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PubMed2005

The role of mitoxantrone in the treatment of indolent lymphomas.

With the introduction of newer therapeutic approaches, survival in indolent non-Hodgkin's lymphoma (NHL) appears to be improving. Mitoxantrone (Novantrone; Serono, Inc.; Rockland, MA, http://www.seronousa.com), an anthracenedione with low cardiotoxic potential, has demonstrated activity in indolent NHL in combination with fludarabine (Fludara; Berlex Laboratories; Wayne, NJ, http://www.berlex.com) and other agents. In a Southwest Oncology Group trial (SWOG 9501), treatment with fludarabine and mitoxantrone (FM) induced a complete remission (CR) rate of 44% and a partial remission (PR) rate of 50% in untreated patients. The estimated 4-year progression-free survival (PFS) rate was 38%. In a multicenter Italian trial comparing the efficacy of FM with that of cyclophosphamide, doxorubicin (Adriamycin; Bedford Laboratories; Bedford, OH, http://www.bedfordlabs.com), vincristine (Oncovin; Eli Lilly and Company; Indianapolis, IN, http://www.lilly.com), and prednisone (Deltasone; Pfizer Pharmaceuticals; New York, NY, http://www.pfizer.com), CHOP, followed by rituximab (Rituxan; Genentech, Inc.; South San Francisco, CA, http://www.gene.com) for patients with incomplete clinical or molecular responses, the CR and molecular response rates were significantly higher in the FM arm, but the PFS and overall survival (OS) rates did not differ between the two arms. However, FM was also significantly less toxic than CHOP. The administration of rituximab following chemotherapy resulted in higher clinical and molecular response rates in both arms. In a separate trial, FM plus dexamethasone (Decadron; Merck and Co., Inc.; Whitehouse Station, NJ, http://www.merck.com), FND, plus concurrent rituximab produced a CR rate of 92%. In a randomized German study, patients with indolent lymphomas received FM plus cyclophosphamide (FCM) or FCM with rituximab. PFS and OS times were significantly better for patients who received combined chemoimmunotherapy. Mitoxantrone-based regimens are highly active and well tolerated in patients with both relapsed and previously untreated indolent lymphomas. The addition of rituximab appears to increase the activity of the FM, FND, and FCM regimens. Although the results of the Italian multicenter study support the superiority of FM over CHOP in terms of clinical and molecular responses and tolerability, additional studies using rituximab in combination with both of these regimens should be attempted to determine the possible further benefit of both in the management of indolent lymphoma. Because cure remains elusive in patients with indolent lymphoma, maximum prolongation of PFS with minimal toxicity and maximum preservation of quality of life should remain central goals of treatment.

Antibodies, Monoclonal↗
PubMed2003

Overview of bladder cancer trials in the Cancer and Leukemia Group B.

The Cancer and Leukemia Group B (CALGB) Genitourinary Committee has developed a broad range of clinical trials across most stages of bladder cancer. Recurrence rates of superficial bladder cancer after transurethral resection range from 50-70%. Although adjuvant bacillus Calmette-Guerin reduces the risk of disease recurrence or progression, only 30% of patients have long-term disease-free survival. Because the development of novel secondline agents is needed, the CALGB is evaluating the utility of intravesicle gemcitabine as well as an oral proapoptotic agent (CP-461). In patients with locally advanced disease with an increased risk of disease recurrence after cystectomy, a randomized trial of conventional chemotherapy versus sequential dose-dense therapy is under development. The gemcitabine/cisplatin combination has become a commonly used regimen for the treatment of advanced transitional cell carcinoma (TCC). The CALGB is undertaking a Phase II study that incorporates a fixed dose rate gemcitabine infusion in this regimen, together with a selective epidermal growth factor receptor tyrosine kinase inhibitor, Iressa (Astra Zeneca, Wilmington, DE). In patients with renal insufficiency, a regimen of carboplatin, gemcitabine, and Iressa is planned. Novel agents, including arsenic trioxide and trastuzumab (Herceptin; Genentech, Inc., South San Francisco, CA), are being evaluated as secondline therapy in patients with advanced TCC who have disease progression after frontline therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Status of c-erbB-2 in gastric adenocarcinoma: a comparative study of immunohistochemistry, fluorescence in situ hybridization and enzyme-linked immuno-sorbent assay.

c-erb-2 amplification and overexpression are currently attracting a great deal of attention because a new adjuvant therapy using an antibody against the c-erbB-2 gene product, trastuzumab (Herceptin; Genentech, Inc., South San Francisco, CA), has proved effective in treating breast cancer with amplification and/or overexpression of c-erbB-2. Aberrations of c-erbB-2 have also been detected in ovarian, endometrial and gastric carcinomas at varied frequencies. Amplification of the c-erbB-2 locus (17q12-q21.32), overexpression of c-erbB-2 protein (p185) and serum levels of soluble c-erbB-2 protein fragments (p105) were examined in gastric cancer patients using fluorescence in situ hybridization (FISH), immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), respectively. Overexpression of c-erbB-2 protein was found in 29 (8.2%) of the 352 gastric carcinomas analyzed. In FISH analysis, all tumors with 3+ immunostaining and 1 of 5 tumors with 2+ staining showed high-level amplification of c-erbB-2. Pre-operative serum p105 was quantified in serum specimens from 129 patients with gastric cancer and 28 patients with benign diseases. There were no significant differences in the serum p105 levels among 11 patients with c-erbB-2-overexpressing carcinomas, 118 patients with c-erbB-2 non-overexpressing carcinomas and 28 controls, although a single case of gastric carcinoma overexpressing c-erbB-2 with extensive liver metastasis had a higher level than the cut-off value. The mechanisms of overexpression of p185 and high-level amplification of c-erbB-2 in gastric adenocarcinomas seem similar to those well-established in breast cancers. Patients having gastric adenocarcinoma with c-erbB-2 amplification are potential candidates for a new adjuvant therapy using humanized monoclonal antibody.

Adenocarcinoma↗
PubMed2005

Hepatic tumor growth: target for angiogenesis inhibition?

Pathologic angiogenesis induced by a tumor is essential for its survival. The promise of tumor inhibition by targeting angiogenesis over the past several years has translated into numerous ongoing clinical trials. Recently, in a phase III trial involving patients with metastatic colorectal cancer, Bevacizumab (Genentech, Inc, San Francisco, CA), a recombinant humanized monoclonal antibody against vascular endothelial growth factor used in conjunction with standard chemotherapy was shown to increase survival, progression-free survival, response rate, and duration of response compared to chemotherapy alone. Thus far, duration of the increased response remains less than 6 months. The majority of deaths in patients with colorectal cancer are related to hepatic metastases. It is hoped that novel approaches directed at the complex interactions between tumor and microenvironment in the angiogenic process will strengthen the therapeutic armamentarium against hepatic malignancies.

Angiogenesis Inhibitors↗
PubMed2000

Locally advanced breast cancer.

Over the past 20 years, the prognosis for women diagnosed with locally advanced breast cancer (LABC; clinical stages IIB through IIIB) has improved significantly with recognition of the efficacy of multimodal therapy for reducing both local and distant recurrences, even in patients with inflammatory breast cancer (IBC). Most patients will respond to induction, or neoadjuvant, chemotherapy (NAC) with an anthracycline-based regimen, enabling many patients with large but operable tumors to undergo breast-conserving surgery (BCS) and enabling resection in most patients with inoperable disease. However, only a small percentage of patients achieve a pathologic complete response (CR) with this approach. Long-term disease-free survival (DFS) and overall survival (OS) correlate with the extent of residual disease in the breast and axillary nodes following NAC. The addition of paclitaxel or docetaxel, either in combination with an anthracycline or as a separate regimen administered before or after anthracycline-based therapy, increases clinical and pathologic response rates and may improve DFS. With the possible exception of patients with IBC, BCS does not compromise outcome. Partial mastectomy should be accompanied by standard nodal dissection in patients with clinically or radiographically positive axillae; in patients with negative axillae, sentinel lymph node (SLN) sampling, with subsequent axillary dissection reserved for patients with involved nodes, may reduce postoperative morbidity. Patients who received only anthracycline-based NAC who are found to have significant residual disease in the breast or involved axillary nodes at surgery should receive adjuvant chemotherapy with paclitaxel. Postoperative radiation to the residual breast or chest wall and regional nodal areas reduces locoregional recurrences, but its impact on OS remains controversial. Adjuvant hormonal therapy with tamoxifen improves DFS and OS in patients with hormone receptor (HR)-positive tumors, and ovarian ablation should be considered in premenopausal patients with HR-positive tumors and multiple involved nodes or stage IIIB disease. Neoadjuvant hormonal therapy with either tamoxifen or an aromatase inhibitor may benefit frail or elderly patients with HR-positive tumors for whom chemotherapy is not an option. No advantage has been demonstrated for high-dose chemotherapy requiring hematopoietic stem-cell support as either NAC or adjuvant therapy in LABC. Newer treatment approaches, including trastuzumab (Herceptin, Genentech, Inc., South San Francisco, CA), in patients with Her-2-overexpressing tumors or other biologic agents, do not have a proven role in the management of LABC at this time.

Antineoplastic Agents↗
PubMed1991

A collaborative study to establish a U.S. reference for tissue plasminogen activator (t-PA).

In 1987 the Second International Standard for tissue plasminogen activator (t-PA) was established by the World Health Organization following an international collaborative study. At that time, the Center for Biologics Evaluation and Research (CBER) decided to establish a national reference t-PA to be used in lot release potency testing of Alteplase, a licensed t-PA biological or of other t-PAs in development. A candidate recombinant t-PA (rt-PA) preparation was donated by Genentech, Inc. (South San Francisco, California) for this purpose and a collaborative study was launched to calibrate this material against the 2nd I.S. Four laboratories (including the Center for Biologics Evaluation and Research (CBER) and three manufacturers) participated in the study to establish the potency of the rt-PA preparation using a clot lysis assay. The results indicate that the potency of the U.S. reference for t-PA is 2900 international units (IU) per vial.

Humans↗
PubMed2006

Capillary electrophoresis-mass spectrometry as a characterization tool for therapeutic proteins.

With the increasing use of capillary electrophoresis (CE) in the biotechnology industry, there is a demand for analytical tools and methodology that can be used to characterize CE profiles. This article describes the implementation and optimization of a robust online CE-mass spectrometry (CE-MS) system used for the characterization of several CE assays developed at Genentech Inc. These assays include CE as a complement to reverse-phase peptide mapping for the identification of small peptides eluting in the void volume, profiling N-linked glycopeptide heterogeneity, and determining O-linked site occupancy. In addition, CE-MS was used to confirm major 8-aminopyrene-1,3,6-trisulfonate (APTS)-labeled glycans released from recombinant antibodies that are routinely profiled by CE-laser-induced fluorescence (CE-LIF). For each study, CE-MS was able to successfully identify components seen in UV or LIF electropherograms, thereby expanding the capability of CE and CE-MS for profiling biomolecules.

Antibodies, Monoclonal↗
PubMed2005

Extramammary Paget's disease: analysis of growth signal pathway from the human epidermal growth factor receptor 2 protein.

Paget's disease is a skin cancer characterized by characteristic (Paget) cells scattered in the epidermis. Although its prognosis is generally favorable with surgical resection, the clinical outcome turns unfavorable in cases with recurrence and metastasis. Therefore, establishment of effective therapeutic regimens is required for advanced Paget's disease. The human epidermal growth factor receptor 2 (HER2) protein, a transmembrane growth factor receptor, is frequently overexpressed in malignancies, causing activation of the phosphatidylinositol 3 kinase (PI3K) and extracellular signal-regulated kinase (ERK) signal pathways. Recently, HER2-targeting molecular therapy using trastuzumab (Herceptin; Genentech, Inc, South San Francisco, Calif) was revealed to be effective in advanced breast cancers overexpressing HER2 protein. Here, we analyzed the correlation between activation of the HER2 signal pathways and clinicopathologic parameters of 36 extramammary Paget's disease samples from 34 Japanese patients, using immunohistochemical analyses for HER2, phosphorylated HER2, phosphorylated AKT, and phosphorylated ERK proteins. We found overexpression of the HER2 protein in 19.4% (7) of the lesions, 3 of which showed HER2 amplification by chromogenic in situ hybridization. Phosphorylated HER2 protein was detected in 12 lesions (33.3%), including 2 of the 7 HER2-overexpressing lesions. Phosphorylated AKT was detected in approximately 75.0% (27/36) and phosphorylated ERK in 38.9% (14/36). Both HER2 and AKT were simultaneously phosphorylated in 9 cases (25.0%) and HER2 and ERK in 9 cases (25.0%), but all 3 molecules were phosphorylated in only 1 sample. Phosphorylated ERK correlated with the maximum diameter of the tumors (P < .025), but other immunohistochemical parameters failed to show any correlation with clinicopathologic features. These results suggest the contribution of the HER2 signaling pathway to the pathogenesis and progression of some cases of extramammary Paget's disease, for which clinical use of molecular target therapy against the HER2 pathway is warranted.

Aged↗
PubMed2006

Accuracy of US Food and Drug Administration-cleared IgE antibody assays in the presence of anti-IgE (omalizumab).

BACKGROUND: Although serological IgE measurements can aid in efficacy assessment of patients with asthma on omalizumab (Xolair [Genentech, Inc., South San Francisco, Calif]; humanized IgG1 antihuman IgE Fc), its effect on clinically used IgE assay performance is unknown. OBJECTIVE: This study investigated the hypothesis that IgE:IgG-anti-IgE immune complex formation after omalizumab administration diminishes accuracy and increases variability of IgE assays performed in diagnostic immunology laboratories. METHODS: Plasma from 4 atopic adults was incubated with omalizumab (50 or 200 molar excess to IgE) or buffer. Paired specimens were sent masked to 159 clinical laboratories in the College of American Pathologists Diagnostic Allergy Proficiency Survey (cycles SE-C-2003, SE-A-2005). Inhibitory effects produced by omalizumab on accuracy and reproducibility of US Food and Drug Administration (FDA)-cleared total and allergen-specific IgE assays were computed by using national proficiency survey data. RESULTS: Total serum IgE levels measured in the 2 ImmunoCAP assays were minimally reduced (2.4-9.0%) by the presence of omalizumab, whereas 5 other assays showed marked reductions from 12.5% to 67.2% (P < .001) that increased in proportion to total serum IgE levels. The degree of interference was not large enough to produce detectable misclassification of IgE antibody results (positive to negative) in 4 multiallergen screening assays. Of 11 FDA-cleared IgE antibody assays, only 3 (ImmunoCAP, UniCAP, Immulite-2000) generated quantitative IU/mL results that could be assessed for interference. Omalizumab produced 0.8% to 27.8% reduction in allergen-specific IgE levels across 8 allergen specificities. CONCLUSION: Although as much as 62% loss in accuracy was observed in FDA-cleared human IgE assays, the ImmunoCAP system was sufficiently robust to provide accurate and reproducible total and allergen-specific IgE antibody results in a clinical setting where therapeutic levels of omalizumab are present in serum. CLINICAL IMPLICATIONS: Accurate monitoring of total and allergen-specific IgE, together with free IgE levels, in serum from patients on omalizumab may help optimize dosing and maximize the efficacy of Xolair therapy.

Adult↗
PubMed2005

Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration twelve-week results of an uncontrolled open-label clinical study.

PURPOSE: To evaluate the short-term safety of systemic bevacizumab (Avastin, Genentech, Inc., South San Francisco, CA) and its effects on visual acuity (VA) and subfoveal choroidal neovascularization (CNV) in patients with neovascular age-related macular degeneration (AMD). DESIGN: Open-label, single-center, uncontrolled clinical study. PARTICIPANTS: Age-related macular degeneration patients with subfoveal CNV (N = 9) and best-corrected VA letter scores of 70 to 20 (approximate Snellen equivalent, 20/40-20/400). METHODS: Patients were treated at baseline with an infusion of bevacizumab (5 mg/kg), followed by 1 or 2 additional doses given at 2-week intervals. Safety assessments were performed at all visits. Ophthalmologic evaluations included protocol VA measurements and ocular examinations, along with optical coherence tomography (OCT) imaging, fluorescein angiography, and indocyanine green angiography. MAIN OUTCOME MEASUREMENTS: Safety assessments were performed, along with assessments of changes from baseline in VA scores, OCT measurements, and angiographic lesion characteristics. RESULTS: There were no serious ocular or systemic adverse events identified. By 6 weeks, the only adverse event identified was a mild elevation of systolic blood pressure (BP) (+12 mmHg; P = 0.035), and this elevation was controlled by either changing or initiating antihypertensive medication. By 12 weeks, the elevation of systolic BP was no longer significant (P = 0.51). In the study eyes, significant increases in VA were evident within 1 week of treatment, and by 12 weeks, the median and mean VA letter scores increased by 8 letters (P = 0.011) and 12 letters (P = 0.008), respectively. The median and mean central retinal thickness measurements decreased by 157 microm (P = 0.008) and 177 microm (P = 0.001), respectively. In the fellow eyes at 12 weeks, the median and mean VA letter scores increased by 27 letters (P = 0.018) and 16 letters (P = 0.012), and the median and mean central retinal thickness measurements decreased by 59 mum (P = 0.028) and 92 microm (P = 0.06). In all study eyes, angiography revealed a marked reduction or an absence of leakage from CNV. CONCLUSION: Overall, bevacizumab therapy was well tolerated, with an improvement in VA, OCT, and angiographic outcomes. Although these preliminary results are promising, a randomized controlled clinical trial is necessary before concluding that systemic bevacizumab therapy is safe and effective for patients with neovascular AMD.

Aged↗
PubMed2000

Tissue plasminogen activator to treat impending pupillary block glaucoma in patients with acute fibrinous HLA-B27 positive iridocyclitis.

PURPOSE: To report the use of intracameral tissue plasminogen activator to dissolve fibrinous membranes and break posterior synechiae in patients with acute HLA-B27-positive iridocyclitis with impending pupillary block. METHODS: Two patients with severe acute fibrinous iridocyclitis and seclusio pupillae were identified. Because of the concern of impending pupillary block, intracameral tissue plasminogen activator (12.5 microg in 0.1 ml, Activase; Genentech, Inc, South San Francisco, California) was injected with a 25-gauge needle through the corneal limbus. RESULTS: Both patients showed complete dissolution of fibrin with disruption of posterior synechiae. There were no adverse events after injection. Neither patient required further invasive intervention, and both fully recovered with medical management. CONCLUSIONS: Intracameral tissue plasminogen activator is a safe and effective agent for patients with severe acute iridocyclitis and pupillary seclusion. Patients with clinical signs suggestive of impending pupillary block glaucoma may be considered for tissue plasminogen activator injection to avoid the possible need for emergency surgical iridectomy and synechiolysis.

Acute Disease↗
PubMed1997

Pioneering recombinant growth hormone manufacturing: pounds produced per mile of height.

The first efforts to produce recombinant human growth hormone (GH) for clinical use were begun by scientists at Genentech, Inc., almost a generation ago, late in 1979. The very small market for GH that was predicted at the time led to this manufacturing effort being done as a demonstration project. Among the early issues was whether the Escherichia coli host cell could be routinely produced in a stable manner and be inactivated after the GH production run (as required by Federal guidelines) without the GH being permanently denatured. A 10 L E. coli process was developed, and phase I testing began in early 1981. The approval of this recombinant GH product by the FDA in 1985 paved the way for many improvements and a sustained production effort in the next decade. The more than 1990 fermentation runs have produced tons of E. coli and more than 130 pounds of GH for both clinical research and the treatment of severely short children.

Biotechnology↗
PubMed2001

New adjuvant strategies for breast cancer: meeting the challenge of integrating chemotherapy and trastuzumab (Herceptin).

Improvements in breast cancer treatment will arrive with better understanding of its biology and through biologically oriented therapeutic interventions as well as better identification of patient populations susceptible to benefit from classical therapies (endocrine and chemotherapy). Among the new chemotherapies, the taxanes have emerged as powerful agents in the treatment of metastatic breast cancer and a strong emphasis has been pursued into their development in the adjuvant setting. Two generations of adjuvant pivotal trials with taxanes have been developed. The first generation compared taxane/anthracycline regimens to nontaxane combinations or sequence regimens. The second generation of trials is presently being performed and contains taxanes in both arms, comparing their use in combination or in sequence. Trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) is the first biologic modifier with significant activity in advanced breast cancer patients amplifying the HER2 gene. As a consequence of these results, including improved survival in the metastatic setting, this agent has been very quickly considered for adjuvant development. However, the significant cardiac toxicity observed with trastuzumab/anthracycline combinations has led to two main strategies for integrating trastuzumab in the adjuvant setting: (1) addition of trastuzumab to mostly anthracycline-based programs (sequential approach); and (2) biology-oriented strategy based on synergism between trastuzumab and chemotherapy agents. Large-scale clinical research programs are presently being developed and will create a challenge for clinical researchers. The adequate scientific hypothesis, related to the pivotal studies of trastuzumab in the adjuvant setting, require large sample sizes (several thousand patients) and a very strict selection of the patient population (tumors amplifying the HER2 gene). Success in a timely fashion requires global collaboration, dedication to high-standard clinical research, and awareness of all available protocols by oncologists and patients with breast cancer.

Antibodies, Monoclonal↗
PubMed1999

Trastuzumab, a recombinant DNA-derived humanized monoclonal antibody, a novel agent for the treatment of metastatic breast cancer.

Amplification of the human epidermal growth factor receptor 2 protein (HER2) in primary breast carcinomas has been shown to correlate with poor clinical prognosis for certain patients. Trastuzumab (Herceptin, Genentech, Inc., South San Francisco, California) is a highly purified recombinant DNA-derived humanized monoclonal immunoglobulin G1 kappa antibody that binds with high affinity and specificity to the extracellular domain of the HER2 receptor. In vitro and in vivo preclinical studies have shown that administration of trastuzumab alone or in combination with paclitaxel or carboplatin significantly inhibits the growth of breast tumor-derived cell lines that overexpress the HER2 gene product. At therapeutic doses in breast cancer patients, the mean half-life of trastuzumab is 5.8 days. Trastuzumab serum concentrations reach steady state with mean trough and peak concentrations of 79 microg/mL and 123 microg/mL, respectively. In a 222-patient, single-arm clinical study, treatment with a loading dose of trastuzumab 4 mg/kg administered IV followed by weekly IV doses of 2 mg/kg produced an overall response rate of 14% (2% complete remission and 12% partial remission). The beneficial effects were greatest in patients with the greatest degree (3+) of HER2 protein overexpression. In another clinical study, 469 women with metastatic breast carcinoma were randomized to a paclitaxel or anthracycline-plus-cyclophosphamide regimen with or without trastuzumab. The overall response rate was significantly greater in the trastuzumab-plus-chemotherapy group than in the chemotherapy-alone cohort. The magnitude of observed effects was greatest with pacli taxel plus trastuzumab. The most common adverse effects attributed to trastuzumab in clinical studies were fever and chills, pain, asthenia, nausea, vomiting, increased cough, diarrhea, headache, dyspnea, infection, rhinitis, and insomnia. Trastuzumab in combination with chemotherapy can lead to cardiotoxicity, leukopenia, anemia, diarrhea, abdominal pain, and infection. Trastuzumab has been approved by the US Food and Drug Administration as a single agent for the treatment of patients who have metastatic breast cancer involving overexpression of the HER2 protein and who have received 1 or more chemotherapy regimens; in combination with paclitaxel, it has been approved for the treatment of such patients who have not received chemotherapy.

Antibodies, Monoclonal↗
PubMed2002

Non-small cell lung cancer clinical trials with trastuzumab: their foundation and preliminary results.

The overexpression of HER2, a transmembrane glycoprotein tyrosine kinase, has been implicated in mitogenesis, cell survival, invasion and angiogenesis. Preclinical evidence suggests that HER2 overexpression contributes to tumor progression in non-small cell lung cancer (NSCLC) and retrospective clinical correlative studies show that it is probably associated with poor clinical outcome. Trastuzumab (Herceptin, Genentech Inc., South San Francisco, CA) is a recombinant humanized monoclonal antibody that targets HER2 and is currently approved for use in the treatment of patients with HER2-overexpressing metastatic breast cancer. Two primary mechanisms proposed for the activity of trastuzumab are downregulation of HER2 and induction of antibody-dependent cell-mediated cytotoxicity. Evidence from preclinical studies of trastuzumab in NSCLC and other cell lines, the presence of HER2 overexpression in NSCLC clinical specimens and the clinical benefit derived from trastuzumab in phase II and III metastatic breast cancer trials have led to the development of clinical trials of trastuzumab in NSCLC. Phase II studies of trastuzumab in patients with stage IIIB or IV NSCLC are being conducted to test the efficacy of trastuzumab as a single agent or in combination with chemotherapy. Preliminary results show combinations of chemotherapy plus trastuzumab are well tolerated, with encouraging response rates of 21-40%. A randomized phase II trial of chemotherapy with or without trastuzumab showed promise in a small subgroup of patients with 3+ HER2 overexpression by immunohistochemistry or HER2 DNA amplification by fluorescence in situ hybridization. Taken together, these data indicate that trastuzumab warrants further investigation in a clinical study in selected patients with NSCLC.

Antibodies, Monoclonal↗
PubMed2006

Optimization and validation of a quantitative capillary electrophoresis sodium dodecyl sulfate method for quality control and stability monitoring of monoclonal antibodies.

In previous work, a capillary electrophoresis sodium dodecyl sulfate (CE-SDS) method using precolumn labeling and laser-induced fluorescence (LIF) detection was developed at Genentech Inc. as part of the control system for the quality control release of a recombinant monoclonal antibody (rMAb) (Hunt, G.; Nashabeh, W. Anal. Chem. 1999, 71, 2390-2397.). In the current work, a generic and quantitative CE-SDS assay with LIF detection of rMAbs with improved accuracy and precision is described. The implementation of an alkylating step with iodoacetamide and optimization of the incubation temperature and time, in the presence of SDS, greatly decrease any thermally induced fragmentation of nonreduced labeled rMAb samples. In addition, a quantitative study of the effects of sample buffer pH on rMAb fragmentation is also presented. Furthermore, the performance of alternative CE-SDS polymer solutions and instrumentation for quantitative analysis of rMAbs is shown in this article. The validation of this method, under the guidelines of the International Committee on Harmonization (ICH), demonstrates that the assay quantitatively determines the consistency of rMAb manufacture as it relates to size heterogeneity and product purity.

Antibodies, Monoclonal↗
PubMed2003

History of antibody therapy for non-Hodgkin's lymphoma.

Monoclonal antibodies (mAbs) were the first successful targeted therapy for cancer. In contrast to the nonspecific nature of most chemotherapy, antibodies bind with high specificity to cell-surface antigens, resulting in targeted killing of malignant cells, relative sparing of normal tissues, and low toxicity. Antibody therapy has undergone substantial development since Ehrlich's notion of a "magic bullet," in 1890. It was not until the 1970s, however, that mAbs became viable as therapeutic tools and clinical studies showed them to be effective. The results were most impressive in hematologic malignancies, especially B-cell non-Hodgkin's lymphoma. In 1997, rituximab (Rituxan; Genentech Inc, South San Francisco, CA, and Biogen Idec Inc, Cambridge, MA) became the first mAb approved by the US Food and Drug Administration for use in the treatment of cancer. The first approval for a radiolabeled antibody to treat cancer was in 2002 for (90)Y ibritumomab tiuxetan (Zevalin; Biogen Idec). This is a conjugate of an anti-CD20 mAb (ibritumomab, the murine parent of rituximab) with the beta-emitter radionuclide (90)Y. (90)Y ibritumomab tiuxetan has been shown to be safe and effective in the indicated patient population. Other radioimmunoconjugates are being investigated for the treatment of non-Hodgkin's lymphoma, as are several immunotoxins. This article reviews important events in the development of mAb therapy and radioimmunotherapy for B-cell non-Hodgkin's lymphoma.

Antibodies, Monoclonal↗