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| http://dx.doi.org/10.3389/fimmu.2021.670864 | DOI Listing |
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CD28 co-stimulation: novel insights and applications in cancer immunotherapy.
Nat Rev Immunol
December 2024
Regeneron Pharmaceuticals, Tarrytown, NY, USA.
Substantial progress in understanding T cell signalling, particularly with respect to T cell co-receptors such as the co-stimulatory receptor CD28, has been made in recent years. This knowledge has been instrumental in the development of innovative immunotherapies for patients with cancer, including immune checkpoint blockade antibodies, adoptive cell therapies, tumour-targeted immunostimulatory antibodies, and immunostimulatory small-molecule drugs that regulate T cell activation. Following the failed clinical trial of a CD28 superagonist antibody in 2006, targeted CD28 agonism has re-emerged as a technologically viable and clinically promising strategy for cancer immunotherapy.
View Article and Find Full Text PDFCD19-CD28: an affinity-optimized CD28 agonist for combination with glofitamab (CD20-TCB) as off-the-shelf immunotherapy.
Blood
May 2024
Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland.
Article Synopsis
- T-cell responses require two signals for effective activation: engagement of T-cell receptors (signal 1) and additional costimulatory signals (signal 2), which T-cell bispecific antibodies (TCBs) can provide by targeting specific antigens and CD3ε.
- The study introduces CD19-CD28, a bispecific CD19-targeted CD28 agonist, designed to enhance the effectiveness of glofitamab, a TCB targeting malignant B cells, by delivering the crucial costimulatory signal 2 needed for stronger T-cell responses.
- Initial results show that combining glofitamab with CD19-CD28 and the 4-1BB agonist significantly improves long
Using Reference Reagents to Confirm Robustness of Cytokine Release Assays for the Prediction of Monoclonal Antibody Safety.
J Vis Exp
September 2023
The Medicines and Healthcare Products Regulatory Agency (MHRA);
New immunostimulatory antibody drugs designed to either directly stimulate specific immune cells or indirectly enhance the immune response by blocking or activating an endogenous regulator of the immune system have the potential to cause serious immune-related adverse events such as cytokine release syndrome (CRS). It is, therefore crucial to assess the safety profile of such drugs with a combination of in vivo and in vitro experiments before first-in-human dose administration. Cytokine release assays (CRAs), where the proposed antibody therapeutic is co-cultured with human immune cells (such as peripheral blood mononuclear cells (PBMCs), whole blood, or otherwise) and the amount of inflammatory cytokine produced is measured, are critical for hazard identification.
View Article and Find Full Text PDFCo-Expression of an IL-15 Superagonist Facilitates Self-Enrichment of GD-Targeted CAR-NK Cells and Mediates Potent Cell Killing in the Absence of IL-2.
Cancers (Basel)
August 2023
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt, Germany.
In contrast to T lymphocytes, natural killer (NK) cells do not require prior sensitization but are rapidly activated upon encountering virally infected or neoplastic cells. In addition, NK cells can be safely applied in an allogeneic setting, making them important effector cells for the development of off-the-shelf therapeutics for adoptive cancer immunotherapy. To further enhance their therapeutic potential, here, we engineered continuously expanding NK-92 cells as a clinically relevant model to express a humanized second-generation chimeric antigen receptor (CAR) with a composite CD28-CD3ζ signaling domain (hu14.
View Article and Find Full Text PDFGeneration of a novel fully human non-superagonistic anti-CD28 antibody with efficient and safe T-cell co-stimulation properties.
MAbs
June 2023
Philochem AG, Libernstrasse 3, Otelfingen, Switzerland.
Antibody-based therapeutics represent an important class of biopharmaceuticals in cancer immunotherapy. CD3 bispecific T-cell engagers activate cytotoxic T-cells and have shown remarkable clinical outcomes against several hematological malignancies. The absence of a costimulatory signal through CD28 typically leads to insufficient T-cell activation and early exhaustion.
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