting: 1. When drug molecules reach cell surfaces to recognize and bind antigens, this step has high requirements on the density and tumor specificity of the cell surface antigen. 2. When ADC-antigen complexes are internalized by cells, ADC drugs are required to have high internalization efficiency. 3. When ADCs are degraded by lysosomes for further toxins release, a step that rapidly sheds playloads to escape from lysosomes is required. 4. When toxins reach intracellular drug targets to perform elimination effects, toxins must possess strong toxicity to kill cancer cells. 5. When cancer cells are eliminated, toxins are released to perform bystander effects to kill neighboring cells, and this step requires toxins to pass through cell membranes sufficiently.
- The target selection will affect therapeutic windows of ADC drugs. Hence, improving ADC safety and efficacy profiles relies significantly on selecting the target antigen and its interaction with the mAb of ADC. The critical parameters involved in the selection of the target antigen are tumor specificity and expression level. Ideally, the chosen target will exhibit a high level of tumor-specific or disease-specific expression and minimal presence in normal tissues. The specificity of the target is critical to reducing the toxicity of ADCs; thus plays a substantial role in the overall success. For oncological indications, the antigen can be expressed as a surface receptor on tumor cells, tumor stem cells, or within the tumor vasculature and microenvironment. In best cases, the antigen will also be expressed homogenously across tumor cells at similar levels. ADCs with sufficient control of bystander effect may overcome the challenge of heterogeneous cell populations within a tumor.
- After selecting a target, mAbs are produced and screened based on selectivity, tumor penetrating ability, and isotype. The antibody selection will affect the endocytosis efficiency of ADC drugs. ADCs, both in development and approved, belong to the IgG1, IgG2, or IgG4 subclasses. These subclasses differ in cross-linking capabilities and biological activity, including ADCC and complement-dependent cytotoxicity effector functions. IgG1 is commonly used due to its enhanced delivery capabilities and additional effector functions compared to IgG2 and IgG4. However, when considering target characteristics and the proposed mechanism of action, effector function may not, in some cases, be desirable, and IgG2 and IgG4 antibodies may be preferred. Isotype selection can also play a role in drug-linker conjugation, particularly when conjugating via cysteine residues.
- The chemical linker is a critical component of the ADC that joins the mAb and cytotoxic payload. The linker facilitates ADC stability in circulation until the ADC reaches the target cell and releases the payload. There are two classes of linkers: cleavable and non-cleavable. Cleavable linkers can be cleaved in response to certain environmental factors and release free drugs into the cytosol. This includes hydrazine linkers that are cleaved in response to the acidic environment of the endosome and lysosome. Cleavable linkers can also be cleaved in the presence of proteases or reducing agents, such as cathepsin B or high levels of glutathione. For non-internalizing ADCs, drug release relies on extracellular cleavage by glutathione and proteases shed as a result of tumor cell death. Non-cleavable linkers are resistant to proteolytic degradation and rely on the full degradation of the antibody to release the attached linker-payload complex. This requires the payload to remain active while linker bound. The proposed mechanism of action of the ADC can be a determinant for linker choice.
- While the mAb is arguably the most important component in ensuring ADC efficiency, the cytotoxic payload is responsible for tumor cell killing execution. The cytotoxic payload is typically a small-molecule drug to elicit cell killing of the targeted tumor cells/tissues. The first generations of ADCs used drugs approved for clinical use, including doxorubicin, and resulted in low clinical activity. The next wave of ADCs adopted the use of more potent small-molecule drugs that were over toxic as a stand-alone treatment but showed promising efficiency when selectively delivered to target cells with IC50 ranging from 0.01-0.1 nM. Even so, due to biodistribution, uptake, and loss of conjugation in circulation, it is estimated that only 1-2% of ADC payload will reach the intracellular target. Thus, the potency of the payload must be high so that even at a lower accumulated concentration, ADCs can still eradicate the target cells.
- In addition to selectively choosing a chemical linker, comparative methods by which payloads are conjugated to antibodies are essential in modulating the homogeneity and potency of ADCs. Depending on the reaction site, conjugation strategies can be divided into non-specific conjugation by native residues or site-specific conjugation by genetic engineering sites and UV cross-linking. Non-specific conjugation techniques include lysine conjugation and cysteine conjugation, which are classical and mature without introducing unnatural amino acids. Site-specific conjugation can enhance the site-specificity of ADC conjugation by altering the amino acid sequence and introducing a reactive handle, including enzymatically modified antibodies. Enzymatically modified antibodies enable enzyme-chemical two-step efficient site-directed conjugation, so certain enzymes recognize specific amino acid tags. Nevertheless, unnatural amino acid conjugation can introduce special groups to facilitate efficient specific conjugation reactions.
- The mechanism of action of ADCs targeting tumor cells comprises several stages: binding to the antigen, internalization, release of conjugates (mainly in the lysosome), release of conjugates into the cytoplasm, then binding to the molecular target and inducing cell death by apoptosis. Each of these steps can be involved in resistance as suggested by several preclinical works on cell lines or in animal models: (i) downregulation of the targeted antigen and/or defects in binding, internalization, trafficking, or recycling of the antibody, (ii) defective lysosomal degradation of the ADC or reduced expression of lysosomal transporters such as SLC46A3, leading to lower release of the payload in the cytosol, (iii) alterations of tubulin or microtubule dynamics modulators or (iv) reduced drug retention within the cell by upregulation of multidrug resistance transporters like MDR1. The clinical relevance of these various potential resistance mechanisms remains to be demonstrated. Indeed, it is complex to access tumor samples immediately before initiating treatment with ADC and then during the relapse following such treatments. Finally, in the context of therapeutic combinations, it can be complex to discern the resistance mechanisms to ADCs from those of the other administered compounds. Despite this, the observations made on preclinical models raise interesting avenues for analyzing resistance to ADCs in humans.
- BOC Sciences, as an expert in chemical coupling, focuses on overcoming challenges relevant to ADC development. We possess years of experience in ADC and professional biological coupling development services, are equipped with a professional team of chemists, and can provide the professional knowledge, equipment, and capabilities you demand. We also support customized solutions from early detection of bioconjugation to development and clinical manufacturing. If you are interested in our antibody-drug conjugates (ADC) custom development service, please contact us in advance.