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Molecular targeted agents for enhancing tumour response
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Michael Baumann, Mechthild Krause, Vincent Grégoire
Other monoclonal antibodies directed against the EGFR have been developed and are being tested in various clinical phases. Nimotuzumab (H-R3) is a humanized antibody that has been tested in a phase I trial in combination with radiotherapy in patients with locally advanced disease (20). A phase II trial is ongoing in HNSCC. In anaplastic astrocytoma and glioblastoma, combination of radiotherapy with Nimotuzumab led to longer patient survival compared to radiotherapy alone in a randomised phase II trial that unfortunately did not include standard radiochemotherapy as a control arm (61). The safety profile of Zalutumumab (HuMax-EGFr), a fully humanized monoclonal antibody, has been evaluated in patients with metastatic or recurrent HNSCC (4). This antibody is undergoing testing in concomitant association with radiotherapy for locally advanced HNSCC. Panitumumab (ABX-EGF) and matuzumab (EMD 72000) are also fully humanized antibodies against EGFR (28,38) and have been tested in various human tumours. Combination of Panitumumab with neoadjuvant radiochemotherapy in locally advanced rectal cancer leads to high gastrointestinal toxicity and pathological complete response rates of 21% and 18%, which appear higher as compared to similar trials on cetuximab; however, long-term survival has not been evaluated yet (34,56).
Epidermal Growth Factor Receptor Inhibition in Non–Small Cell Lung Cancer
Published in Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo, Lung Cancer, 2016
Antonio Jimeno, Manuel Hidalgo
Matuzumab (EMD72000, Merck, Whitehouse Station, New Jersey, U.S.A.) is a humanized MAb directed at the EGFR, which has shown potent antitumor activity in preclinical studies (75,76). A significant difference with the above mentioned EGFR-targeted MAbs is a longer half-life, a feature that has prompted its evaluation every two and three weeks (77). Clinical activity was documented in subjects with colorectal and renal cancer. This study included pharmacodynamic assessment and correlative studies, evidencing that EMD72000 induced a complete inhibition of pEGFR and pMAPK with an increase in p27 in skin biopsies in all patients, whereas pAkt was only inhibited in responding patients. An expanded phase of the prior study has shown dose-dependent inhibition of downstream pathways in surrogate tissues, supporting an optimal biologic dose-seeking approach (78). A weekly schedule in patients with EGFR-expressing solid tumors has been recently reported, evidencing that headache and fever were dose limiting, and documenting a response rate of 23%, including patients with head and neck, colorectal, and esophageal cancers (79). A phase II study of matuzumab in combination with pemetrexed in NSCLC is ongoing.
The Treatment of Metastatic Colorectal Cancer
Published in Jim Cassidy, Patrick Johnston, Eric Van Cutsem, Colorectal Cancer, 2006
Eric Van Cutsem, Leonard Saltz
Matuzumab (EMD 72000), another fully humanized monoclonal antibody against the EGFR, has also shown some antitumor activity in CRC in early clinical trials; however, clinical data on this agent are more limited at this time (92).
Antibody prodrugs for cancer
Published in Expert Opinion on Biological Therapy, 2020
A third masking approach involves using the cognate antigens themselves, or derivatives thereof, as masks tethered to the antibody [1]. For example, Donaldson et al. reported using a domain of epidermal growth factor receptor (EGFR) tethered to single-chain variable fragments (scFvs) derived from the anti-EGFR antibodies cetuximab and matuzumab through a matrix metallopeptidase 9 (MMP-9)-cleavable linker [1]. Yang et al. [41,42] masked panitumumab with a peptide that mimicked a panitumumab epitope on EGFR and combined it with the same protease substrate sequence reported by Desnoyers et al. [12] While this approach ensures that the mask will be of high affinity and will effectively block binding to the target, the affinity of these masks is more difficult to optimize, and there is the potential of antidrug antibodies (ADAs) generated to the mask cross-reacting with the native ligand and causing unintended autoimmunity.
An overview of patents on therapeutic monoclonal antibodies in Europe: are they a hurdle to biosimilar market entry?
Published in mAbs, 2020
Evelien Moorkens, Arnold G. Vulto, Isabelle Huys
For treatment of cancer, combination therapies are often used to improve efficacy in this heterogeneous disease.54 This is as well reflected in the patent filing strategies of the selected case studies relating to anti-cancer compounds, with, for example, combinations with chemotherapy. Additionally, combinations with other monoclonal antibodies are patented, for example trastuzumab and pertuzumab (both from Roche), trastuzumab and bevacizumab (both from Roche), and cetuximab and matuzumab (both from Merck KGaA). This last combination has not been commercialized, as the development of matuzumab was stopped when clinical trial outcomes were not as promising as expected.55 These limited examples might indicate that companies are in the first instance looking for in-house combination therapies. The TNF inhibitors and rituximab are for their use as treatments for rheumatoid arthritis often combined with methotrexate, and also patented as such.
Lung cancer: active therapeutic targeting and inhalational nanoproduct design
Published in Expert Opinion on Drug Delivery, 2018
Nasser Alhajj, Chin Fei Chee, Tin Wui Wong, Noorsaadah Abd Rahman, Noor Hayaty Abu Kasim, Paolo Colombo
In another study, cetuximab has been conjugated to gemcitabine-loaded poly (lactic) acid nanoparticles for targeting at A549 NSCLC [157]. The cetuximab-conjugated nanoparticles exhibit a higher cellular uptake than unconjugated nanoparticles. These nanoparticles significantly reduce or arrest the cancer cell proliferation with 40% of cells undergo apoptosis, comparing to that of free drug and unconjugated nanoparticles with 25% and 15% of apoptosis, respectively [157]. Maya et al. (2014) had conjugated cetuximab to docetaxel-loaded chitosan cross-linked-poly (γ glutamic acid) nanoparticles for targeting at EGFR in lung cancer cells [158]. Forty-five percent of A549 cells take up the cetuximab-conjugated nanoparticles and only 15% with unconjugated nanoparticles. Cetuximab has been conjugated to liposome loaded with siRNA for targeting at LS174T-Luc cancer cells grown in orthotopically in mouse lungs. The cetuximab-conjugated liposome exhibits a more effective in vivo transfection following systemic administration compared to the unconjugated liposome. On day 23, the survival rates for mice that are treated with saline, unconjugated liposome, and cetuximab-conjugated liposome are 0%, 33%, and 100% respectively [159]. Matuzumab, another EGFR antibody, is conjugated to magnetic nanoparticles through a PEG-linker for capturing circulating EGFR-expressing PC9 (lung adenocarcinoma) tumor cells. The matuzumab-conjugated nanoparticles show a capture efficiency of 57% in 20 min of exposure instead of 2% in the case of EGFR antibody-less nanoparticles [160].