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Tumor immunology
Published in Gabriel Virella, Medical Immunology, 2019
With the growing interest and positive clinical results using T-cell therapies in the treatment of cancer, alternative methods have been developed to target tumors using T cells. Blinatumomab is a bispecific monoclonal antibody that is able to bind to T cells (via CD3) and tumor cells (via CD19); it belongs to a class of molecules called bispecific T-cell engagers (BiTEs) (Figure 26.5). Blinatumomab acts as a link between non-tumor-reactive T cells and tumor cells. Once blinatumomab binds T cells via CD3, it activates them; binding to CD19 (a molecule overexpressed in ALL and many lymphomas), blinatumomab brings T cells in close proximity to tumor cells where a cytolytic synapse forms and tumor cells are killed via classical T-cell killing pathways. The advantage of such an approach is that tumor-reactive T cells are not required, and T-cell activation does not require TCR-MHC complex interaction. Blinatumomab is used for the treatment of ALL and is currently being studied for treatments of different types of lymphomas. In addition, additional bispecific T-cell engagers are being developed to target other types of cancer.
Diabetic retinopathy: a complex pathophysiology requiring novel therapeutic strategies
Published in Expert Opinion on Biological Therapy, 2018
Michael Whitehead, Sanjeewa Wickremasinghe, Andrew Osborne, Peter Van Wijngaarden, Keith R. Martin
Regarding DR therapeutic paradigms, a number of therapies are now available to clinicians and these have demonstrated modest benefits in patients. While VEGF plays a central role in retinal neovascularization and vascular hyperpermeability in diabetes, it is only one of many angiogenic factors that are upregulated in DR. Future anti-angiogenic therapies for DR are likely to be individualized and will typically target more than one factor. An example is the bispecific monoclonal antibody against Ang-2 and VEGF that is currently undergoing clinical evaluation in Phase III trials (Genentech/Roche). In addition, increasing awareness of retinal neuronal injury in diabetes and the interplay between neurons, glia, and blood vessels (the NVU) has focused attention on neuroprotective therapies. The administration of therapies to minimize glutamate-induced excitotoxicity and neuronal apoptosis as well as regulation of RGC apoptosis are currently under evaluation in DR and may be used in future.
Pre-clinical development of a novel CD3-CD123 bispecific T-cell engager using cross-over dual-variable domain (CODV) format for acute myeloid leukemia (AML) treatment
Published in OncoImmunology, 2021
Hélène Bonnevaux, Stephane Guerif, Jana Albrecht, Erwan Jouannot, Thibaud De Gallier, Christian Beil, Christian Lange, Wulf Dirk Leuschner, Marion Schneider, Cendrine Lemoine, Anne Caron, Céline Amara, Cédric Barrière, Justine Siavellis, Valérie Bardet, Ernesto Luna, Pankaj Agrawal, Donald R. Drake, Ercole Rao, Peter Wonerow, Chantal Carrez, Véronique Blanc, Karl Hsu, Dmitri Wiederschain, Paula G. Fraenkel, Angéla Virone-Oddos
Herein, we evaluate the preclinical activity of a bispecific monoclonal antibody T-cell engager (TCE), CD123-cross-over dual-variable TCE (CD123-CODV-TCE), as a potential therapy for AML. One arm of CD123-CODV-TCE targets the CD3εδ subunit of the T-cell co-receptor at the surface of the T cell; the other targets CD123 on the malignant cell. Bispecific TCEs can co-engage T cells and CD123-positive malignant cells, leading to the formation of a cytolytic synapse,21 which induces T-cell activation, resulting in tumor cell-specific killing. CD123-CODV-TCE is a potential therapeutic agent that demonstrates activity in vitro and in vivo, against human cell lines overexpressing CD123, as well as primary human AML samples including LSCs.
Colon carcinoma treatment using bispecific anti-GITR/CTLA-4 antibodies: a patent evaluation of WO2018091739
Published in Expert Opinion on Therapeutic Patents, 2020
Lourdes Millán-Pérez Peña, Perez-Santos Martin, Irma Herrera-Camacho, Cindy Bandala, Maricruz Anaya-Ruiz
It should be noted that the infiltration of different immune populations, including Treg cells, was not determined. The latter derived from the fact that the objective was to determine the effectiveness of the bispecific monoclonal antibody. It would be relevant for subsequent studies to analyze infiltrating immune cells, including possible subpopulations of infiltrating Treg cells. It would be interesting to consider in future studies an analysis of additional immune markers, as well as the effect that these bispecific antibodies could have against innate immune populations, such as macrophages and neutrophils, because of their role in promoting tumor progression [32].