Costimulatory T cell engagement via a novel bispecific anti-CD137 /anti-HER2 protein

Hinner, Marlon J.; Aiba, Rachida-Siham Bel; Wiedenmann, Alexander; Schlosser, Corinna; Allersdorfer, Andrea; Matschiner, Gabriele; Rothe, Christine; Moebius, Ulrich; Kohrt, Holbrook E.; Olwill, Shane A.

doi:10.1186/2051-1426-3-s2-p187

Cited by 11 publications

(10 citation statements)

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“…2B ). These bsAbs also activate T cells through binding of TAA and IAA such as CD3ε in TCR complex or CD137 or CD28, thereby bypassing major histocompatibility complex (MHC) restriction and causing activation in independence of the epitope specificity of the TCR [ 98 , 99 ].…”

Section: Bsab Molecules: Their Architectures and Moasmentioning

confidence: 99%

Development of bispecific antibodies in China: overview and prospects

Zhang

Zhou

2020

Antibody Therapeutics

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A bispecific antibody (bsAb) can simultaneously bind two different epitopes or antigens, allowing for multiple mechanistic functions with synergistic effects. BsAbs have attracted significant scientific attentions and efforts towards their development as drugs for cancers. There are 21 bsAbs currently undergoing clinical trials in China. Here, we review their platform technologies, expression and production, and biological activities and bioassay of these bsAbs, and summarize their structural formats and mechanisms of actions. T-cell redirection and checkpoint inhibition are two main mechanisms of the bsAbs that we discuss in detail. Furthermore, we provide our perspective on the future of bsAb development in China, including CD3-bsAbs for solid tumors and related cytokine release syndromes, expression and chemistry, manufacturing and controls, clinical development, and immunogenicity.

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Section: Bsab Molecules: Their Architectures and Moasmentioning

confidence: 99%

Development of bispecific antibodies in China: overview and prospects

Zhang

Zhou

2020

Antibody Therapeutics

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“…PRS-343 is designed to promote CD137 clustering by bridging CD137-positive T-cells with HER2-positive tumor cells, thereby providing a potent costimulatory signal to tumor antigen-specific T-cells that has demonstrated tumor inhibition and TIL expansion in a humanized mouse model. 53 The two clinical studies evaluating PRS-343 in HER2-positive solid tumors are ongoing, either as a single-drug agent (ClinicalTrials.gov identifier: NCT03330561) or in combination with atezolizumab (ClinicalTrials.gov identifier: NCT03650348).…”

Section: Novel Strategies To Overcome Resistance To Her2-targeted Thementioning

confidence: 99%

HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance

2019

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The introduction of anti-HER2 therapies to the treatment of patients with HER2-positive breast cancer has led to dramatic improvements in survival in both early and advanced settings. Despite this breakthrough, nearly all patients with metastatic HER2-positive breast cancer eventually progress on anti-HER2 therapy due to de novo or acquired resistance. A better understanding not only of the underlying mechanisms of HER2 therapy resistance but of tumor heterogeneity as well as the host and tumor microenvironment is essential for the development of new strategies to further improve patient outcomes. One strategy has focused on inhibiting the HER2 signaling pathway more effectively with dual-blockade approaches and developing improved anti-HER2 therapies like antibody–drug conjugates, new anti-HER2 antibodies, bispecific antibodies, or novel tyrosine kinase inhibitors that might replace or be used in addition to some of the current anti-HER2 treatments. Combinations of anti-HER2 therapy with other agents like immune checkpoint inhibitors, CDK4/6 inhibitors, and PI3K/AKT/mTOR inhibitors are also being extensively evaluated in clinical trials. These add-on strategies of combining optimized targeted therapies could potentially improve outcomes for patients with HER2-positive breast cancer but may also allow de-escalation of treatment in some patients, potentially sparing some from unnecessary treatments, and their related toxicities and costs.

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“…e ., CD27, CD40, OX40, glucocorticoid-induced tumor necrosis factor (TNF) receptor (TNFR)-related protein (GITR), and CD137, are members of the TNFR superfamily, whereas two other stimulatory checkpoint molecules, i . e ., CD28 and inducible T-cell costimulatory (ICOS), belong to the B7-CD28 superfamily ( Table 1 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ).…”

Section: Checkpoint Targets and Pathways With Different Effectsmentioning

confidence: 99%

Application of immune checkpoint targets in the anti-tumor novel drugs and traditional Chinese medicine development

Wang

Zhang

Wang³

et al. 2021

Acta Pharmaceutica Sinica B

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Immune checkpoints are the crucial regulators of immune system and play essential roles in maintaining self-tolerance, preventing autoimmune responses, and minimizing tissue damage by regulating the duration and intensity of the immune response. Furthermore, immune checkpoints are usually overexpressed in cancer cells or noninvasive cells in tumor tissues and are capable of suppressing the antitumor response. Based on substantial physiological analyses as well as preclinical and clinical studies, checkpoint molecules have been evaluated as potential therapeutic targets for the treatment of multiple types of cancers. In the last few years, extensive evidence has supported the immunoregulatory effects of traditional Chinese medicines (TCMs). The main advantage of TCMs and natural medicine is that they usually contain multiple active components, which can act on multiple targets at the same time, resulting in additive or synergistic effects. The strong immune regulation function of traditional Chinese medicine on immune checkpoints has also been of great interest. For example, Astragalus membranaceus polysaccharides can induce anti-PD-1 antibody responses in animals, and these antibodies can overcome the exhaustion of immune cells under tumor immune evasion. Furthermore, many other TCM molecules could also be novel and effective drug candidates for the treatment of cancers. Therefore, it is essential to assess the application of immune checkpoints in the development of new drugs and TCMs. In this review, we focus on research progress in the field of immune checkpoints based on three topics: (1) immune checkpoint targets and pathways, (2) development of novel immune checkpoint-based drugs, and (3) application of immune checkpoints in the development of TCMs.

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Costimulatory T cell engagement via a novel bispecific anti-CD137 /anti-HER2 protein

Cited by 11 publications

References 0 publications

Development of bispecific antibodies in China: overview and prospects

Development of bispecific antibodies in China: overview and prospects

HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance

Application of immune checkpoint targets in the anti-tumor novel drugs and traditional Chinese medicine development

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