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A Comprehensive Guide to ADC Payload Classes

ADC payloads are critical components of the ADC structure, and their selection and design are crucial for achieving optimal therapeutic efficacy and minimizing toxicity.

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A Comprehensive Guide to ADC Payload Classes

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  1. Huateng Pharma https://us.huatengsci.com A Comprehensive Guide to ADC Payload Classes Antibody-drug conjugates (ADCs) are a class of targeted cancer therapies that combine the specificity of monoclonal antibodies (mAbs) with the cytotoxic activity of chemotherapeutic drugs. ADCs use mAbs to selectively deliver a cytotoxic payload to cancer cells, resulting in targeted killing of tumor cells while sparing normal cells. Figure 1. The general components of ADC. Source: reference [3] In 2000, the first ADC drug, Mylotarg, was marketed, and no other ADC drugs were marketed for the next decade. As ADC drug technology matured, the FDA approved three ADC drugs in the next seven or eight years, and even three ADC drugs were approved consecutively in one year in 2019. To date, 15 drugs have been approved and hundreds of clinical trials are underway to explore new targets and indications.

  2. Huateng Pharma https://us.huatengsci.com Figure 2. Approved ADCs These approved drug drugs drive a new round of growth of ADC, with the market size gradually expanding. In 2021, the ADC market size is about $5.4 billion, and in 2022, according to incomplete statistics (some companies' annual reports are not published), the market size has exceeded $7.6 billion. ADC payloads are critical components of the ADC structure, and their selection and design are crucial for achieving optimal therapeutic efficacy and minimizing toxicity. Payload Selection for ADC Payloads are the components that exert the tumor-killing effect. After the ADC drug enters the cell, the payload is the main agent that ultimately causes the death of the target cell; therefore, the toxicity and physicochemical properties of the payload directly affect the ability of the drug to kill the tumor and consequently impact the efficacy. Payloads for conjugation must have a clear mechanism of action, small molecular weight, high cytotoxicity, and retain antitumor activity after chemical conjugation to antibodies.

  3. Huateng Pharma https://us.huatengsci.com ▶ ▶ Higher cytotoxicity. Considering the poor penetration and endocytosis efficiency of the antibody, as well as the low antigen expression on the cell surface, the amount of payload that can ultimately be delivered to the target cells is limited. Assuming an efficiency of 50% for each step in the ADC mechanism of action, only 1.56% of the toxin is able to enter the cell and exert its effect, and the actual figure in humans is even lower. Therefore, to ensure the drug effeciency, the toxin selected for ADC needs to have a high enough toxic potency to effectively kill tumors. ▶ ▶ Smaller molecular weight. An increase in the overall molecular weight of ADC may lead to the aggregation of ADC drugs, causing them to be cleared faster. Therefore, the molecular weight of the toxin should be controlled in a reasonable range. In addition, the smaller molecular weight allows the toxin to diffuse through the cell membrane to neighboring cells, exerting a bystander effect and further increasing the tumor elimination effect. ▶ ▶ Explicit mechanism of action. Since ADC drugs exert their effects by being internalized by the target cells, the toxin is mainly released intracellularly, which requires targeting intracellular targets and inducing cancer cell death through apoptotic mechanisms, so the mechanism of action needs to be clarified. ADC Payload Classes The payloads currently used for ADCs fall into the following three major categories: tubulin inhibitor (e.g., maytansine analogs and auristatin analogs), DNA damaging agent (e.g., calicheamicin and pyrrolobenzodiazepine analogs) and transcription inhibitors. Figure 3. Summary diagram of the different classes of cytotoxic molecules used in ADC construction. Source: reference [1]

  4. Huateng Pharma https://us.huatengsci.com Tubulin Inhibitors as Payloads of ADCs Microtubules exist in all eukaryotic cells and are one of the critical components that make up the cytoskeleton. Microtubules play a crucial role in supporting cell structure maintenance, cell division, and intracellular transport. Disruption of microtubules induces cell cycle arrest in the G2/M phase, which makes microtubules an attractive target for drug discovery. Tubulin inhibitors can be classified into two major categories according to their mechanisms of action: agents promoting tubulin polymerization (e.g., paclitaxel, epothilones, discodermolide and taccalonolides) or causing tubulin depolymerization (such as maytansinoids, auristatins, vinblastine and vincristine). Figure 4. Structure, polymerization and depolymerization of microtubules. Source: reference [3] Auristatins The auristatins originate from dolastatin-10, a natural compound found in the sea hare Dolabella auricularia. In order to produce effective cytotoxic payloads for antibody-drug conjugates (ADCs), monomethyl auristatin-E (MMAE) and monomethyl auristatin-F (MMAF) were developed based on the structure of auristatin. An example of an ADC utilizing MMAE is Brentuximab vedotin (Adcetris®), which contains approximately 4 MMAE molecules conjugated through cysteines of reduced interchain disulfide bonds via a

  5. Huateng Pharma https://us.huatengsci.com protease-cleavable linker. Brentuximab vedotin was granted accelerated approval in 2011 and full approval in 2015 for the treatment of classical Hodgkin’s lymphoma, systemic anaplastic large cell lymphoma, and peripheral T-cell lymphoma. Figure 5. Structure of Brentuximab vedotin, Source: reference [2] Maytansinoids Maytansinoids are anti-mitotic tubulin inhibitors, which are derived from maytansine. This benzoansamacrolide was initially isolated from an alcoholic extract in the bark of African shrubs Maytenus serrata and Maytenus buchananii in 1972. Maytansine and maytansinoids attach to the maytansine site, leading to the suppression of microtubule dynamics and causing cell cycle arrest in the G2/M phase. Through a semi-synthesis approach, a series of maytansine analogs (DM1, DM3, and DM4) containing disulfide or thiol groups that enable covalent linkage with monoclonal antibodies (mAbs) were created in two steps. Ado-trastuzumab emtansine (Kadcyla®, T-DM1) is a conjugate of approximately 3.5 maytansinoid DM1 molecules attached to the anti-HER2 antibody trastuzumab through surface-exposed lysines. Trastuzumab emtansine received FDA approval in 2013 for the treatment of HER-2 positive metastatic breast cancer (mBC), with additional approved uses including monotherapy and combination administration, as well as an adjuvant treatment for early breast cancer. Figure 6. Structure of trastuzumab emtansine, Source: reference [2]

  6. Huateng Pharma https://us.huatengsci.com The most widely used tubulin inhibitors are the aforementioned auristatins and maytansinoids, but other kinds of tubulin inhibitors have been tried in ADC, including derivatives of paclitaxel (Taxol), vincristine, and colchicine. Recently, Eribulin has also been used as a toxin molecule in the ADC drug MORAb-202, and has entered the clinical phase. DNA Damaging Agents as Payloads of ADCs DNA damaging agents may be more effective than microtubule inhibitors, which can kill target cells at any stage of their life cycle. There are at least four mechanisms of action exerted by DNA-damaging agents, which are as follows: (a) DNA double-strand breakage, (b) DNA alkylation, (c) DNA intercalation, and (d) DNA cross-linking. The most used DNA-damaging payloads are pyrrolobenzodiazepine, duocarmycins, doxorubicin, and calicheamicins Gemtuzumab ozogamicin (Mylotarg®), with calicheamicin derivatives as payload, was the first ADC approved by the FDA and was effective in treating acute myeloid leukemia, but it was withdrawn from the market in 2010 due to unstable linker toxicity. In 2017, Myelotarg was once again approved by the FDA. Among the DNA damaging agents, camptothecin (CPT) is of comparative interest. Unlike other DNA damaging agents, CPT inhibits DNA replication and transcription by acting on DNA topoisomerase Ӏ leading to tumor cell death. CPT has strong in vitro antitumor activity, but poor water solubility and low bioavailability have limited clinical application. In contrast, 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of CPT derivative irinotecan (CPT-11), is widely used in ADC drugs due to its high bioavailability and antitumor activity, such as Sacituzumab govitecan and Labetuzumab govitecan both use SN-38 as payload. More notably, Exatecan methanesulfonate (DXd/Dx-8951f) has stronger topoisomerase Ӏ inhibition activity and antitumor activity compared with other CPT-based derivatives, and has been successfully used in the development of next-generation ADC drugs such as T-DXd and Dato-DXd.

  7. Huateng Pharma https://us.huatengsci.com Figure 7. Structure of Sacituzumab govitecan and Trastuzumab Deruxtecan, source: Reference [2] Transcription inhibitors as Payloads of ADCs The final class of promising payloads are the transcription inhibitors targeting RNA polymerase II. Example of these compounds are the amatoxins. To date, α-amatoxins are the most potent and specific inhibitors of RNA polymerase II, leading to apoptosis. The development of amatoxins as ADC drug "warheads" has the following characteristics: first, high solubility in aqueous media to facilitate conjugation reactions; second, less potential for aggregation of amatoxin-based ADC drugs; and third, fewer side effects and rapid excretion from urine. Based on these advantages, amatoxin is a very promising ADC payload. Conclusion Payloads are an important part of ADCs, and payload diversification will play a key role in the future development of ADCs. A key issue in the development of these novel payloads is the mitigation of their side effects. Currently approved ADCs have been shown to have expected (myelosuppression, neurotoxicity) or unexpected (e.g., ocular or pulmonary) toxicity. Therefore, obtaining satisfactory therapeutic indices will be key to the future development of innovative ADC payloads.

  8. Huateng Pharma https://us.huatengsci.com Huateng Pharma is dedicated to being your most reliable partner to provide chemical synthesis and high-quality PEG linkers for ADC drugs. We are committed to promoting the progress of your ADC discovery and development projects. References: [1] Ponziani S, Di Vittorio G, Pitari G, Cimini AM, Ardini M, Gentile R, Iacobelli S, Sala G, Capone E, Flavell DJ, Ippoliti R, Giansanti F. Antibody-Drug Conjugates: The New Frontier of Chemotherapy. Int J Mol Sci. 2020 Jul 31;21(15):5510. doi: 10.3390/ijms21155510. PMID: 32752132; PMCID: PMC7432430. [2]Twomey JD, Zhang B. Targeting cancer with antibody-drug conjugates: Promises and challenges [published correction appears in MAbs. 2021 Jan-Dec;13(1):1966993]. MAbs. 2021;13(1):1951427. doi:10.1080/19420862.2021.1951427 [3] Chen H, Lin Z, Arnst KE, Miller DD, Li W. Tubulin Inhibitor-Based Antibody-Drug Conjugates for Cancer Therapy. Molecules. 2017 Aug 1;22(8):1281. doi: 10.3390/molecules22081281. PMID: 28763044; PMCID: PMC6152078. [4] Fu Y, Ho M. DNA damaging agent-based antibody-drug conjugates for cancer therapy. Antib Ther. 2018 Sep;1(2):33-43. doi: 10.1093/abt/tby007. Epub 2018 Aug 30. PMID: 30294716; PMCID: PMC6161754. Related Articles: Approved Antibody–Drug Conjugates (ADCs) and In Clinical Trials Bystander Effect of Antibody-drug Conjugates (ADCs) Clinical Toxicity Of Antibody Drug Conjugates Directions for Next Generation Antibody-Drug Conjugates ADC Linker - Development and Challenges

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