A canine chimeric monoclonal antibody targeting PD-L1 and its clinical efficacy in canine oral malignant melanoma or undifferentiated sarcoma

Maekawa, Naoya; Konnai, Satoru; Takagi, Satoshi; Kagawa, Yumiko; Okagawa, Tomohiro; Nishimori, Asami; Ikebuchi, Ryoyo; Izumi, Yūsuke; Deguchi, Takao; Nakajima, Chie; Kato, Yukinari; Yamamoto, Keiichi; Uemura, Hidetoshi; Suzuki, Yasuhiko; Shiro, Motoo; Ohashi, Kazuhiko

doi:10.1038/s41598-017-09444-2

Cited by 125 publications

(178 citation statements)

References 44 publications

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“…A pilot study using this antibody in seven dogs with oral malignant melanoma and two dogs with undifferentiated sarcoma showed good tolerability. Objective tumour responses in one dog from each tumour category were observed when c4G12 was given intravenously biweekly at 2 or 5 mg/kg . PD‐L1 expression was confirmed in the primary tumours of these dogs prior to enrollment.…”

Section: Immunotherapy Approaches For Canine Sarcomasmentioning

confidence: 99%

“…Blocking the PD‐1/PD‐L1 pathway with an anti‐PD‐1 or PD‐L1 antibody can restore multiple effector functions of antigen‐specific T cells, overcoming immune escape mechanisms by cancer cells . In dogs, PD‐1 and PD‐L1 expression have been reported in sarcomas, specifically hemangiosarcoma and osteosarcoma, but the therapeutic potential of PD‐1/PD‐L1blockade has not yet been fully elucidated . Recently, a novel rat‐dog chimeric anti‐PD‐L1 monoclonal antibody (c4G12) was tested in vitro and enhanced cytokine production and proliferation of dog peripheral mononuclear cells.…”

Section: Immunotherapy Approaches For Canine Sarcomasmentioning

confidence: 99%

“…135,136 In dogs, PD-1 and PD-L1 expression have been reported in sarcomas, specifically hemangiosarcoma and osteosarcoma, but the therapeutic potential of PD-1/PD-L1blockade has not yet been fully elucidated. 29,30,129,133,[137][138][139] Recently, a novel rat-dog chimeric anti-PD-L1 monoclonal antibody Objective tumour responses in one dog from each tumour category were observed when c4G12 was given intravenously biweekly at 2 or 5 mg/kg. 30 PD-L1 expression was confirmed in the primary tumours of these dogs prior to enrollment.…”

Section: Checkpoint Inhibitorsmentioning

confidence: 99%

“…29,30,129,133,[137][138][139] Recently, a novel rat-dog chimeric anti-PD-L1 monoclonal antibody Objective tumour responses in one dog from each tumour category were observed when c4G12 was given intravenously biweekly at 2 or 5 mg/kg. 30 PD-L1 expression was confirmed in the primary tumours of these dogs prior to enrollment. c4G12 appeared safe and well tolerated with no systemic toxicity or autoimmune disease reported in the dogs enrolled in the trial despite repeated administrations.…”

Section: Checkpoint Inhibitorsmentioning

confidence: 99%

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Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

Borgatti

Dickerson

Lawrence

2019

Vet Comparative Oncology

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Sarcomas represent a group of genomically chaotic, highly heterogenous tumours of mesenchymal origin with variable mutational load. Conventional therapy with surgery and radiation therapy is effective for managing small, low‐grade sarcomas and remains the standard therapeutic approach. For advanced, high‐grade, recurrent, or metastatic sarcomas, systemic chemotherapy provides minimal benefit, therefore, there is a drive to develop novel approaches. The discovery of “Coley's toxins” in the 19th century, and their use to stimulate the immune system supported the application of unconventional therapies for the treatment of sarcomas. While promising, this initial work was abandoned and treatment paradigm and disease course of sarcomas was largely unchanged for several decades. Exciting new therapies are currently changing treatment algorithms for advanced carcinomas and melanomas, and similar approaches are being applied to advance the field of sarcoma research. Recent discoveries in subtype‐specific cancer biology and the identification of distinct molecular targets have led to the development of promising targeted strategies with remarkable potential to change the landscape of sarcoma therapy in dogs. The purpose of this review article is to describe the current standard of care and limitations as well as emerging approaches for sarcoma therapy that span many of the most active paradigms in oncologic research, including immunotherapies, checkpoint inhibitors, and drugs capable of cellular metabolic reprogramming.

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Section: Immunotherapy Approaches For Canine Sarcomasmentioning

confidence: 99%

Section: Immunotherapy Approaches For Canine Sarcomasmentioning

confidence: 99%

Section: Checkpoint Inhibitorsmentioning

confidence: 99%

Section: Checkpoint Inhibitorsmentioning

confidence: 99%

See 2 more Smart Citations

Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

Borgatti

Dickerson

Lawrence

2019

Vet Comparative Oncology

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“…We found that PD-1 and PD-L1 play critical roles in immune exhaustion and disease progression in bovine chronic infections [6–10] and in canine cancers including malignant melanoma [11, 12]. Importantly, we noted that the PD-1/PD-L1 blockade enhances T-cell responses in cattle and dogs and exhibits therapeutic effects in bovine chronic infections and canine malignant melanoma [6–10, 13–17].…”

Section: Introductionmentioning

confidence: 99%

PD-L1 expression in equine malignant melanoma and functional effects of PD-L1 blockade

Ganbaatar

Konnai

Okagawa

et al. 2020

Preprint

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24 Programmed death-1 (PD-1) is an immunoinhibitory receptor expressed on exhausted T cells 25 during chronic illness. Interaction of PD-1 with its ligand PD-ligand 1 (PD-L1) delivers inhibitory 26 signals and impairs proliferation, cytokine production, and cytotoxicity of T cells. We reported 27 that the PD-1/PD-L1 pathway is closely associated with T-cell exhaustion and disease progression 28 in bovine chronic infections and canine tumors. Moreover, we found that blocking antibodies 29 targeting PD-1 and PD-L1 restore T-cell functions and may be used in immunotherapy in cattle 30 and dogs. However, the immunological role of the PD-1/PD-L1 pathway remains unclear for 31 chronic equine diseases, including tumors. In this study, we identified nucleotide sequences of 32 equine PD-1 (EqPD-1) and PD-L1 (EqPD-L1) and investigated the role of anti-bovine PD-L1 33 monoclonal antibodies (mAbs) against EqPD-L1 using in vitro assays. We also evaluated the 34 expression of PD-L1 in tumor tissues of equine malignant melanoma (EMM). 35The amino acid sequences of EqPD-1 and EqPD-L1 share a high identity and similarity with 36 homologs from other mammalian species. Two clones of the anti-bovine PD-L1 mAbs recognized 37 EqPD-L1 in flow cytometry, and one of these cross-reactive mAbs blocked the binding of equine 38 PD-1/PD-L1. Importantly, PD-L1 expression was confirmed in EMM tumor tissues by 39 immunohistochemistry. A cultivation assay revealed that PD-L1 blockade enhanced the 40 production of Th1 cytokines in equine immune cells.41 These results suggest that our anti-PD-L1 mAbs may be useful for investigating the expression 42 and role of the equine PD-1/PD-L1 pathway. Further research is required to discover the 43 immunological role of PD-1/PD-L1 in chronic equine diseases and elucidate a future application 44 in immunotherapy for horse. 45 Keywords: horse, PD-1, PD-L1, IFN-γ, T cells, chronic diseases, melanoma 3 46 Introduction 47 Programmed cell death-1 (PD-1) is an immunoinhibitory receptor, which is expressed on activated 48 and exhausted T cells [1]. Its ligand programmed death ligand 1 (PD-L1) is expressed on immune 49 cells, including antigen-presenting cells, and tumor cells [1]. The interaction of PD-1 and PD-L1 50 suppresses the activation signal mediated by T-cell receptors and inhibits effector functions of T 51 cells, such as cytokine production and cell proliferation [1]. This pathway is invaluable for 52 regulating excessive immune responses. In cancers, however, tumor cells utilize the suppression 53 of T cells mediated by PD-1/PD-L1 to avoid anti-tumor immune responses [1]. In human medicine, 54 the blocking antibodies targeting PD-1 or PD-L1 have been leveraged for treatment of various 55 types of cancers and resulted in remarkable outcomes with 20%-90% response rates in multiple 56 clinical trials [1].57 Equine malignant melanoma (EMM) is a common neoplasm among aged gray horses, which 58 results in dermal tumors at multiple sites [2]. A previous study reported that around 80% of aged 59 gray horses deve...

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Role of the tumour microenvironment in bladder cancer pathogenesis and value of the reverse translational approach: a tale of two species

Ahmed,

Zdyrski,

Cheville

et al. 2023

Clinical and Translational Dis

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BackgroundBladder cancer is a significant malignancy in humans and canines, with high death rates and devastating clinical symptoms. Despite significant advances in therapeutic management over the years, only a small fraction of bladder cancer patients respond to immunotherapies as a second line of treatment. Since immunotherapies act on various cellular and molecular targets in the bladder cancer tumour microenvironment (TME), a greater understanding of the various types of immune cells, immune checkpoint molecules and cytokines involved in antitumour immunity will help to improve the success rate of current and novel immunotherapies, therefore enhancing the patients quality of life. Accumulating evidence shows fundamental similarities between human and canine muscle‐invasive bladder cancer (MIBC) in their clinical, histological and molecular features.AimThis review focuses on comparative aspects of MIBC in both species, highlighting the role that canines can play as a model for studying MIBC. Additionally, we discuss the various types of immune cells within bladder cancer TME that can influence the prognosis and response to immunotherapy and chemotherapy in both species.ConclusionIt remains challenging to recapitulate the heterogeneity and complexity of the bladder cancer tumour microenvironment using in vivo and in vitro models, such as zebrafish and 3D organoids models. Optimization of these techniques to create a more representative translational model has been facilitated through in vitro immune‐oncology cocultures, which are considered promising tools to help select the ideal individualized treatment options and predict disease prognosis.

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A canine chimeric monoclonal antibody targeting PD-L1 and its clinical efficacy in canine oral malignant melanoma or undifferentiated sarcoma

Cited by 125 publications

References 44 publications

Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

PD-L1 expression in equine malignant melanoma and functional effects of PD-L1 blockade

Role of the tumour microenvironment in bladder cancer pathogenesis and value of the reverse translational approach: a tale of two species

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