Brentuximab vedotin ..Reem Ibrahim
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Brentuximab vedotin as monoclonal antibody drug conjugate new approach of anticancer drug targeting
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Brentuximab vedotin ..Reem Ibrahim
- 3. Antibody–Drug Conjugate (ADC) • Anti-CD30 Antibody >> chimeric monoclonal antibody AC10 (cAC10, brentuximab). • Drug >> monomethyl auristatin E (MMAE) the small-molecule microtubule inhibitor (Anti neoplastic agent ) • Protease cleavable linker
- 4. • It is an anti-neoplastic agent used in the treatment of Hodgkin lymphoma and systemic anaplastic large cell lymphoma.
- 5. Lymphoma • Lymphoma is cancer of the lymphatic system Hodgkin lymphoma Non Hodgkin lymphoma • In Hodgkin lymphoma, it is cells in the lymph nodes that have become cancerous
- 8. • Antibody-drug conjugates or ADCs are an important class of highly potent biopharmaceutical drugs designed as a targeted therapy for the treatment of cancer by allow sensitive discrimination between healthy and diseased tissue . Potency as anticancer Side effect
- 9. • Drug >> monomethyl auristatin E (MMAE) • chimeric monoclonal antibody AC10 (cAC10, brentuximab). >> Anti-CD30 Antibody • CD30 is a glycoprotein and a member of the tumor necrosis factor (TNF) receptor family. • CD30 is highly expressed by cells in Hodgkin lymphoma and on anaplastic large cell lymphoma (ALCL) cells. Brentuximab vedotin
- 10. SG30 drug • Naked antibody cAC10 antibody
- 11. SG30 drug • entered clinical development in 2003 • administered as weekly doses as high as 12 mg/kg, • In phase 2 trials, the overall response rate (ORR) in ALCL patients was 17 % in HL (0 %ORR) did not warrant further development and therefore a corporate decision was made to discontinue the program.
- 13. • Depends on the cell type receiving the signal • Environment in which the signal is delivered. Signaling mediated by CD30 cell proliferation survival Anti proliferation cell death. cAC10 nuclear factor kappa B
- 14. The chimeric monoclonal antibody cAC10 binds with CD30 : • Promote arrest of tumor cell growth • Cause DNA fragmentation • Targeting the MMAE to the cancer cell
- 18. Anticancer activity of Brentuximab Vedotin 1) Binding of the ADC to CD30-expressing cells 2)Internalization of the ADC–CD30 complex 3) Release of MMAE via proteolytic cleavage. 4) Binding of MMAE to tubulin 5)Disrupts the microtubule network within the cell. 6)Inducing cell cycle arrest and apoptotic death of the cells
- 19. • Rapidly release of potent cytotoxic component inside the tumor cell >>> Rapid effect • Limits systemic release of the cytotoxic agent >>> lower systemic side effect. Benefits of antibody–drug conjugate (ADC)
- 21. • Absorption: intravenous infusion >>> 100% absorption. • Protein binding: MMAE is highly-protein bound drugs that has a plasma protein binding range of 68-82%. • Metabolism: Only a small fraction of MMAE is metabolized primarily via oxidation by CYP3A4 and CYP3A5.
- 22. • Execration:: Monomethyl auristatin E is eliminated by the feces and urine. • Half Life: The terminal half-life is 4-6 days. • Clearance: Monomethyl auristatin E is cleared by the liver but not quantitative studies have been performed.
- 23. Common side effects • Numbness or tingling in fingers and toes It starts within a few days or weeks and usually goes within a few months of finishing treatment. • Feeling or being sick • Tiredness and weakness (fatigue) • Diarrhea • Constipation
- 24. • An increased risk of getting an infection due to a drop in white blood cells. • Cough, sore throat • Aching muscles • A high temperature (fever( • Headaches • A skin reaction a rash, itchy and dry skin • pain passing urine
- 25. Toxicity • The most severe toxic reaction seen in patients is progressive multifocal leukoencephalopathy. • peripheral neuropathy • Pancreatitis • Pulmonary toxicity • bone marrow suppression • infusion reactions • Stevens-Johnson syndrome • tumor lysis syndrome
- 26. • Many other ADCs are in clinical trials and further research towards bi- and multispecific hapten binding antibodies will hopefully lead to a next generation of ADCs. Nanobodies
- 27. • https://www.youtube.com/watch?v=ZpUMsaclrq8 • https://www.youtube.com/watch?v=oeGQjB395Eo • https://www.youtube.com/watch?v=xH8xGT1nRu4 • https://www.youtube.com/watch?v=08q2Th3GQ5w Video animation
- 28. How a Drug Becomes a Drug • https://www.youtube.com/watch?v=U96He40 1wj4
Editor's Notes
- . Monoclonal antibodies (MABs) are copies of a single antibody
- Lymph nodes glands found all over the body that are part of the lymphatic system./ They are connected by lymph vessels Tissue fluid called lymph The lymph glands filter germs out of the lymph fluid and contain specialised white blood cells , Hodgkin lymphoma can start just about anywhere. more than one place The most common in the neck WBC start to divide before they are fully mature. So they can't fight infection as normal white blood cells do
- العلاج التقليدي المستخدم يؤثر على الخلايا الطبيعيىة والسرطانية كونها متشابهة مما يقلل نسبة الخلايا السرطانية المتأثرة من جهة ويزبد من الأعراض الجانبية بسبب تدمير الخلايا الطبيعية من جهة أخرى لحل المشكلة بحثو عن شيء ما يميز الخلايا السرطانية عن غيرها فوجدو ظهور بعض ) (transcription factor )Ag الخاصة بهايمكن الاعتماد عليها ك target
- علاج لمرض lymphoma MMAE>>> >>> targeted by باستخدم AB (Anti CD30) يرتبط بcd30 الموجودة على سطح الخلايا الليمفوية السرطانية
- لكن قبل ظهور فكرة ADCSلهذا الدواء MMAE كان يتم استخدام AB اصلا لوحده بدون أي دواء مربوط كعلاج وكان اسمه SG30 لانه وجدو انه هذا AB بعدارتباطه ينشط نوع من signal الها علاقة ب appoptosis وهذا الدوااء كان اسمه SG30 دخل phase 1 . 2 clinical trial
- لكن قبل ظهور فكرة ADCSلهذا الدواء MMAE كان يتم استخدام AB اصلا لوحده بدون أي دواء مربوط كعلاج وكان اسمه SG30 لانه وجدو انه هذا AB بعدارتباطه ينشط نوع من signal الها علاقة ب appoptosis وهذا الدوااء كان اسمه SG30 دخل phase 1 . 2 clinical trial
- ليس المهم فقط هو احضار مادة ترتبط ب AGواعتبارها Ab الاهم من ذلك معرفة طبيعة الاشرة التي تنشط بعد الارتباط بال AG تعتمد على نوع االرابط لانه CD30 موجود بالاصل على سطح الخلية لزيادة الانقسام مثل nuclear factor kappa B
- لما ركبو الدوا على AB استخدمو رابط مكوناته تناسب تكوين رابطة من جهة AB وترتبط فيه (تعمل روابط مع s of custine a.a ومكوناته من جهه الدواء قادرة على عمل رو بط مناسبة من جهة الدواء للحفاظ عليه مستقر في الدم حتى يصل للخلايالاالسرطانيةد دون ان يؤثر على االخلايا الطبيعية ولكن بنفس الوقت هذا الرابط يحتوي على مكونات تمكن انزيمات القطع (proteases( انها تشتغل عليه وتفصل الدواء عن الAB في الوقت المناسب بعد دخولها للخلية السرطانية The linker system in brentuximab vedotin, which consists of a thiol reactive maleimid _o_ caproyl spacer, the dipeptide valine–citrulline linker, and a self-immolative, p-amino-benzyloxycarbonyl or PABC, spacer, is designed to be stable in the bloodstream
- من ضمن التحديات اللي واجهتهم انه هذه الجزيئات بالنسبة لنانو كبيرة نوعا ما فممكن يستخدموvariable chain fragment of AB