Discovery of TSR-022, a novel, potent anti-human TIM-3 therapeutic antibody

Murtaza, Anwar; Laken, Haley; Correia, Jean da Silva; McNeeley, Patricia; Altobell, Laurence J.; Zhang, J.; Vancutsem, Paul M.; Wilcoxen, Keith; Jenkins, David W.

doi:10.1016/s0959-8049(16)32903-3

Cited by 28 publications

(18 citation statements)

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“…This has led to the development of many new mAbs targeting other immune checkpoint molecules, which are currently being tested in clinical trials (13). These include targets such as TIM3 (14)(15)(16), CD27 (17)(18)(19), and OX40 (20)(21)(22), sometimes combined with already approved mAbs, such as ipilimumab, pembrolizumab, and nivolumab (23)(24)(25)(26). To make educated decisions with the expanding choice of mAbs targeting different immune checkpoints, it is of great importance to investigate the expression profiles of these immune checkpoint molecules on both immune cells and tumor cells within the tumor microenvironment (TME).…”

mentioning

confidence: 99%

Eight-Color Multiplex Immunohistochemistry for Simultaneous Detection of Multiple Immune Checkpoint Molecules within the Tumor Microenvironment

Gorris

Halilović

Rabold

et al. 2018

The Journal of Immunology

195

183

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Therapies targeting immune checkpoint molecules CTLA-4 and PD-1/PD-L1 have advanced the field of cancer immunotherapy. New mAbs targeting different immune checkpoint molecules, such as TIM3, CD27, and OX40, are being developed and tested in clinical trials. To make educated decisions and design new combination treatment strategies, it is vital to learn more about coexpression of both inhibitory and stimulatory immune checkpoints on individual cells within the tumor microenvironment. Recent advances in multiple immunolabeling and multispectral imaging have enabled simultaneous analysis of more than three markers within a single formalin-fixed paraffin-embedded tissue section, with accurate cell discrimination and spatial information. However, multiplex immunohistochemistry with a maximized number of markers presents multiple difficulties. These include the primary Ab concentrations and order within the multiplex panel, which are of major importance for the staining result. In this article, we report on the development, optimization, and application of an eight-color multiplex immunohistochemistry panel, consisting of PD-1, PD-L1, OX40, CD27, TIM3, CD3, a tumor marker, and DAPI. This multiplex panel allows for simultaneous quantification of five different immune checkpoint molecules on individual cells within different tumor types. This analysis revealed major differences in the immune checkpoint expression patterns across tumor types and individual tumor samples. This method could ultimately, by characterizing the tumor microenvironment of patients who have been treated with different immune checkpoint modulators, form the rationale for the design of immune checkpoint-based immunotherapy in the future.

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mentioning

confidence: 99%

Eight-Color Multiplex Immunohistochemistry for Simultaneous Detection of Multiple Immune Checkpoint Molecules within the Tumor Microenvironment

Gorris

Halilović

Rabold

et al. 2018

The Journal of Immunology

195

183

View full text Add to dashboard Cite

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“…Considering the promising results, several clinical trials have been initiated to evaluate the efficacy of TIM-3 antagonistic mAbs. One of these is a multicentre, open-label study (NCT02817633) intended for studying a novel IgG4 anti-TIM-3 mAb, TSR-022 (Cobolimab), as a monotherapy or in combination with anti-PD-1 mAb in patients with advanced solid tumour which showed clinical benefits in the combination cohort [110] with a 15% objective response rate and 40% stable disease [111].…”

Section: T Cell Immunoglobulin and Mucin-domain Containing-3-tim-3mentioning

confidence: 99%

Advances in Anti-Cancer Immunotherapy: Car-T Cell, Checkpoint Inhibitors, Dendritic Cell Vaccines, and Oncolytic Viruses, and Emerging Cellular and Molecular Targets

Alard

Butnariu

Grillo

et al. 2020

Cancers

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Unlike traditional cancer therapies, such as surgery, radiation and chemotherapy that are typically non-specific, cancer immunotherapy harnesses the high specificity of a patient’s own immune system to selectively kill cancer cells. The immune system is the body’s main cancer surveillance system, but cancers may evade destruction thanks to various immune-suppressing mechanisms. We therefore need to deploy various immunotherapy-based strategies to help bolster the anti-tumour immune responses. These include engineering T cells to express chimeric antigen receptors (CARs) to specifically recognise tumour neoantigens, inactivating immune checkpoints, oncolytic viruses and dendritic cell (DC) vaccines, which have all shown clinical benefit in certain cancers. However, treatment efficacy remains poor due to drug-induced adverse events and immunosuppressive tendencies of the tumour microenvironment. Recent preclinical studies have unveiled novel therapies such as anti-cathepsin antibodies, galectin-1 blockade and anti-OX40 agonistic antibodies, which may be utilised as adjuvant therapies to modulate the tumour microenvironment and permit more ferocious anti-tumour immune response.

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“…Additional antibodies blocking LAG‐3 like TSR‐033 are currently being explored in preclinical studies . Moreover, TSR‐022, a monoclonal antibody developed to target TIM‐3 with potential IC inhibitory and anti‐tumor activities in preclinical studies, supported its clinical investigation in cancer patients.…”

Section: Targeting Immune Checkpointsmentioning

confidence: 99%

Therapeutic prospects of targeting myeloid‐derived suppressor cells and immune checkpoints in cancer

Toor

Elkord

2018

Immunol Cell Biol

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Immune evasion is a characteristic of most human malignancies and is induced via various mechanisms. Immunosuppressive cells, including myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), are key mediators in assisting tumors to escape immune surveillance. Expansion of MDSC, Treg and elevated levels of immune checkpoints (IC) are frequently detected in the tumor microenvironment and periphery of cancer patients. Various therapeutic agents have been shown to target MDSC and to block IC for inducing anti-tumor immunity and reversal of tumor immune escape. Importantly, some recent studies have shown that MDSC targeting improves the efficacy of IC blockade in cancer therapy. However, there is a pressing need to improve our understanding of the distinct role of these cells to develop combination therapy that attacks tumor cells from all frontiers to improve cancer therapeutics. Herein, we discuss the role of MDSC in cancer progression, interactions with IC in the context of anti-cancer immunity and the current therapeutic strategies to target MDSC and block IC in cancer.

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Discovery of TSR-022, a novel, potent anti-human TIM-3 therapeutic antibody

Cited by 28 publications

References 0 publications

Eight-Color Multiplex Immunohistochemistry for Simultaneous Detection of Multiple Immune Checkpoint Molecules within the Tumor Microenvironment

Eight-Color Multiplex Immunohistochemistry for Simultaneous Detection of Multiple Immune Checkpoint Molecules within the Tumor Microenvironment

Advances in Anti-Cancer Immunotherapy: Car-T Cell, Checkpoint Inhibitors, Dendritic Cell Vaccines, and Oncolytic Viruses, and Emerging Cellular and Molecular Targets

Therapeutic prospects of targeting myeloid‐derived suppressor cells and immune checkpoints in cancer

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