Transtuzumab is a monoclonal antibody (trade name Herceptin). it is used to treat breast cancer. Transtuzumab is given alone or in combination with other treatment. In many cases, combination treatment with chemoterapy has been found to yield better result. Herceptin is given via intravenous infusion in the arm or hand. basically it is Humanized anti-HER2 antibody by Genentech approved by FDA in September 1998. The drug was jointly developed by that company, where the antibody was first discovered by the scientist that included Dr. Axel Ullrich, and the jonsson cancer center at UCLA , by recombinant DNA technology in a mammalian cell (Chinese hamster ovary) culture containing antibiotic Gentamicin.
Transtuzumab, a recombinant DNA derived humanized anti-HER2 monoclonal antibody, is an antineoplastic agent. Transtuzumab ia an IgG1 kappa Immunoglobulin containing human framework regions and the complemantarity-determining regions of a murine antibody (4D5) that binds to HER2/neu, tranmembrane protein that is overexpressed in selected cancer cells. Herceptin is a sterile, white to pale yellow, preservative free lyophilized powder for intravenous administration. Each multi use vial of Herceptin contain 440 mg transtuzumab, 400 mg alfa, alfa trehalose dehydrate, 9.9 mg L-histidine HC1, 6.4 mg L-histidin, and 1.8 mg polysorbate 20, U.S.P. Reconstitution with 20 ml of appropriate diluents (BWFI or SWFI ) yields a solution containing 21 mg/ml transtuzumab, at a pH of approximately 6.0.
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Transtuzumab was originally developed in mice, as a mouse antibody. Because human have immune reaction to mouse protein, it was later developed into human (humanized) antibody. Because the antibodies were produced from one cell that was grown into a clone of identical cells, it is called a monoclonal antibody. The molecular formula is C6470H10012N172602013S42 having molecular mass of 145531.5 g/mol.
Antibodies consist of two identical light chain and two identical heavy chain, which form a Y shape, and connected throgh disulphide bond. Antigen binding occurs at the end of the arms of the Y, and each arm is antigen binding fragment (Fab). Thus each antibody molecule can bind two antigens. The ends of the arm vary extensively in sequence and provide the binding specificity for the antigen. Each variable domain contains three complementry-determining regions (CDRs) to give a total of six for binding each antigen molecule.
The discovery of HER2 gene amplification in upto 30% of woman with breast cancer led to development of transtuzumab, a humanized recombinant monoclonal antibody directed against the HER2 receptor protein on breast cancer cell. In large multicenter trials of transtuzumab as a single agent or in combination with chemotherapy as first line or second line therapy for metastatic breast cancer. Response rate have ranged from 12% to 23 % for single agent transtuzumab and from 25% to 62% for transtuzumab plus chemotherapy. Transtuzumab increased time to disease progression and survival time when administered in combination with chemotherapy. The National comprehensive cancer network guidelines for the treatment of breast cancer now include transtuzumab and paclitaxel as an poption for patient with Metastatic breast cancer in which the HER2 receptor protein is overexpressed.Transtuzumab administered weekly, with an initial i.v. dose of 4 mg/kg followed by weekly doses of 2 mg/kg.
Transtuzumab, either as a single agent or in combination with chemotherepy, can be an effective therapeutic option for metastatic breast cancer patient who overexpress the HER2 receptor protein and had changed the standard of care.These encouraging results led to approval of transtuzumab as an anticancer agent in several countries.
Flourescence In situ Hybridization (FISH) is a method used to determine women with HER2/neu overexpression in metastatic breast cancer which are likely to benefit from transtuzumab. The FISH test is considered the most accurate test for the determination of HER2/neu gene malfunction.
MECHANISM OF ACTION
The way in which Transtuzumab acts :
(a) By binding to HER2 receptors on the tumour cell surface, it blocks HER2 receptors, hence the tumour cell is not activated to grow or divide.
(b) The natural killer cells detect transtuzumab attached to the HER2 receptor aa abnormal and kill them. Thus it stimulates and signals the immune system to destroy breast cancer cells. Transtuzumab is a mediator of antibody-dependant
Cellular cytotoxicity (ADCC).
(c) Transtuzumab and conventional anti-cancer agents act in a different manner. But when given together, the two drugs are synergistic in nature and more effectively decrease the tumour size, increase the median time of disease progression and also improve the one year survival rates.
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Intravenous infusion of 10-500 mg doses once weekly have dose-dependant Pharmacokinetics.With a loading dose of 4 mg/kg and weekly maintenance dose of 2 mg/kg. a mean half lfe of 5.8 days was seen. Mean half life increased, and clearance decreased at 10 mg and 500 mg dose level respectively. Disposition of transtuzumab is not altered based on age or serum creatinine upto 2 mg/dl. The volume of distribution is 44mL/kg. Given weekly at highest dose of 500 mg. the Mean peak serum concentration is 377 Âµg/ml
In studies of woman receiving adjuant therapy for breast cancer, a mean half life of transtuzumab of 16 days (range: 11-23 days) was observed after an initial dose of 6 mg/kg every three weeks. Between weeks 6 and 37, Transtuzumab serum concentration reached at steady state with mean trough and peak concentration of 63 Âµg/ml 216 Âµg/ml respectively.
Sixty percent of women with metastatic breast cancer had detectable circulating extracellular domain of the HER2 receptorwhich ranged as high as 1880 ng/ml (median 11ng/ml). Mean serum concentration of transtuzumab, when administered in combination with paclitaxel, were consistently elevated approximately 1.5 fold as compared with serum concentration of transtuzumab when used in combination with anthracyclin plus cyclophosphamide.
Herceptin is indicated for adjuant treatment of HER2 overexpressing node positive or node negative breast cancer.
As a monotherapy for treatment ofmetastatic breast cancer that has relapsed following prior chemotherapy for metastatic disease.
In combination with anthracyclin and cyclophosphmide for initial treatment of metastatic breast cancer.
As a part of treatment regimen containgdoxorubicin,cyclphosphamide,dosetaxel and carboplatin.
Fever, Chills, nause, diarrhea, headache, pulmonary infilrates, hupoxia and pulmonary insufficiency were reported
Severe hypersensitivity reaction such as anaphylaxis within 24 hours of administraration.
Development of ventricular dyfunction and Congestive heart failure specially if patient receive combination of anthracyclin and transtuzumab.
Arthralgia, Back pain, Myalgia, bone pain, muscle spasm.
Anaemia, neutropenia, thrombocytopenia.