Trastuzumab Herceptin Trastuzu

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is a prototype for future antibody-based immunotherapeutics. It is a recombinant DNA-produced, humanized monoclonal antibody (IgGj-x chain) containing human framework regions and complementarity determining regions (CDRs) of mouse monoclonal antibody, 4D5 (34). It selectively binds to the extracellular domain of the human epidermal growth factor receptor-2 (EGF-2), also known as Her-2 with an affinity of 5 nM. The Her-2 protein is overexpressed on approximately 2530% of primary human breast tumors as well as several other adenocarcinomas. Overexpression of Her-2 is often associated with increased tumor aggressiveness. Because Tras-tuzumab inhibits the proliferation of tumors overexpressing Her-2, it has been shown to be more effective against aggressive tumors in patients with an otherwise poor prognosis (35, 36). One of the effector mechanisms of Trastuzumab tumor cell killing is ADCC (37). ADCC occurs after multiple antibodies have bound to a tumor cell, exposing the Fc portion of the antibodies so that immune cells with IgG Fc receptors, such as macrophages, neutrophils, eosinophils, or NK cells, bind and either phagocytosethe tumor cell or secrete lytic granules that result in tumor cell death. Another potential mechanism of tumor cell kill-ingis induction of p27KIPl and the Rb-related protein, pl30, which results in a significant reduction in the number of cells in S-phase, thereby reducing tumor growth. Trastu-

zumab also induces phenotypic changes in tumors, which include down-modulation of the Her-2 receptor, increased cytokine susceptibility, restored E-cadherin expression, and reduced vascular endothelial growth factor production (38).

Because Her-2/neu is overexpressed on many adenocarcinomas, including breast tumors, Trastuzumab was tested for efficacy in humans with breast cancer. Phase III clinical trials designed to evaluate Trastuzumab in over 500 patients with metastatic breast cancer, either in combination with paclitaxel or as a single agent, demonstrated a significantly longer time to disease progression, a higher overall response rate, longer duration of response, and higher 1-year survival compared with chemotherapy alone. Trastuzumab is supplied lyophilized and reconstituted to 21 with supplied diluent followed by further dilution in 0.95% sodium chloride. In studies using a loading dose of 4 mg/kg followed by weekly infusions of 2 mg/kg, a mean half-life of 5.8 days was observed (range, 1-32 days), with a mean serum concentration between 79 and 123 mg/ml between weeks 16 and 32, respectively. Trastuzumab is approved by the FDA for use in patients with metastatic breast cancer whose tumors overexpress Her-2 and who have previously received one or more chemotherapy regimens for their metastatic disease.

Adverse events from Trastuzumab administration are rare but can result in severe hy-persensitivity, including systemic anaphy-laxis, urticaria, bronchospasm, angioedema, or hypotension. A recent warning of cardiotox-icity has been issued for Trastuzumab, where its use in patients with cardiac dysfunction has resulted in congestive heart failure. This phenomenon is currently under further evaluation and investigation.

2.2.3 Rituximab. Rituxan (Rituximab) was the first monoclonal antibody to be approved by the FDA for cancer treatment. It is a genetically engineered monoclonal antibody that binds to CD20. CD20 is a B-lymphocyte lineage-restricted differentiation antigen found on normal and malignant B-lymphocytes, but not on other normal hematopoietic cells or an-tibody-producingplasma cells. CD20 has a mo

lecular weight of 35 kDa and is a hydrophobic transmembrane protein that regulates cell cycle activation and differentiation during B-lymphocyte development (39). In contrast to Trastuzumab, Rituximab (MW 145 kDa) contains murine heavy and light chain variable regions genetically fused to human IgGl heavy chain constant regions and human k chain constant regions; it is a chimeric mu-rine/human antibody (40,41). The binding affinity for the CD20 antigen is approximately 8 nM. Rituximab-mediated killing of CD20-pos-itive tumor cells in vivo is largely because of ADOC, and to a minor degree, induction of apoptosis by direct ligation of CD20 and complement-dependent lysis (40, 42).

Rituximab was initially approved for the treatment of low-grade or follicular, relapsed, cr refractory CD20-positive B-cell non-Hodgkin's lymphoma. In clinical trials, pa-| tients were treated weekly with either four or eight doses of Rituximab at 375 mg/m2 as an IV infusion at a concentration of 1-4 mg/mL in 0.9% sodium chloride or 5% dextrose in water. The overall response rate for four doses I, weekly was 48% with six complete responses; lor eight doses weekly it was 57% with a 14% complete response rate. The mean serum half-of Rituxan is dependent on dose, but also depends greatly on tumor burden and circulating CD20-positive tumor cells or B-lympho-cytes. Peak and trough serum levels are inversely proportional to the number of circulatingCD20-positive cells. After the third or fourth dose, normal B-cells remain depleted for 6-9 months after treatment, after which cell numbers returned to normal by 12 jnonths. Retreatment can be attempted, because only 4 of 356 patients developed a human anti-chimeric antibody response. How-r, patients should be closely monitored on letreatment for serum sickness. Rituximab is Ipurrently under study for the treatment of r B-cell malignancies including chronic lymphocytic leukemia, Hodgkins disease, and qtner lymphoid malignancies which CD20 I).

Adverse events caused by Rituximab infu-m include severe infusion reactions, includ-hypotension, angioedema, hypoxia, bron-¬°shospasm, pulmonary infiltrates, myocardial 'arction, ventricular fibrillation, and cardio-

genic shock. Tumor lysis syndrome has been observed in patients with high levels of circulation CD20-positive tumor cells, in which rapid reduction of tumor volume is followed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatasemia. Patients with known IgE-mediated immediate hypersensitivity reactions to murine proteins should not receive Rituximab.

2.2.4 Gemtuzumab. Mylotarg (Gemtuzu-mab ozogamicin, CMA-676; Wyeth-Ayerst Laboratories) is an FDA-approved monoclonal antibody specific for CD33, a sialoadhesion protein found on leukemic blasts in 80-90% of patients with acute myelogenous leukemia (AML) (44). OD33 is also expressed on normal immature cells of the myelomonocytic lineage. The humanization of Gemtuzumab is similar to Trastuzumab in that it contains mouse CDRs and human framework and constant regions, such that over 98% of the antibody is human. Gemtuzumab is an IgG4 with a k light chain chemically linked to the cytotoxic agent, calicheamicin. In the formulation of the drug, 50% of the antibody is linked to AT-acetyl-y-calicheamicin through a bifunctional linker at between 4 and 6 moles of calicheamicin per mole of antibody, whereas the remaining 50% is not derivatized (Fig. 6.2) (45). Tumor cell internalization of Gemtuzumab linked to cali-cheamicin results in release of the cytotoxin from the antibody in the lysosome. Calicheamicin is then free to bind to the minor groove in DNA causing double strand breaks and cell death (46). The exact mechanisms of induction of leukemic cell death by Gemtuzumab without calicheamicin linkage are not yet known, but the binding of the antibody to OD33 on the leukemia cell surface is thought to induce apoptosis (47).

Gentuzumab was approved in May 2000 by the FDA for the treatment of patients 60 years and older in first relapse with CD33+ AML who are not considered candidates for other types of cytotoxic chemotherapy. In combined phase II studies, 142 patients with CD33-pos-itive AML in first relapse demonstrated a 30% overall response rate with Mylotarg therapy alone. Treated patients had relatively high incidences of myelosuppression, hyperbiliru-binemia, and elevated hepatic transaminases

Herceptin Chemical Structure

Figure 6.2. Diagram and chemical structure of Gemtuzumab ozogamicin. Calicheamicin (ozogami-cin) is coupled to Gemtuzumab at an average loading of 4-6 moles per mole of antibody. The antibody is linked to N-acetyl y calicheamicin. The molecular weight of the antibody-toxin conjugate is 151153 kD. The injected formulation consists of 50% conjugated antibody and 50% unconjugated antibody.

Figure 6.2. Diagram and chemical structure of Gemtuzumab ozogamicin. Calicheamicin (ozogami-cin) is coupled to Gemtuzumab at an average loading of 4-6 moles per mole of antibody. The antibody is linked to N-acetyl y calicheamicin. The molecular weight of the antibody-toxin conjugate is 151153 kD. The injected formulation consists of 50% conjugated antibody and 50% unconjugated antibody.

(48). The incidences of severe mucositis and infections were low compared with mucositis resulting from conventional chemotherapeu-tic treatment. Sixteen percent of the patients had a complete response (CR), while 19% had a CR requiring platelet transfusions. The clinical data support the use of Gemtuzumab in AML patients with CD33-positive leukemia.

Adverse events caused by the administra-of Gemtuzumab ozogamicin include severe myelosuppression, especially neutropenia, requiring careful hematological monitoring. Patients should be monitored for in fection after Gemtuzumab administration and treated appropriately if necessary. Other adverse events associated with Gem-tuzumab are hypersensitivity reactions, including anaphylaxis, infusion reactions, and pulmonary events including pulmonary edema, dyspnea, pleural effusions, hypoxia, and acute respiratory distress syndrome. Patients with greater than 30,000 leukemic cells/jxL should be considered for leukore-to avoid tumor lysis syndrome, similar to that observed with Rituximab therapy.

2.2.5 Alemtuzumab. Campath (Alemtuzumab) is a recombinant DNA-derived humanized monoclonal antibody directed against CD52, a 21- to 28-kDa cell surface glycoprotein. CD52 is expressed on the surfaces of normal and malignant B- and T-lympho-cytes, NK cells, monocytes, macrophages, a subset of granulocytes, and tissues of the male reproductive tract, but not on hematopoietic stem cells. Alemtuzumab is an IgGl with a k light chain containing human variable framework and constant regions and (CDRs) from a rat monoclonal antibody (Campath-1G). CD52 is a glycosylphosphatidylinositol (GPI)-an-chored protein with unknown function (49). Binding cf Alemtuzumab to CD52 is thought omplement-dependent lysis and ADCC on tumor and normal cells (50).

is indicated for the treatment of B-cell chronic lymphocytic leukemia (B-CLL) in patients who have been treated withalkylatingagents and who have failed flu-darabine therapy. In a study where Alemtu-i zurnab was infused intravenously once weekly a maximum of 12 weeks over a range of erall average half-life during | treatment was about 12 days. Alemtuzumab administered as a 30-mg intravenous infusion three times per week evaluated in CLL patients demonstrated variable peak and trough body during the first few weeks of treatment, but seemed to level off by iweek 6. Inter-patient variability was likely caused ty tumor burden and circulating numbers of leukemia cells. However, increases in serum levels of Alemtuzumab corresponded to stic cells. Clinical trials have shown that in previously treated B-CLL Ipatients, partial responses occur at a rate of with 2-4% CRs. Responses are more in blood and bone marrow compared with lymph nodes. The median duration of res. Because of the strong depleting activity on circulating lymphocytes, ft has been used for purging residual disease in B-CLL, followed by autologous stem-cell transplantation (51, 52).

Alemtuzumab is provided as a sterile, clear, colorless, isotonic solution, pH 6.8-7.4, for infection. Each single use vial of antibody contains 30 mg Alemtuzumab, 24.0 mg sodium chloride, 3.5 mg dibasic sodium phosphate, 0.6

mg potassium chloride, 0.6 mg monobasic potassium phosphate, 0.3 mg polysorbate 80, and 0.056 mg disodium edetate. No preservatives are added. Infusions should be initiated at an initial dose of 3 mg with gradual escalation to 30 mg. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients taking antihy-pertensive medications. If therapy is interrupted for 7 or more days, Alemtuzumab may be reinstituted with gradual dose escalation.

Adverse events are infusion related and are caused by tumor necrosis factor (TNF)-a and release, usually during the first intravenous infusion, and include fever, rigor, nausea, vomiting, and hypotension that responds to steroids. Adverse events are usually less severe with subsequent infusions and can be prevented by with appropriate medication. Antihistamine and acetaminophen are recommended before infusion. Because CD52 is present on many types of leukocytes, immu-nosuppression resulting from depletion of normal B- and T-lymphocytes usually occurs, resulting in an increased risk for opportunistic infections.

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  • j huber
    What happens to herceptin capped cells?
    4 years ago

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