How to find the core components of ADO-Trastuzumab Emtansine?
ADO-Trastuzumab Emtansine, also known as Kadcyla, is an antibody-drug conjugate (ADC) developed by Genentech, a member of the Roche Group. It targets HER2, a protein that is overexpressed in certain types of breast cancer. As a novel therapeutic agent, ADO-Trastuzumab Emtansine is designed to deliver a potent cytotoxic payload specifically to tumor cells expressing HER2, thereby minimizing toxicity to healthy tissues.
Summary of Research Progress of ADO-Trastuzumab Emtansine
The research progress of ADO-Trastuzumab Emtansine has been significant. The drug works by binding to HER2 on the surface of cancer cells, internalizing the ADC, and releasing the cytotoxic payload within the cell. This mechanism allows for targeted delivery of the drug, enhancing its efficacy while reducing systemic side effects. ADO-Trastuzumab Emtansine has received approval from the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with HER2-positive, unresectable locally advanced or metastatic breast cancer who have received prior trastuzumab and a taxane. It is also approved for use in the adjuvant setting for patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant treatment with trastuzumab and taxane-based chemotherapy. Globally, the drug is approved in numerous countries, with ongoing efforts to secure approvals in additional markets.
The global competition in the ADC market is intense, with several other ADCs targeting various cancers at different stages of development. Key competitors include Seattle Genetics' Adcetris (brentuximab vedotin) for Hodgkin lymphoma and systemic anaplastic large cell lymphoma, and Astellas Pharma and Seattle Genetics' Enfortumab Vedotin for urothelial cancer. Despite this competition, ADO-Trastuzumab Emtansine stands out due to its specific targeting of HER2 and its potential in treating HER2-positive breast cancer, an area with significant unmet medical needs. Clinical trials have shown promising results, particularly in patients with HER2-positive metastatic breast cancer who have progressed on or after prior trastuzumab-based therapy. The EMILIA trial, a Phase III study, demonstrated that ADO-Trastuzumab Emtansine significantly improved progression-free survival and overall survival compared to lapatinib plus capecitabine.
Structural Characteristics of ADO-Trastuzumab Emtansine
The overall structural characteristics of ADO-Trastuzumab Emtansine are designed to optimize its therapeutic potential. The ADC consists of three main components: the antibody, the linker, and the cytotoxic payload. The antibody is trastuzumab, a humanized IgG1 monoclonal antibody that binds to HER2 with high affinity and specificity. The linker is a thioether-based non-cleavable linker, which ensures the payload remains attached to the antibody during circulation and is released only upon internalization into the target cell. The cytotoxic payload is DM1 (maytansine derivative), a potent microtubule-disrupting agent.
The selection and advantages of the antibody in ADO-Trastuzumab Emtansine are crucial for its effectiveness. The antibody used, trastuzumab, is a well-characterized humanized IgG1 monoclonal antibody that binds to HER2 with high affinity and specificity. HER2 is a transmembrane receptor tyrosine kinase that is overexpressed in approximately 20-30% of breast cancers. The high affinity and specificity of trastuzumab ensure that the ADC can effectively target and bind to HER2-expressing cancer cells, thereby maximizing the delivery of the cytotoxic payload. Additionally, trastuzumab has been extensively studied and used clinically, providing a wealth of data on its safety and efficacy. The antibody has been engineered to enhance its stability and reduce immunogenicity, making it suitable for repeated dosing. The high binding affinity and low immunogenicity of the antibody contribute to the overall safety and efficacy of ADO-Trastuzumab Emtansine. The antibody also has a favorable pharmacokinetic profile, with a long half-life that allows for less frequent dosing, improving patient convenience and compliance.
The linker in ADO-Trastuzumab Emtansine is a key component that ensures the stability of the ADC in circulation and the controlled release of the payload inside the target cell. The linker used is a thioether-based non-cleavable linker. This linker is stable in the bloodstream and remains intact during circulation, ensuring that the payload does not prematurely detach and cause systemic toxicity. Once the ADC is internalized into the target cell, the payload is released through the action of lysosomal enzymes. This design minimizes the risk of off-target toxicity and ensures that the cytotoxic agent is delivered directly to the tumor cells. The non-cleavable nature of the linker also provides a high degree of control over the release of the payload, enhancing the therapeutic index of the ADC. The linker is designed to maintain the integrity of the ADC during systemic circulation, preventing the payload from being released before reaching the target cells. This stability is crucial for minimizing systemic toxicity and ensuring that the drug reaches its intended target. The non-cleavable linker also provides a high drug-to-antibody ratio (DAR), typically around 3.5, which enhances the therapeutic index of the ADC.
The cytotoxic drug payload in ADO-Trastuzumab Emtansine is DM1 (maytansine derivative), a potent microtubule-disrupting agent. DM1 works by binding to tubulin and disrupting microtubule dynamics, leading to cell cycle arrest and apoptosis in rapidly dividing cancer cells. DM1 is chosen for its high potency and ability to induce cell death at low concentrations. The payload is linked to the antibody through the non-cleavable linker, ensuring that it remains inactive during circulation and is only activated once inside the target cell. This design enhances the safety and efficacy of the ADC by minimizing systemic toxicity. DM1 is particularly effective against cancer cells because it targets the microtubules, which are essential for cell division. By disrupting the formation of the mitotic spindle, DM1 prevents cancer cells from completing the cell cycle, leading to cell death. The high potency of DM1 allows for the use of lower doses of the ADC, further reducing the risk of side effects. Additionally, DM1 has a broad spectrum of activity against various cancer types, making it a versatile choice for the development of ADCs.
Summary and Prospect
In summary, ADO-Trastuzumab Emtansine represents a significant advancement in the treatment of HER2-positive breast cancer, particularly for patients with unresectable locally advanced or metastatic disease who have progressed on or after prior trastuzumab-based therapy. The drug's unique mechanism of action, combined with its optimized antibody, linker, and cytotoxic payload, positions it as a promising therapeutic option. Ongoing clinical trials continue to evaluate its safety and efficacy, and if successful, ADO-Trastuzumab Emtansine has the potential to become a standard treatment for HER2-positive breast cancer, addressing a critical unmet medical need. Future research will focus on expanding its use to other HER2-expressing cancers and exploring combination therapies to further enhance its therapeutic benefits. The detailed selection and engineering of the antibody, the stability and non-cleavable nature of the linker, and the high potency of the cytotoxic payload all contribute to the overall effectiveness and safety of ADO-Trastuzumab Emtansine, making it a promising candidate in the field of targeted cancer therapy.
How to find the the core components of an ADC drug?
In Patsnap Synapse and Patsnap Bio, you can find the sequence and latest research and development advances of all ADC drugs.
Taking ADO-Trastuzumab Emtansine as an example, First, you can log in to Patsnap Synapse, enter ' ADO-Trastuzumab Emtansine ' in the search box and click to view the details. On the details page, you can find the basic information and research progress of ADO-Trastuzumab Emtansine.
After entering the details page, drop down to find the core Structure information of ADC drug and click view Structure in the Linker section to find the structure and type of ADC drug Linker.
The details page also lists the complete sequence information of the antibody part. By clicking on "Find Similar Sequence", you can be redirected to Patsnap Bio to search for similar sequences of the antibody.
Clicking on the sequence name will provide you with all the basic information of that sequence.
Patsnap Bio helps you turn weeks into minutes with cutting-edge AI-enabled tools built to master the complexities of sequence retrieval and automate IP analysis with precision and ease.
