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CETUXIMAB

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Vaishali Kanyal

Cetuximab is a monoclonal antibody used to treat colon cancer, rectal cancer, head and neck cancer, and squamous cell carcinoma. It works by blocking the epidermal growth factor receptor, preventing cancer cell growth and making cells more sensitive to chemotherapy and radiation. Cetuximab is administered intravenously once per week at an initial dose of 400 mg/m2 for 120 minutes then 250 mg/m2 for 60 minutes for subsequent doses. Common side effects include skin rashes, fever, chills, and fatigue. It is most effective for cancers with high levels of epidermal growth factor receptors and a normal KRAS gene.

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CETUXIMAB (ERBITUX 速) Presented by- Vaishali Kanyal Biochemical Engineering (III year) Roll no- 10180110051
Brief description of Cetuximab: Cetuximab (pronounced see-tux-ee-mab) is a type of recombinant monoclonal antibody Brand name: Erbitux. Formula: Molecular mass- 145618 g/mol Erbitux 5 mg/mL solution for infusion. Cetuximab is a colourless liquid. It is a treatment for : Advanced bowel cancer in combination with chemotherapy (CRC). Advanced bowel cancer (CRC) on its own in patients who have had oxaliplatin and irinotecan chemotherapy that is no longer working. Locally advanced squamous cell cancer of the head and neck combined with radiotherapy.(SCCHN) Head and neck cancer that has come back or has spread (combined with platinum based chemotherapy). C6484H10042N1732O2023S36
CETUXIMAB
Mechanism:When epidermal growth factor (a protein made in the body) attaches to the epidermal growth factor receptors(EGFRs), this triggers the cancer to grow and spread. Cetuximab locks on to epidermal growth factor receptors. This stops them from stimulating the cancer to grow and spread. It may also make the cancer cells more sensitive to the effects of chemotherapy and radiotherapy. It also helps the immune system to recognise the cancer cells so that it can attack them Cetuximab is most likely to work for cancers with large numbers of EGFRs on their surfaces. Condition for using Cetuximab ; it only works for bowel cancers that have a normal KRAS gene. So before it's used to treat bowel cancer, the cancer cells are tested for changes (mutations) in the KRAS gene. This helps the doctors decide if the treatment is appropriate. Testing can be done on samples of the cancer cells at the same time as diagnosis of the cancer or by using cells from previous biopsies or surgery.
Pharmacology Cetuximab mediated ADCC in SCC and other tumour cells, is dependent on cetuximab concentration and EGFR expression levels, at clinically-relevant concentrations. K-RAS gene mutation was significantly associated with an absence of clinical response to cetuximab in CRC (colorectal cancer ) patients. Combination treatment with FOLFOX (oxaliplatin, Folinic acid, 5- Fluorouracil) and FOLFIRI (5-FU, folinic acid and irinotecan) increased the efficacy of cetuximab against some CRC tumour cells in vivo. The in vitro efficacy of cetuximab against an SCC cell line was improved by combination treatment with platinum derivatives (cisplatin, carboplatin and oxaliplatin), but was dependent on the sequence of treatment. Erbitux is administered once a week . The initial dose is 400 mg/m2 body surface area. All subsequent weekly doses are 250 mg/m2 each. Half life- 72-96 hours.
Method of administration:- Erbitux 5 mg/mL is administered intravenously with an infusion pump, gravity drip or a syringe pump. For the initial dose, the recommended infusion period is 120 minutes. For the subsequent weekly doses, the recommended infusion period is 60 minutes. The maximum infusion rate must not exceed 10 mg/min.
Production: Cetuximab is a chimeric monoclonal IgG1 antibody produced in a mammalian cell line by recombinant DNA technology. Gene construct The chimeric antibody is encoded from the variable region cDNAs of the murine monoclonal antibody M225 and the cDNAs for human kappa and gamma 1 constant regions. The cDNAs are inserted into an expression vector containing separate expression cassettes for light chain and heavy chain, respectively. Cell culture and harvesting Cetuximab is produced by cell culture in 10,000 L or 12,000 L scale stirred tank bioreactors, using batch mode. All cell culture steps upon thawing of WCB(working culture bank ) is performed in serum-free media. Purification The cell-free media is concentrated and classified by diafiltration at 0.2亮m. The final purification step is diafiltration into formulation buffer. This solution is sterile filtered and can be stored 1 year at 2-8 属C. Final preparation of drug substance is performed by dilution of the concentrated bulk to 2 mg/ml in formulation buffer (NaCl, Sodium dihydrogen phosphate, disodium phosphate dihydrate, water ).
Cost and manufacturers:- The cost is $3.20/mg. 100mg vial - $320.00, 400mg - $1280.00. Rs. 17,500 per vial in India. Manufactured by- 1. Germany- Merck KGaA ,Boehringer Ingelheim Pharma GmbH & Co KG. 2. USA- ImClone
Side effects:-Infusion-related side effects :-In more than 1 out of 100 patients these side effects are likely to be severe. Such reactions may be allergic in nature. They normally occur during the infusion, within 1 hour afterwards, or sometimes also after this period. fever ,chills, dizziness, breathing difficulties, hives, fainting, chest pain. Side effects concerning the skin- Most of these side effects develop within the first three weeks of treatment. They usually disappear over time after the end of Erbitux therapy: acne-like skin alterations, itching ,dry skin, scaling, excessive hair growth, nail disorders. Side effects concerning the lungs- In uncommon cases (may affect up to 1 in 100 people) patients may experience an inflammation of the lungs (called interstitial lung disease) Other side effects :-inflammation of the lining of the intestine, mouth, and nose (in some cases severe), which may lead to nose bleeding in some patients, headache, tiredness, irritation and redness of the eye ,diarrhoea, etc. If a patient receives Erbitux in combination with an anticancer medicine(containing fluoropyrimidines) or radiation therapy it is more likely that he/she experience the effects of the other therapy as well : chest pain, heart attack, heart failure, inflammation of the lining of the intestine and mouth,skin reactions typical for radiation therapy, etc.
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CETUXIMAB

  • 1. CETUXIMAB (ERBITUX 速) Presented by- Vaishali Kanyal Biochemical Engineering (III year) Roll no- 10180110051
  • 2. Brief description of Cetuximab: Cetuximab (pronounced see-tux-ee-mab) is a type of recombinant monoclonal antibody Brand name: Erbitux. Formula: Molecular mass- 145618 g/mol Erbitux 5 mg/mL solution for infusion. Cetuximab is a colourless liquid. It is a treatment for : Advanced bowel cancer in combination with chemotherapy (CRC). Advanced bowel cancer (CRC) on its own in patients who have had oxaliplatin and irinotecan chemotherapy that is no longer working. Locally advanced squamous cell cancer of the head and neck combined with radiotherapy.(SCCHN) Head and neck cancer that has come back or has spread (combined with platinum based chemotherapy). C6484H10042N1732O2023S36
  • 4. Mechanism:When epidermal growth factor (a protein made in the body) attaches to the epidermal growth factor receptors(EGFRs), this triggers the cancer to grow and spread. Cetuximab locks on to epidermal growth factor receptors. This stops them from stimulating the cancer to grow and spread. It may also make the cancer cells more sensitive to the effects of chemotherapy and radiotherapy. It also helps the immune system to recognise the cancer cells so that it can attack them Cetuximab is most likely to work for cancers with large numbers of EGFRs on their surfaces. Condition for using Cetuximab ; it only works for bowel cancers that have a normal KRAS gene. So before it's used to treat bowel cancer, the cancer cells are tested for changes (mutations) in the KRAS gene. This helps the doctors decide if the treatment is appropriate. Testing can be done on samples of the cancer cells at the same time as diagnosis of the cancer or by using cells from previous biopsies or surgery.
  • 5. Pharmacology Cetuximab mediated ADCC in SCC and other tumour cells, is dependent on cetuximab concentration and EGFR expression levels, at clinically-relevant concentrations. K-RAS gene mutation was significantly associated with an absence of clinical response to cetuximab in CRC (colorectal cancer ) patients. Combination treatment with FOLFOX (oxaliplatin, Folinic acid, 5- Fluorouracil) and FOLFIRI (5-FU, folinic acid and irinotecan) increased the efficacy of cetuximab against some CRC tumour cells in vivo. The in vitro efficacy of cetuximab against an SCC cell line was improved by combination treatment with platinum derivatives (cisplatin, carboplatin and oxaliplatin), but was dependent on the sequence of treatment. Erbitux is administered once a week . The initial dose is 400 mg/m2 body surface area. All subsequent weekly doses are 250 mg/m2 each. Half life- 72-96 hours.
  • 6. Method of administration:- Erbitux 5 mg/mL is administered intravenously with an infusion pump, gravity drip or a syringe pump. For the initial dose, the recommended infusion period is 120 minutes. For the subsequent weekly doses, the recommended infusion period is 60 minutes. The maximum infusion rate must not exceed 10 mg/min.
  • 7. Production: Cetuximab is a chimeric monoclonal IgG1 antibody produced in a mammalian cell line by recombinant DNA technology. Gene construct The chimeric antibody is encoded from the variable region cDNAs of the murine monoclonal antibody M225 and the cDNAs for human kappa and gamma 1 constant regions. The cDNAs are inserted into an expression vector containing separate expression cassettes for light chain and heavy chain, respectively. Cell culture and harvesting Cetuximab is produced by cell culture in 10,000 L or 12,000 L scale stirred tank bioreactors, using batch mode. All cell culture steps upon thawing of WCB(working culture bank ) is performed in serum-free media. Purification The cell-free media is concentrated and classified by diafiltration at 0.2亮m. The final purification step is diafiltration into formulation buffer. This solution is sterile filtered and can be stored 1 year at 2-8 属C. Final preparation of drug substance is performed by dilution of the concentrated bulk to 2 mg/ml in formulation buffer (NaCl, Sodium dihydrogen phosphate, disodium phosphate dihydrate, water ).
  • 8. Cost and manufacturers:- The cost is $3.20/mg. 100mg vial - $320.00, 400mg - $1280.00. Rs. 17,500 per vial in India. Manufactured by- 1. Germany- Merck KGaA ,Boehringer Ingelheim Pharma GmbH & Co KG. 2. USA- ImClone
  • 9. Side effects:-Infusion-related side effects :-In more than 1 out of 100 patients these side effects are likely to be severe. Such reactions may be allergic in nature. They normally occur during the infusion, within 1 hour afterwards, or sometimes also after this period. fever ,chills, dizziness, breathing difficulties, hives, fainting, chest pain. Side effects concerning the skin- Most of these side effects develop within the first three weeks of treatment. They usually disappear over time after the end of Erbitux therapy: acne-like skin alterations, itching ,dry skin, scaling, excessive hair growth, nail disorders. Side effects concerning the lungs- In uncommon cases (may affect up to 1 in 100 people) patients may experience an inflammation of the lungs (called interstitial lung disease) Other side effects :-inflammation of the lining of the intestine, mouth, and nose (in some cases severe), which may lead to nose bleeding in some patients, headache, tiredness, irritation and redness of the eye ,diarrhoea, etc. If a patient receives Erbitux in combination with an anticancer medicine(containing fluoropyrimidines) or radiation therapy it is more likely that he/she experience the effects of the other therapy as well : chest pain, heart attack, heart failure, inflammation of the lining of the intestine and mouth,skin reactions typical for radiation therapy, etc.