Antibody to CD137 Activated by Extracellular Adenosine Triphosphate Is Tumor Selective and Broadly Effective<i>In Vivo</i>without Systemic Immune Activation

Kamata-Sakurai, Mika; Narita, Yoshinori; Hori, Yuji; Nemoto, Takayuki; Uchikawa, Ryo; Honda, Masaki; Hironiwa, Naoka; Taniguchi, Kenji; Shida-Kawazoe, Meiri; Metsugi, Shoichi; Miyazaki, Taro; Wada, Naoko; Ohte, Yuki; Shimizu, Shun; Mikami, Hirofumi; Tachibana, Tatsuhiko; Ono, Natsuki; Adachi, Kenji; Sakiyama, Tetsushi; Matsushita, Tomochika; Kadono, Shojiro; Komatsu, Shunichiro; Sakamoto, Akihisa; Horikawa, Sayuri; Hirako, Ayano; Hamada, Keiko; Naoi, Sotaro; Savory, Nasa; Satoh, Yasuko; Sato, Motohiko; Noguchi, Yuki; Shinozuka, Junko; Kuroi, Haruka; Ito, Atsushi; Wakabayashi, Tetsuya; Kamimura, Masaki; Isomura, Fumihisa; Tomii, Yasushi; Sawada, Noriaki; Kato, Atsuhiko; Ueda, Otoya; Nakanishi, Yoshito; Endo, Mika; Jishage, Kou-ichi; Kawabe, Yojiro; Kitazawa, Takio; Igawa, Tomoyuki

doi:10.1158/2159-8290.cd-20-0328

Cited by 60 publications

(69 citation statements)

References 48 publications

(48 reference statements)

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“…In a very innovative approach, an agonistic mAb targeting human CD137 has been selected in such a fashion that it only binds to its target in tissues with a high concentration of ATP, as is usually found in tumours. This mAb, STA551, was active against tumours in human CD137 knock-in mice while avoiding severe liver inflammation-related toxicities observed with other anti-CD137 mAbs, thus suggesting the potential for clinical translation of this immunotherapy 239 .…”

Section: Dual Tumour and Immune Targetingmentioning

confidence: 95%

Intratumoural administration and tumour tissue targeting of cancer immunotherapies

et al. 2021

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Immune-checkpoint inhibitors and chimeric antigen receptor (CAR) T cells are revolutionizing oncology and haematology practice. With these and other immunotherapies, however, systemic biodistribution raises safety issues, potentially requiring the use of suboptimal doses or even precluding their clinical development. Delivering or attracting immune cells or immunomodulatory factors directly to the tumour and/or draining lymph nodes might overcome these problems. Hence, intratumoural delivery and tumour tissue-targeted compounds are attractive options to increase the in situ bioavailability and, thus, the efficacy of immunotherapies. In mouse models, intratumoural administration of immunostimulatory monoclonal antibodies, pattern recognition receptor agonists, genetically engineered viruses, bacteria, cytokines or immune cells can exert powerful effects not only against the injected tumours but also often against uninjected lesions (abscopal or anenestic effects). Alternatively, or additionally, biotechnology strategies are being used to achieve higher functional concentrations of immune mediators in tumour tissues, either by targeting locally overexpressed moieties or engineering 'unmaskable' agents to be activated by elements enriched within tumour tissues. Clinical trials evaluating these strategies are ongoing, but their development faces issues relating to the administration methodology, pharmacokinetic parameters, pharmacodynamic end points, and immunobiological and clinical response assessments. Herein, we discuss these approaches in the context of their historical development and describe the current landscape of intratumoural or tumour tissue-targeted immunotherapies.

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Section: Dual Tumour and Immune Targetingmentioning

confidence: 95%

Intratumoural administration and tumour tissue targeting of cancer immunotherapies

et al. 2021

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“…Accordingly, increased levels of extracellular ATP can be measured in the tumor microenvironment and are influenced by the principal anticancer treatments, including chemo and radiotherapy [ 62 , 63 , 64 , 65 ]. In a recent study, Kamata-Sakurai and colleagues demonstrated that extracellular ATP could be exploited to activate anti-tumoral therapeutics such as an anti-CD137 antibody only in the tumor milieu, thus increasing their tumor-suppressing activity while reducing unwanted systemic side effects [ 66 ]. ATP also modulates tumor-associated immune response via the direct activation of inflammatory pathways [ 67 ] or causing immune suppression via the generation of its degradation product adenosine through CD39 and CD73 ectonucleotidase activation [ 68 ].…”

Section: Human P2x7 Splice Variants and Single-nucleotide Polymorpmentioning

confidence: 99%

P2X7 Variants in Oncogenesis

Pegoraro

Marchi

Adinolfi

2021

Cells

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The P2X7 receptor for extracellular ATP is a well-established mediator of tumoral development and progression both in solid cancers and hematological malignancies. The human P2X7 gene is highly polymorphic, and several splice variants of the receptor have been identified in time. P2X7 single-nucleotide polymorphisms (SNPs) have been broadly analyzed by studies relating them to pathologies as different as infectious, inflammatory, nervous, and bone diseases, among which cancer is included. Moreover, in the last years, an increasing number of reports concentrated on P2X7 splice variants’ different roles and their implications in pathological conditions, including oncogenesis. Here, we give an overview of established and recent literature demonstrating a role for human P2X7 gene products in oncological conditions, mainly focusing on current data emerging on P2X7 isoform B and nfP2X7. We explored the role of these and other genetic variants of P2X7 in cancer insurgence, dissemination, and progression, as well as the effect of chemotherapy on isoforms expression. The described literature strongly suggests that P2X7 variants are potential new biomarkers and therapeutical targets in oncological conditions and that their study in carcinogenesis deserves to be further pursued.

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“…Advanced technologies are used to mitigate activation of Kupffer cells induced by urelumab for some new agonistic mAb to CD137. STA551 is a switch Ig antibody only activated where immunosuppressive extracellular adenosine triphosphate (ATP) presents and is currently being investigated in solid tumors in a phase I study either as monotherapy or in combination with atezolizumab [ 81 ].…”

Section: Technological Advances To Mitigate Hepatotoxicity For Cd137 Targeting Moleculesmentioning

confidence: 99%

CD137 as an Attractive T Cell Co-Stimulatory Target in the TNFRSF for Immuno-Oncology Drug Development

Hashimoto¹

2021

Cancers

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Immune checkpoint inhibitors have altered the treatment landscape significantly in several cancers, yet not enough for many cancer patients. T cell costimulatory receptors have been pursued as targets for the next generation of cancer immunotherapies, however, sufficient clinical efficacy has not yet been achieved. CD137 (TNFRSF9, 4-1BB) provides co-stimulatory signals and activates cytotoxic effects of CD8+ T cells and helps to form memory T cells. In addition, CD137 signalling can activate NK cells and dendritic cells which further supports cytotoxic T cell activation. An agonistic monoclonal antibody to CD137, urelumab, provided promising clinical efficacy signals but the responses were achieved above the maximum tolerated dose. Utomilumab is another CD137 monoclonal antibody to CD137 but is not as potent as urelumab. Recent advances in antibody engineering technologies have enabled mitigation of the hepato-toxicity that hampered clinical application of urelumab and have enabled to maintain similar potency to urelumab. Next generation CD137 targeting molecules currently in clinical trials support T cell and NK cell expansion in patient samples. CD137 targeting molecules in combination with checkpoint inhibitors or ADCC-enhancing monoclonal antibodies have been sought to improve both clinical safety and efficacy. Further investigation on patient samples will be required to provide insights to understand compensating pathways for future combination strategies involving CD137 targeting agents to optimize and maintain the T cell activation status in tumors.

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Antibody to CD137 Activated by Extracellular Adenosine Triphosphate Is Tumor Selective and Broadly EffectiveIn Vivowithout Systemic Immune Activation

Cited by 60 publications

References 48 publications

Intratumoural administration and tumour tissue targeting of cancer immunotherapies

Intratumoural administration and tumour tissue targeting of cancer immunotherapies

P2X7 Variants in Oncogenesis

CD137 as an Attractive T Cell Co-Stimulatory Target in the TNFRSF for Immuno-Oncology Drug Development

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