Fig 3 - available via license: Creative Commons Attribution-NonCommercial 2.0 Generic
Content may be subject to copyright.
Catumaxomab-(A) and ertumaxomab-(B ) mediated cytotoxicity of MNC from HNSCC patients before, at several monthly time-points during, and at the end of radio-chemotherapy (studies I and II). (●: samples obtained before start of CTX,
Source publication
Background
Trifunctional antibodies, such as catumaxomab (anti-EpCAM×anti-CD3) and ertumaxomab (anti-HER-2/neu×anti-CD3), transiently link immune effector cells to tumour cells, which results in cellular cytotoxicity towards the tumour cells. A functional immune system is therefore essential for effective anti-tumour activity. However, the commonly...
Citations
... Humanized CmAbs are predominantly (90%) engineered from a human source except that the Fab portion's complementarity-determining regions are of murine origin [7]. Chimeric trifunctional CmAbs are characterized by a unique capacity to bind with three different cell types: tumor cells, T lymphocyte cells, and accessory cells; thus, they transiently link immune effector cells to tumor cells, which produce cellular cytotoxicity toward the tumor cells [22,23]. The development of chimeric CmAbs that possess a fully human Fc portion provided considerably less immunogenic and more efficient interaction with human effector cells and the complement system than murine CmAbs. ...
Plant-based products have expanded to include cancer immunotherapy, which has made great strides over recent years. Plants are considered inexpensive and facile production platforms for recombinant monoclonal antibody (mAb) due to the latest advancements and diversification of transgenic techniques. Current human biologics, including those based on mAbs produced by fermentation technologies using primarily mammalian cell cultures, have been replaced by plant-produced mAbs, which are cost effective, more scalable, speedy, versatile, and safer. Moreover, the use of animals for antibody production is always a question of ethical unambiguity, and the suitability of animal models for predicting the immunogenicity of therapeutic mAbs in humans and transposition of the immunogenic potential of therapeutic antibodies in animals to the human situation has no scientific rationale. Quite a few plant-based mAbs are approved for the treatment of cancer, ranging from tumors to hematological malignancies. This review focuses on the cutting-edge approaches for using plant-derived mAbs to suppress or prevent cancers. It also discusses the avenues taken to prevent infection by oncogenic viruses, solid tumors, lymphomas, and other cancerous conditions using mAbs. The review emphasizes the use of a plant-derived monoclonal antibody as a premier platform to combat cancer.
... Therefore, for the patients with tumor of low HER2 expression or high HER2 expression but trastuzumabrefractory, ertumaxomab may be a promising therapeutic approach [98]. The trifunctional antibodies induced efficient killing of tumor cells via activating immune effector cells from patients that have received standard chemotherapy and radiotherapy [99]. ...
HER2-targeted immunotherapy consists of monoclonal antibodies (e.g. trastuzumab, pertuzumab), bispecific antibodies (e.g. MM-111, ertumaxomab) and activated T cells armed with anti-HER2 bispecific antibody (HER2Bi-aATC). Trastuzumab is a classic drug for the treatment of HER2 positive metastatic breast cancer. The combined application of pertuzumab, trastuzumab and paclitaxel has been suggested as a standard therapy for HER2 positive advanced breast cancer. The resistance to anti-HER2 antibody has resulted in disease progression. HER2-directed bispecific antibody may be a promising therapeutic approach for these patients. Ertumaxomab enhanced the interaction of immune effector cells and tumor cells. MM-111 simultaneously binds to HER2 and HER3 and blocks downstream signaling. Besides, HER2Bi-aATC is also an alternative therapeutic approach for HER2 positive cancers. In this review, we summarized the recent advancement of HER2-targeted monoclonal antibodies (trastuzumab, pertuzumab and T-DM1) and bispecific antibodies (MM-111, ertumaxomab and HER2Bi-aATC), especially focus on clinical trial results.
... Importantly, no additional activation of immune cells is necessary for tumor cell elimination by catumaxomab, which therefore represents a self-supporting system [78]. In contrast to antibody constructs of the BiTE class, triomabs exert a vaccination effect and induce a significant antitumor T-cell immune response, most probably due to their Fc-mediated interaction with Fcγ receptors expressed on dendritic cells and macrophages [79,80]. Different studies demonstrate that catumaxomab is capable of inducing regression of malignant pleural effusions, malignant ascites and peritoneal carcinomatosis in patients with advanced epithelial cancers resistant to conventional chemotherapy [81][82][83]. ...
... 144,145 Treatment with ertumaxomab might complement the therapeutic activity of chemotherapy and other anti-HER2/anti-EGFR receptor reagents. 146,147 Antibody combination Preclinical data have shown that the use of two or more inhibitors against the same EGFR family member leads to synergistic anti-tumor activity. 148,149 This dual-targeting approach has been successfully translated to the clinic with the combination of trastuzumab, pertuzumab and docetaxel for HER2-positive breast cancer. ...
Approximately 30 therapeutic monoclonal antibodies have already been approved for cancers and inflammatory diseases, and monoclonal antibodies continue to be one of the fastest growing classes of therapeutic molecules. Because aberrant signaling by receptor tyrosine kinases (RTKs) is a commonly observed factor in cancer, most of the subclasses of RTKs are being extensively studied as potential targets for treating malignancies. The first two RTKs that have been targeted by antibody therapy, with five currently marketed antibodies, are the growth factor receptors EGFR and HER2. However, due to systemic side effects, refractory patients and the development of drug resistance, these treatments are being challenged by emerging therapeutics. This review examines current monoclonal antibody therapies against RTKs. After an analysis of agents that have already been approved, we present an analysis of antibodies in clinical development that target RTKs. Finally, we highlight promising RTKs that are emerging as new oncological targets for antibody-based therapy.
... Importantly, no additional activation of immune cells is necessary for tumor cell elimination by catumaxomab, which therefore represents a self-supporting system [78]. In contrast to antibody constructs of the BiTE class, triomabs exert a vaccination effect and induce a significant antitumor T-cell immune response, most probably due to their Fc-mediated interaction with Fcγ receptors expressed on dendritic cells and macrophages [79,80]. Different studies demonstrate that catumaxomab is capable of inducing regression of malignant pleural effusions, malignant ascites and peritoneal carcinomatosis in patients with advanced epithelial cancers resistant to conventional chemotherapy [81][82][83]. ...
... Importantly, no additional activation of immune cells is necessary for tumor cell elimination by catumaxomab, which therefore represents a self-supporting system [78]. In contrast to antibody constructs of the BiTE class, triomabs exert a vaccination effect and induce a significant antitumor T-cell immune response, most probably due to their Fc-mediated interaction with Fcγ receptors expressed on dendritic cells and macrophages [79,80]. Different studies demonstrate that catumaxomab is capable of inducing regression of malignant pleural effusions, malignant ascites and peritoneal carcinomatosis in patients with advanced epithelial cancers resistant to conventional chemotherapy [81][82][83]. ...
Cancer stem cells (CSCs) are a subpopulation of tumor cells that display self-renewal and tumor initiation capacity and the ability to give rise to the heterogenous lineages of cancer cells that comprise the tumor. CSCs exhibit intrinsic mechanisms of resistance to modern cancer therapeutics, allowing them to survive current cancer therapies and to initiate tumor recurrence and metastasis. Various cell surface and transmembrane proteins expressed by CSCs, including CD44, CD47, CD123, EpCAM (CD326), CD133, IGF receptor I, and proteins of the Notch and Wnt signaling pathways have been identified. Recently, monoclonal antibodies and antibody constructs raised against these CSC proteins have shown efficacy against CSCs in human cancer xenograft mice, and some of them have demonstrated antitumor activity in clinical studies. Since current cancer therapies fail to eliminate CSCs, leading to cancer recurrence and progression, selective targeting of CSCs with monoclonal antibodies and antibody constructs may represent a novel therapeutic strategy against cancer.
... Other investigators search to stimulate immune effector cells and to enhance receptor specific effects. Schroeder et al [95] valuated the potency of catumaxomab (anti-EpCAM  anti-CD3) and ertumaxomab (anti-HER-2/neu  anti-CD3) with a cytotoxicity assay using mononuclear cells isolated from the samples of 12 patients with SCCHN (who had undergone treatment with 5-fluorouracil, cisplatin and radiotherapy), in co-culture with a tumor target cell line. The study showed that most patients had decreased immune cell counts during the course of chemotherapy. ...
... Specifically, the role of protooncogene HER-2/neu in the diagnosis of cancers and the immunotherapy is progressing rapidly (Argyriou andKalofonos 2009, Liu et al., 2012). It has been verified that Anti-HER-2 antibody has significant inhibition effect on the HER2-over-expression tumor (Morishita et al., 2010;Albarello et al., 2011;Schroeder et al., 2011;Liu et al., 2012;Somlo et al., 2012). As the time goes by, it is more and more concerned that the use of bispecific antibodies (BsAb) may be possible therapeutic agents for cancer treatment. ...
This study is conducted to evaluate the effects of anti-HER-2 anti-CD3 bi-specific antibodies(BsAb) on HER-2/neuover-expressing human colorectal carcinoma cells.
Growth was assessed by MTT assays after exposure of HCT-116 cells to Herceptin, anti-CD3 and BsAb antibodies. Immunocytochemistry was applied to test the HER-2 level of HCT-116. In a nude mouse model, HER-2 CD3 BsAb was combined with effector cells (peripheral blood lymph cells from normal human being) for observations on in Vivo growth of tumors.
Compared with the control group, using effector cells combined with anti-CD3 McAb, Herceptin or HER2 CD3 BsAb, tumor cell growth in vitro and in vivo was significantly inhibited (P<0.05), most remarkably in the HER2 CD3 BsAb case. The growth of xenografts with HER2 CD3 BsAb combined with effector cells was also significantly inhibited when compared with the anti-CD3 McAb or Herceptin groups (P<0.05).
HER-2/neu might be a useful target for immunotherapy in colorectal carcinoma, anti-HER2 anti-CD3 BsAb exerting clear anti-tumor effects.
Monoclonal antibodies (mAbs) are a swiftly growing class of targeted therapeutics for malignancies. After their first advent, the antibody (Ab) engineering trail has shown an evolutionary trajectory – from the rodent-derived Abs to the chimeric, humanized and fully human Abs with higher efficacy and lower/no immunotoxicity. Despite possessing great clinical potentials, several reports have highlighted that monospecific mAbs, even with high-affinity, often fail to induce sufficient immunologic responses. The full activation of the immune system demands cooperative interactions of immunotherapies with target antigen (Ag) towards functional avidity. Although the monospecific mAbs show affinity to a target Ag, they often fail to render sufficient avidity necessary for the activation of intracellular signaling mechanisms and the provocation of the immune system. Thus, various Ab/non-Ab scaffolds with much greater therapeutic impacts have been engineered based on the adjustment of their affinity and avidity balance. Novel multivalent Ab scaffolds (e.g., MDX-447, MT110, CD20Bi, TF2, and FBTA05) and mimetic Abs (e.g., Adnectin, DARPins, Ecallantide) offer improved pharmacokinetic and pharmacodynamic properties. Here, we discuss the avidity and multivalency and provide comprehensive insights into advanced Ab scaffolds used for immunotargeting and therapy of cancer.
In squamous cell carcinoma of the head and neck (SCCHN), Epidermal Growth Factor Receptor (EGFR)
overexpression is linked with poor prognosis. Cetuximab is a chimeric IgG1 monoclonal antibody (mAb) that specifically binds to the EGFR with high affinity. Cetuximab combined with radiotherapy (RT) improves loco-regional control and survival (OS) compared to RT alone in patients with stage III/IV SCCHN, and the addition of cetuximab to 5-fluorouracil and platinum-based chemotherapy improves OS in the first-line treatment of incurable disease. However, the addition of cetuximab to cisplatin-based chemoradiation
does not improve progression-free survival (PFS) or OS and only a minority of patients benefits from anti-EGFR mAbs. Other anti-EGFR agents (potentially more potent anti-EGFR mAbs), multiple tyrosine kinase inhibitors (TKIs)
and EGFR antisense are currently under investigation. Furthermore, treatment combinations with radio-and or chemotherapy regimens or other monoclonal antibodies have been evaluated and are also under investigation. Efforts to include translational research in all these trials are needed in order to better understand the molecular mechanisms involved, to define molecular criteria for the selection of appropriate patients for targeted therapy and to elucidate the anti-EGFR resistance mechanisms.
