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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
At the time of writing, three bsAbs have been approved for the treatment of different diseases. Catumaxomab (Removab™) was the first to be approved for the treatment of malignant ascites but was later withdrawn for economic reasons. Blinatumomab (Blyncito™), developed by Amgen, was the next to be approved in 2014 through the FDA’s Accelerated Approval Program for the treatment of Philadelphia chromosome (Ph) negative relapsed or refractory B-cell precursor ALL in adults. Later, in 2015, it was granted approval for the treatment of ALL in children, and then full approval for use in adults in 2017. In 2018, the FDA extended the approval for use in minimal residual disease-positive B-cell precursor ALL, with blinatumomab becoming the first agent to be approved for this condition. Currently, blinatumomab is the lead bsAb with many clinical trials still ongoing in various hematological malignancies. In 2018, a third bsAb, emicizumab-kxwh (Hemlimbra™), was approved for the treatment of hemophilia A without factor VIII inhibitor, and is not used as a cancer therapy.
Immunotherapy of peritoneal carcinomatosis
Published in Wim P. Ceelen, Edward A. Levine, Intraperitoneal Cancer Therapy, 2015
Michael A. Ströhlein, Markus M. Heiss
Catumaxomab was also shown to induce relevant activity against tumor stem cells after i.p. immunotherapy in patients with malignant ascites. Peritoneal fluid samples from 258 patients with malignant ascites randomized to catumaxomab or control groups in the phase II/III study mentioned earlier were investigated for molecular effects of catumaxomab treatment. After catumaxomab treatment, the number of tumor cells and VEGF levels decreased, whereas the CD4+ and CD8+ T-cell activation increased substantially after treatment. Notably, CD133(+)/EpCAM(+) cancer stem cells vanished from the catumaxomab samples but not from the control samples. In vitro investigations indicated that catumaxomab eliminated tumor cells in a manner associated with release of proinflammatory Th1 cytokines [37].
Development of palliative medicine in the United Kingdom and Ireland
Published in Eduardo Bruera, Irene Higginson, Charles F von Gunten, Tatsuya Morita, Textbook of Palliative Medicine and Supportive Care, 2015
59 Heiss MM, Murawa P, Koralewski P, Kutarska E et al. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial. Int. J. Cancer. 2010;127:2209-2221.
Bispecific antibodies for the treatment of breast cancer
Published in Expert Opinion on Biological Therapy, 2022
Patrick M. Dillon, Jogender Tushir-Singh, Lawrence G. Lum
Ultimately, the first BsAb to be approved by a regulatory body was Catumaxomab (Fresenius Biotech, Germany) [6]. Catumaxomab is a Murine IgG2a anti-CD3 hemi-antibody with rat IgG2b anti-epithelial cell adhesion molecule (EpCAM) which was approved in Europe in 2009 for palliation of malignant ascites. Catumaxomab is a Trifunctional antibody or Triomab (Figure 2) that recognizes Fcγ receptor types I and III, thus directing dendritic cells, macrophages and NK cells to the tumor cells. This BsAb successfully resulted in high levels of Th1 cytokine release and puncture-free ascites control when given by intraperitoneal infusion. Unfortunately, Catumaxomab was unable to be tolerated intravenously as there was nonspecific activation of T-cells manifested by cytokine release syndrome. The agent was withdrawn from the European Medicines Agency (EMA) in 2017 and from the US in 2013 for commercial reasons.
Conditionally active T cell engagers for the treatment of solid tumors: rationale and clinical development
Published in Expert Opinion on Biological Therapy, 2022
Early signs that TCEs have the potential for T cell-mediated toxicity against solid tumors came from the first engager-approved, catumaxomab. Developed by Fresenius Biotech and Trion Pharma (subsequently acquired by Neovii), it is a tri-functional molecule consisting of a rat/mouse hybrid antibody with targeting domains against human EpCAM and CD3e, along with an active Fc domain capable of binding to Fc-gamma receptors and potentially eliciting antibody-dependent effector functions. Although virtually all patients suffered manageable cases of cytokine release syndrome (CRS) [6], early attempts to administer the drug intravenously failed because of severe liver toxicity, which was linked to Fc-mediated off-target Kupffer and T cell activation in the liver [7]. In 2009, catumaxomab was approved by the European Medicines Agency for the intraperitoneal treatment of malignant ascites, but it was pulled from the market in 2017. What caused its market failure is unclear, but bispecific antibody (BsAb) researchers have since learned to use inert constant regions to not only reduce potential Fc-mediated T cell toxicity but also enhance lymphocyte trafficking and anti-tumor potency [8].
Intraperitoneal chemotherapy for peritoneal metastases: an expert opinion
Published in Expert Opinion on Drug Delivery, 2020
Wim Ceelen, Helena Braet, Gabrielle van Ramshorst, Wouter Willaert, Katrien Remaut
A major drawback of IPDD is the fact that none of the currently used drugs were developed or approved for intraperitoneal instillation. Therefore, clinical practice is limited to off-label use. The most commonly used chemotherapy drugs for IP use are the platinum compounds (cisplatin, carboplatin, oxaliplatin), mitomycin C, and paclitaxel. Intraperitoneal immune therapy has as yet found only a very limited clinical application. The trifunctional antibody Catumaxomab contains binding sites for EpCAM and CD3+T cells, while the Fc domain binds to type I, IIa, and III Fcγ receptors on DCs, NKs, and macrophages. The molecule was approved by the European Medicines Agency for palliation of ascites in EpCAM positive epithelial cancers. Analysis of clinical ascites samples showed that treatment with IP Catumaxomab enhances the expression of the activation molecules CD69 and CD38 in T cells, NK cells, and macrophages, while accumulation of CD8+T cells into the peritoneal cavity was enhanced [63]. Also, IP Catumaxomab was shown to promote recruitment of inflammatory TH1 cells (capable of degranulating and secreting IFN-γ) and to stimulate expression of TRAIL by NK cells, and costimulatory molecules by monocytes [64]. However, due to its high immunogenicity rate and narrow indications, commercial sale of Catumaxomab was discontinued in 2017. A comparable approach was reported by Froysnes et al., who successfully treated colorectal PM patients with IP MOC31PE immunotoxin, consisting of an antibody recognizing EpCAM conjugated to the potent Pseudomonas exotoxin A [65].