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Adjuvant Therapy of Colon Cancer
Published in Peter Sagar, Andrew G. Hill, Charles H. Knowles, Stefan Post, Willem A. Bemelman, Patricia L. Roberts, Susan Galandiuk, John R.T. Monson, Michael R.B. Keighley, Norman S. Williams, Keighley & Williams’ Surgery of the Anus, Rectum and Colon, 2019
The survival gain (observed in stage III colon cancer patients against resection alone) achieved with the murine antibody Edrecolomab (directed against glycoprotein 17-1A, i.e. EpCAM) in a small national study with 189 randomised patients in stage III colon carcinoma41 was not confirmed by 2 large multinational trials with 2,761 and 1,738 randomised patients with either UICC stage III disease or UICC stage II.42,43
Adjuvant Therapy for Colorectal Cancer
Published in Jim Cassidy, Patrick Johnston, Eric Van Cutsem, Colorectal Cancer, 2006
Several mAbs have been examined in clinical trials for patients with resected colon cancer. Edrecolomab is a murine IgG2a mAb to the glycoprotein antigen 17-1A (or epithelial cell adhesion molecule—EpCAM), which is present on the cell surface of many epithelial cancers as well as normal tissues. An initial randomized study found edrecolomab to be superior to observation in patients with resected stage III colorectal cancer (65). On the basis of these promising data, a subsequent randomized study comprising 2761 patients compared 5-FU/LV, 5-FU/LV plus edrecolomab, and edrecolomab alone (66). Disappointingly, edrecolomab monotherapy was associated with significantly poorer disease-free and overall survival compared to 5-FU/LV. Furthermore, the addition of edrecolomab to 5-FU/LV did not improve disease-free or overall survival.
Trispecific T-cell engagers for dual tumor-targeting of colorectal cancer
Published in OncoImmunology, 2022
Antonio Tapia-Galisteo, Íñigo Sánchez Rodríguez, Oscar Aguilar-Sopeña, Seandean Lykke Harwood, Javier Narbona, Mariola Ferreras Gutierrez, Rocío Navarro, Laura Martín-García, Cesáreo Corbacho, Marta Compte, Javier Lacadena, Francisco J. Blanco, Patrick Chames, Pedro Roda-Navarro, Luis Álvarez-Vallina, Laura Sanz
Another issue to take into account is that most antigens targeted by therapeutic antibodies are tumor-associated, but not unique to tumor cells: that is to say, they are also expressed at lower levels in normal tissues. EpCAM expression on healthy epithelia of the gastrointestinal tract has limited the therapeutic window of EpCAM-directed therapies due to on-target/off tumor side effects.19 The mAb edrecolomab, the first anti-EpCAM mAb approved for the treatment of CRC, was subsequently withdrawn when larger studies showed no benefit compared with standard chemotherapy.43 While edrecolomab efficacy may have been impaired by low binding affinity, the mAbs ING-1 and 3622W94 displayed such a high affinity that they no longer discriminated between normal and malignant cells, and risk of pancreatitis precluded further studies as monotherapy.44 A moderate binding affinity could account for the larger therapeutic window observed in patients treated with the anti-EpCAM mAb adecatumumab.45
A multicenter phase 1 study of solitomab (MT110, AMG 110), a bispecific EpCAM/CD3 T-cell engager (BiTE®) antibody construct, in patients with refractory solid tumors
Published in OncoImmunology, 2018
Maxim Kebenko, Marie-Elisabeth Goebeler, Martin Wolf, Annette Hasenburg, Ruth Seggewiss-Bernhardt, Barbara Ritter, Beate Rautenberg, Djordje Atanackovic, Andrea Kratzer, James B. Rottman, Matthias Friedrich, Eva Vieser, Stefanie Elm, Ingrid Patzak, Dorothea Wessiepe, Sabine Stienen, Walter Fiedler
The epithelial cell adhesion molecule (EpCAM, CD326) is a transmembrane, 40 kDa glycoprotein highly expressed in colon, gastric, prostate, ovarian, lung, and pancreatic cancer and often correlated with a poor prognosis, thus representing an attractive therapeutic target.1-4 Although EpCAM can be detected on the basolateral membrane of various normal epithelial tissues, including colon, small intestine, and hepatoblasts,5,6 it is believed to be less accessible to traditional antibody constructs due to sequestration within tight cellular junctions.7,8 The univalent EpCAM antibodies edrecolomab and adecatumumab have shown modest single-agent activity in the treatment of colon, prostate, and breast cancer.9-11
Systematic analysis of the varied designs of 819 therapeutic antibodies and Fc fusion proteins assigned international nonproprietary names
Published in mAbs, 2022
We attempted to identify all monoclonal antibodies and Fc fusion proteins with sequence listings in the WHO INN lists (i.e., molecules containing some component of an immunoglobulin). These included INNs with the suffixes -mab, -cept, -fusp, -cog, -bart, the prefix ef- and a few others. Since we focused on protein sequences, additional terms indicating glycoforms, drug conjugates and the like were removed. Where possible, sequences were extracted directly from the plain text of the INN .pdf or individual .doc files, unwanted spaces and numbers were stripped out and the contiguous sequences were assembled in an Excel spreadsheet. However, many of the original sequences were present as embedded images and could not be read directly. To extract these sequences, the pdf files were converted to text using the optical character recognition (OCR) function of Adobe Acrobat Pro DC (64 bit). This process was by no means free from error. Some of the recognized text appeared visually to be correct, but contained non-alphabetical characters. Sometimes characters were misread (e.g., W for VV or M for AA) and sometimes the sequences were misaligned due to erratic insertion of text boxes. To identify and correct errors, the sequences were aligned and compared with corresponding sequences from Thera-SAbDab, IMGT and Inxight databases. Discrepancies were checked by manually inspecting the original documents and errors in our transcribed INN sequences were corrected. Discrepancies between the INN lists and published databases were flagged to the respective database curators. Some entries in the IMGT database had been assigned to an obsolete or unofficial INN; these have now been corrected. The Inxight database contained a sequence listing for edrecolomab which was a duplicate of nimotuzumab; it has now been removed. We have been informed by the curators that other sequence discrepancies have been checked and corrected where necessary. We understand that the Inxight database is being superseded by the GSRS (Global Substance Registration System) software and database produced by NIH/NCATS (see https://gsrs.ncats.nih.gov/#/). When a complete sequence was only available in one list, it was used as a probe to search for identical sequences in the Lens patent database using the default BLAST options with a maximum of 500 hits. The hits were filtered to count the number of exact matches (100% coverage, 100% identity) and if there were few, then close matches (100% coverage, 98% identity) (Supplementary Table 4). A substantial number of exact matches was taken to indicate a higher probability that the probe sequence was correct. However, the lack of a complete match in patents did not necessarily show that the sequence was incorrect since is it quite common for only the sequence of variable regions to be reported. The final data were assembled and checked in an Excel spreadsheet using Microsoft Excel 2016 MSO version 2204 32-bit.