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MAbs 2012Therapeutic monoclonal antibodies (mAbs) are currently being approved for marketing in Europe and the United States, as well as other countries, on a regular basis. As...
Therapeutic monoclonal antibodies (mAbs) are currently being approved for marketing in Europe and the United States, as well as other countries, on a regular basis. As more mAbs become available to physicians and patients, keeping track of the number, types, production cell lines, antigenic targets, and dates and locations of approvals has become challenging. Data are presented here for 34 mAbs that were approved in either Europe or the United States (US) as of March 2012, and nimotuzumab, which is marketed outside Europe and the US. Of the 34 mAbs, 28 (abciximab, rituximab, basiliximab, palivizumab, infliximab, trastuzumab, alemtuzumab, adalimumab, tositumomab-I131, cetuximab, ibrituximab tiuxetan, omalizumab, bevacizumab, natalizumab, ranibizumab, panitumumab, eculizumab, certolizumab pegol, golimumab, canakinumab, catumaxomab, ustekinumab, tocilizumab, ofatumumab, denosumab, belimumab, ipilimumab, brentuximab) are currently marketed in Europe or the US. Data for six therapeutic mAbs (muromonab-CD3, nebacumab, edrecolomab, daclizumab, gemtuzumab ozogamicin, efalizumab) that were approved but have been withdrawn or discontinued from marketing in Europe or the US are also included.
Topics: Animals; Antibodies, Monoclonal; Drug Approval; Europe; Humans; Immunotherapy; Marketing; Product Recalls and Withdrawals; United States
PubMed: 22531442
DOI: 10.4161/mabs.19931 -
Cancer Cell International Nov 2010Epithelial cell adhesion molecule (EpCAM) is frequently and highly expressed on human carcinomas. The emerging role of EpCAM as a signalling receptor and activator of...
BACKGROUND
Epithelial cell adhesion molecule (EpCAM) is frequently and highly expressed on human carcinomas. The emerging role of EpCAM as a signalling receptor and activator of the wnt pathway, and its expression on tumor-initiating cells, further add to its attractiveness as target for immunotherapy of cancer. Thus far, five conventional monoclonal IgG antibodies have been tested in cancer patients. These are murine IgG2a edrecolomab and its murine/human chimeric IgG1 antibody version, and humanized, human-engineered and fully human IgG1 antibodies 3622W94, ING-1, and adecatumumab (MT201), respectively. Here we compared all anti-EpCAM antibodies in an attempt to explain differences in clinical activity and safety.
METHODS
We recombinantly produced all antibodies but murine edrecolomab and investigated them for binding affinity, EpCAM epitope recognition, ADCC and CDC, and inhibition of breast cancer cell proliferation.
RESULTS
ING-1 and 3622W94 bound to EpCAM with much higher affinity than adecatumumab and edrecolomab. Edrecolomab, ING-1, and 3622W94 all recognized epitopes in the exon 2-encoded N-terminal domain of EpCAM, while adecatumumab recognized a more membrane proximal epitope encoded by exon 5. All antibodies induced lysis of EpCAM-expressing cancer cell lines by both ADCC and CDC with potencies that correlated with their binding affinities. The chimeric version of edrecolomab with a human Fcγ1 domain was much more potent in ADCC than the murine IgG2a version. Only adecatumumab showed a significant inhibition of MCF-7 breast cancer cell proliferation in the absence of complement and immune cells.
CONCLUSION
A moderate binding affinity and recognition of a distinct domain of EpCAM may best explain why adecatumumab showed a larger therapeutic window in cancer patients than the two high-affinity IgG1 antibodies ING-1 and 3622W94, both of which caused acute pancreatitis.
PubMed: 21044305
DOI: 10.1186/1475-2867-10-44 -
Archivum Immunologiae Et Therapiae... 2006Gene amplification, over-expression, and mutation of growth factors, or the receptors themselves, causes increased signaling through receptor kinases, which has been... (Review)
Review
Gene amplification, over-expression, and mutation of growth factors, or the receptors themselves, causes increased signaling through receptor kinases, which has been implicated in many human cancers and is associated with poor prognosis. Tumor growth has been shown to be decreased by interrupting this process of extensive growth factor-mediated signaling by directly targeting either the surface receptor or the ligand and thereby preventing cell survival and promoting apoptosis. Monoclonal antibodies have long been eyed as a potential new class of therapeutics targeting cancer and other diseases. Antibody-based therapy initially entered clinical practice when trastuzumab/Herceptin became the first clinically approved drug against an oncogene product as a well-established blocking reagent for tumors with hyperactivity of epidermal growth factor signaling pathways. In the first part of this review we explain basic terms related to the development of antibody-based drugs, give a brief historic perspective of the field, and also touch on topics such as the "humanization of antibodie" or creation of hybrid antibodies. The second part of the review gives an overview of the clinical usage of bispecific antibodies and antibodies "armed" with cytotoxic agents or enzymes. Further within this section, cancer-specific, site-specific, or signaling pathway-specific therapies are discussed in detail. Among other antibody-based therapeutic products, we discuss: Avastin (bevacizumab), CG76030, Theragyn (pemtumomab), daclizumab (Zenapax), TriAb, MDX-210, Herceptin (trastuzumab), panitumumab (ABX-EGF), mastuzimab (EMD-72000), Erbitux (certuximab, IMC225), Panorex (edrecolomab), STI571, CeaVac, Campath (alemtuizumab), Mylotarg (gemtuzumab, ozogamicin), and many others. The end of the review deliberates upon potential problems associated with cancer immunotherapy.
Topics: Antibodies, Bispecific; Antibodies, Monoclonal; Antigens, Neoplasm; Antineoplastic Agents; Drug Design; Humans; Neoplasms; Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Tumor Necrosis Factor; Signal Transduction
PubMed: 16648969
DOI: 10.1007/s00005-006-0011-5 -
Cancers Jan 2018The epithelial cell adhesion molecule (EpCAM), or CD326, was one of the first cancer associated biomarkers to be discovered. In the last forty years, this biomarker has... (Review)
Review
The epithelial cell adhesion molecule (EpCAM), or CD326, was one of the first cancer associated biomarkers to be discovered. In the last forty years, this biomarker has been investigated for use in personalized cancer therapy, with the first monoclonal antibody, edrecolomab, being trialled in humans more than thirty years ago. Since then, several other monoclonal antibodies have been raised to EpCAM and tested in clinical trials. However, while monoclonal antibody therapy has been investigated against EpCAM for almost 40 years as primary or adjuvant therapy, it has not shown as much promise as initially heralded. In this review, we look at the reasons why and consider alternative targeting options, such as aptamers, to turn this almost ubiquitously expressed epithelial cancer biomarker into a viable target for future personalized therapy.
PubMed: 29329202
DOI: 10.3390/cancers10010019 -
Journal of Clinical Oncology : Official... Sep 2016Conventional staging methods are inadequate to identify patients with stage II colon cancer (CC) who are at high risk of recurrence after surgery with curative intent....
Association Between Results of a Gene Expression Signature Assay and Recurrence-Free Interval in Patients With Stage II Colon Cancer in Cancer and Leukemia Group B 9581 (Alliance).
PURPOSE
Conventional staging methods are inadequate to identify patients with stage II colon cancer (CC) who are at high risk of recurrence after surgery with curative intent. ColDx is a gene expression, microarray-based assay shown to be independently prognostic for recurrence-free interval (RFI) and overall survival in CC. The objective of this study was to further validate ColDx using formalin-fixed, paraffin-embedded specimens collected as part of the Alliance phase III trial, C9581.
PATIENTS AND METHODS
C9581 evaluated edrecolomab versus observation in patients with stage II CC and reported no survival benefit. Under an initial case-cohort sampling design, a randomly selected subcohort (RS) comprised 514 patients from 901 eligible patients with available tissue. Forty-nine additional patients with recurrence events were included in the analysis. Final analysis comprised 393 patients: 360 RS (58 events) and 33 non-RS events. Risk status was determined for each patient by ColDx. The Self-Prentice method was used to test the association between the resulting ColDx risk score and RFI adjusting for standard prognostic variables.
RESULTS
Fifty-five percent of patients (216 of 393) were classified as high risk. After adjustment for prognostic variables that included mismatch repair (MMR) deficiency, ColDx high-risk patients exhibited significantly worse RFI (multivariable hazard ratio, 2.13; 95% CI, 1.3 to 3.5; P < .01). Age and MMR status were marginally significant. RFI at 5 years for patients classified as high risk was 82% (95% CI, 79% to 85%), compared with 91% (95% CI, 89% to 93%) for patients classified as low risk.
CONCLUSION
ColDx is associated with RFI in the C9581 subsample in the presence of other prognostic factors, including MMR deficiency. ColDx could be incorporated with the traditional clinical markers of risk to refine patient prognosis.
Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Clinical Trials, Phase III as Topic; Cohort Studies; Colonic Neoplasms; Disease-Free Survival; Female; Gene Expression Profiling; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Multicenter Studies as Topic; Neoplasm Recurrence, Local; Neoplasm Staging; Oligonucleotide Array Sequence Analysis; Randomized Controlled Trials as Topic
PubMed: 27432924
DOI: 10.1200/JCO.2015.65.4699 -
International Journal of Cancer Jul 2002In our study, a novel, fully human, recombinant monoclonal antibody of the IgG1 isotype, called MT201, was characterized for its binding properties, complement-dependent... (Comparative Study)
Comparative Study
In our study, a novel, fully human, recombinant monoclonal antibody of the IgG1 isotype, called MT201, was characterized for its binding properties, complement-dependent (CDC) and antibody-dependent cellular cytotoxicity (ADCC), as well as for its in vivo antitumor activity in a nude mouse model. MT201 was found to bind its target, the epithelial cell adhesion molecule (Ep-CAM; also called 17-1A antigen, KSA, EGP-2, GA733-2), with low affinity in a range similar to that of the clinically validated, murine monoclonal IgG2a antibody edrecolomab (Panorex(R)). MT201 exhibited Ep-CAM-specific CDC with a potency similar to that of edrecolomab. However, the efficacy of ADCC of MT201, as mediated by human immune effector cells, was by 2 orders of magnitude higher than that of edrecolomab. Addition of human serum reduced the ADCC of MT201 while it essentially abolished ADCC of edrecolomab within the concentration range tested. In a nude mouse xenograft model, growth of tumors derived from the human colon carcinoma line HT-29 was significantly and comparably suppressed by MT201 and edrecolomab. The fully human nature and the improved ADCC of MT201 with human effector cells will make MT201 a promising candidate for the clinical development of a novel pan-carcinoma antibody that is superior to edrecolomab.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibody-Dependent Cell Cytotoxicity; Antigens, Neoplasm; CHO Cells; Cell Adhesion Molecules; Colonic Neoplasms; Complement System Proteins; Cricetinae; Cytotoxicity, Immunologic; Epithelial Cell Adhesion Molecule; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms; Tumor Cells, Cultured
PubMed: 12115595
DOI: 10.1002/ijc.10443 -
British Journal of Cancer Apr 2007Despite advances in surgery and adjuvant regimes, gastrointestinal malignancy remains a major cause of neoplastic mortality. Immunotherapy is an emerging and now... (Review)
Review
Despite advances in surgery and adjuvant regimes, gastrointestinal malignancy remains a major cause of neoplastic mortality. Immunotherapy is an emerging and now successful treatment modality for numerous cancers that relies on the manipulation of the immune system and its effector functions to eradicate tumour cells. The discovery that the pan-epithelial homotypic cell adhesion molecule EpCAM is differentially expressed on gastrointestinal tumours has made this a viable target for immunotherapy. Clinical trials using naked anti EpCAM antibody, immunoconjugates, anti-idiotypic and dendritic cell vaccines have met variable success. The murine IgG2a Edrecolomab was shown to reduce mortality and morbidity at a level slightly lower than treatment with 5FU and Levamisole when administered to patients with advanced colorectal carcinoma in a large randomised controlled trial. Fully human and trifunctional antibodies that specifically recruit CD3-positive lymphocytes are now being tested clinically in the treatment of minimal residual disease and ascites. Although clinical trials are in their infancy, the future may bring forth an EpCAM mediated approach for the effective activation and harnessing of the immune system to destroy a pathological aberrance that has otherwise largely escaped its attention.
Topics: Antigens, Neoplasm; CD3 Complex; Cell Adhesion Molecules; Epithelial Cell Adhesion Molecule; Gastrointestinal Neoplasms; Humans; Immunotherapy
PubMed: 17325709
DOI: 10.1038/sj.bjc.6603505 -
Annals of Oncology : Official Journal... Jul 2002The aim of our study was to evaluate the efficacy of the monoclonal antibody edrecolomab after chemo- and radiotherapy in the elimination of disseminated tumour cells in...
BACKGROUND
The aim of our study was to evaluate the efficacy of the monoclonal antibody edrecolomab after chemo- and radiotherapy in the elimination of disseminated tumour cells in bone marrow in the adjuvant therapy of breast cancer.
PATIENTS AND METHODS
The bone marrow of 25 patients with breast cancer was tested for the presence of disseminated tumour cells using the pancytoceratine antibody and the alkaline phosphatase-anti-alkaline-phosphatase (APAAP) technique. To characterize tumour cells simultaneously, immunofluorescent double labelling of pancytoceratine and epithelial cell adhesion molecule (antibody 17-1A) was performed on tumour cells after magneto bead enrichment. Patients positive for the 17-1A antigen in bone marrow after chemotherapy were treated with edrecolomab (500 mg Panorex) initially, then 100 mg/month over 4 months) and investigated for the presence of micrometastases 6 weeks after the last treatment.
RESULTS
Of the 17 patients showing bone marrow micrometastases (BM-MM), 14 tested 17-1A positive before adjuvant chemotherapy. After chemotherapy, nine patients remained positive for the 17-1A antigen and were treated with edrecolomab. The final investigation after immunotherapy showed a complete elimination of the 17-1A-positive BM-MM in seven patients and a significant reduction of these cells in two patients.
CONCLUSIONS
Sequential treatment of breast cancer with edrecolomab after adjuvant chemotherapy can reduce disseminated tumour cells in the bone marrow and eliminate 17-1A-positive micrometastases.
Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Biomarkers, Tumor; Biopsy, Needle; Bone Marrow; Breast Neoplasms; Cohort Studies; Combined Modality Therapy; Culture Techniques; Female; Humans; Immunotherapy; Mastectomy, Segmental; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Prospective Studies; Sensitivity and Specificity; Survival Analysis; Treatment Outcome
PubMed: 12176782
DOI: 10.1093/annonc/mdf184 -
Stem Cells Translational Medicine Jun 2018Colorectal cancer (CRC) is one of the most common malignancies worldwide. In spite of various attempts to ameliorate outcome by escalating treatment, significant... (Review)
Review
Colorectal cancer (CRC) is one of the most common malignancies worldwide. In spite of various attempts to ameliorate outcome by escalating treatment, significant improvement is lacking particularly in the adjuvant setting. It has been proposed that cancer stem cells (CSCs) and the epithelial-to-mesenchymal transition (EMT) are at least partially responsible for therapy resistance in CRC. The epithelial cell adhesion molecule (EpCAM) was one of the first CSC antigens to be described. Furthermore, an EpCAM-specific antibody (edrecolomab) has the merit of having launched the era of monoclonal antibody treatment in oncology in the 1990s. However, despite great initial enthusiasm, monoclonal antibody treatment has not proven successful in the adjuvant treatment of CRC patients. In the meantime, new insights into the function of EpCAM in CRC have emerged and new drugs targeting various epitopes have been developed. In this review article, we provide an update on the role of EpCAM in CSCs and EMT, and emphasize the potential predictive selection criteria for novel treatment strategies and refined clinical trial design. Stem Cells Translational Medicine 2018;7:495-501.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Colorectal Neoplasms; Epithelial Cell Adhesion Molecule; Epithelial-Mesenchymal Transition; Humans; Neoplastic Stem Cells
PubMed: 29667344
DOI: 10.1002/sctm.17-0289 -
Journal of Clinical Oncology : Official... Aug 2011We conducted a randomized trial comparing adjuvant treatment with edrecolomab versus observation in patients with resected, low-risk, stage II colon cancer. This study... (Randomized Controlled Trial)
Randomized Controlled Trial
Documenting the natural history of patients with resected stage II adenocarcinoma of the colon after random assignment to adjuvant treatment with edrecolomab or observation: results from CALGB 9581.
PURPOSE
We conducted a randomized trial comparing adjuvant treatment with edrecolomab versus observation in patients with resected, low-risk, stage II colon cancer. This study also prospectively studied patient- and tumor-specific markers of treatment outcome.
PATIENTS AND METHODS
After surgical resection, patients with stage II colon cancer were randomly assigned to either five infusions of edrecolomab at 28-day intervals or observation without adjuvant therapy.
RESULTS
Final accrual included 1,738 patients; 865 patients received edrecolomab, and 873 patients were observed without adjuvant treatment. Median follow-up time was 7.9 years. There were no significant outcome differences between study arms (overall survival [OS], P = .71; disease-free survival, P = .64). The combined 5-year all-cause OS was 0.86 (95% CI, 0.84 to 0.88), and the combined 5-year disease-specific OS was 0.93 (95% CI, 0.91 to 0.94). The relationships between demographic and histopathologic factors and survival differed for all-cause and disease-specific survival outcomes, but no combined prognostic factor model was found to adequately classify patients at higher risk of recurrence or death as a result of colon cancer.
CONCLUSION
Edrecolomab did not prolong survival. Consequently, this large study with a long duration of follow-up provided unique data concerning the natural history of resected stage II colon cancer. Prognostic factors identified in previous retrospective and pooled analyses were associated with survival outcomes in this stage II patient cohort. Results from ongoing molecular marker studies may enhance our ability to determine the risk profile of these patients.
Topics: Adenocarcinoma; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; Digestive System Surgical Procedures; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Male; Neoplasm Staging; Treatment Outcome
PubMed: 21747085
DOI: 10.1200/JCO.2010.32.5357