Exploitation of Elevated Extracellular ATP to Specifically Direct Antibody to Tumor Microenvironment

Mimoto, Futa; Tatsumi, Kanako; Shimizu, Shun; Kadono, Shojiro; Haraya, Kenta; Nagayasu, Miho; Suzuki, Yuki; Fujii, Etsuko; Kamimura, Masaki; Hayasaka, Akira; Kawauchi, Hiroki; Ohara, Kazuhiro; Matsushita, Masayuki; Baba, Takeshi; Susumu, Hiroaki; Sakashita, Takuya; Muraoka, Terushige; Aso, Kosuke; Katada, Hitoshi; Tanaka, Eriko; Nakagawa, Kenji; Hasegawa, Masami; Ayabe, Miho; Yamamoto, Tessai; Tanba, Shigero; Ishiguro, Takahiro; Kamikawa, Takayuki; Nambu, Takeru; Kibayashi, Tatsuya; Azuma, Yumiko; Tomii, Yasushi; Kato, Atsuhiko; Ozeki, Kazuhisa; Murao, Naoaki; Endo, Mika; Kikuta, Junichi; Kamata-Sakurai, Mika; Ishii, Masaru; Hattori, Kunihiro; Igawa, Tomoyuki

doi:10.1016/j.celrep.2020.108542

Cited by 43 publications

(30 citation statements)

References 46 publications

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“…A second possible engineering strategy to further elevate tumor specificity is to incorporate tumor-specific antigen binding. Mimoto and coworkers recently presented an antibody that bound hIL-6R only in the presence of ATP, which is found in high concentrations in the tumor microenvironment (TME), but only in low concentrations in healthy tissue (98). An additional method to elevate tumor specificity is to incorporate pH-responsive binding modalities into the antibody (99).…”

Section: Discussionmentioning

confidence: 99%

Design of a Trispecific Checkpoint Inhibitor and Natural Killer Cell Engager Based on a 2 + 1 Common Light Chain Antibody Architecture

et al. 2021

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Natural killer cell engagers gained enormous interest in recent years due to their potent anti-tumor activity and favorable safety profile. Simultaneously, chicken-derived antibodies entered clinical studies paving the way for avian-derived therapeutics. In this study, we describe the affinity maturation of a common light chain (cLC)-based, chicken-derived antibody targeting EGFR, followed by utilization of the same light chain for the isolation of CD16a- and PD-L1-specific monoclonal antibodies. The resulting binders target their respective antigen with single-digit nanomolar affinity while blocking the ligand binding of all three respective receptors. Following library-based humanization, bispecific and trispecific variants in a standard 1 + 1 or a 2 + 1 common light chain format were generated, simultaneously targeting EGFR, CD16a, and PD-L1. The trispecific antibody mediated an elevated antibody-dependent cellular cytotoxicity (ADCC) in comparison to the EGFR×CD16a bispecific variant by effectively bridging EGFR/PD-L1 double-positive cancer cells with CD16a-positive effector cells. These findings represent, to our knowledge, the first detailed report on the generation of a trispecific 2 + 1 antibodies exhibiting a common light chain and illustrate synergistic effects of trispecific antigen binding. Overall, this generic procedure paves the way for the engineering of tri- and oligospecific therapeutic antibodies derived from avian immunizations.

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Section: Discussionmentioning

confidence: 99%

Design of a Trispecific Checkpoint Inhibitor and Natural Killer Cell Engager Based on a 2 + 1 Common Light Chain Antibody Architecture

et al. 2021

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“…One novel subclass of tetherbody-like multispecific biotherapeutics drugs is the condition-activated tetherbody that can enrich the active drugs in a particular location through the design of conditional activation. The conditional activation mechanisms take advantage of special conditions in tumor microenvironment such as increased levels of specific proteases [184], ATP [185,186], and others [20]. Because the presence of tumor antigen in healthy tissues can cause on-target toxicity by ADCs or bsTCEs, Probodies TM (CytomX) with a protease-cleavable peptide linker and a masking peptide can presumably remain inert until proteolytically activated locally in disease tissues [184].…”

Section: Tetherbodiesmentioning

confidence: 99%

Recent Advances in the Molecular Design and Applications of Multispecific Biotherapeutics

Zhong

D’Antona

2021

Antibodies

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Recombinant protein-based biotherapeutics drugs have transformed clinical pipelines of the biopharmaceutical industry since the launch of recombinant insulin nearly four decades ago. These biologic drugs are structurally more complex than small molecules, and yet share a similar principle for rational drug discovery and development: That is to start with a pre-defined target and follow with the functional modulation with a therapeutic agent. Despite these tremendous successes, this “one target one drug” paradigm has been challenged by complex disease mechanisms that involve multiple pathways and demand new therapeutic routes. A rapidly evolving wave of multispecific biotherapeutics is coming into focus. These new therapeutic drugs are able to engage two or more protein targets via distinct binding interfaces with or without the chemical conjugation to large or small molecules. They possess the potential to not only address disease intricacy but also exploit new therapeutic mechanisms and assess undruggable targets for conventional monospecific biologics. This review focuses on the recent advances in molecular design and applications of major classes of multispecific biotherapeutics drugs, which include immune cells engagers, antibody-drug conjugates, multispecific tetherbodies, biologic matchmakers, and small-scaffold multispecific modalities. Challenges posed by the multispecific biotherapeutics drugs and their future outlooks are also discussed.

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“…Since adenosine is produced from extracellular ATP, counteracting the elevation of extracellular ATP concentration in the TME would allow initial control of adenosine formation and thus maintain effective antitumor immunity. To achieve this, Mimoto’s team generated an antibody that binds to the human IL6 receptor only when ATP concentration is increased [ 174 ]. IL6R is an attractive target protein because many cancers (colon, ovary, liver, prostate, etc.)…”

Section: Combination Of Metabolic Intervention and Immunotherapymentioning

confidence: 99%

Targeting Metabolism to Control Immune Responses in Cancer and Improve Checkpoint Blockade Immunotherapy

Luby

Alves-Guerra

2021

Cancers

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Over the past decade, advances in cancer immunotherapy through PD1–PDL1 and CTLA4 immune checkpoint blockade have revolutionized the management of cancer treatment. However, these treatments are inefficient for many cancers, and unfortunately, few patients respond to these treatments. Indeed, altered metabolic pathways in the tumor play a pivotal role in tumor growth and immune response. Thus, the immunosuppressive tumor microenvironment (TME) reprograms the behavior of immune cells by altering their cellular machinery and nutrient availability to limit antitumor functions. Today, thanks to a better understanding of cancer metabolism, immunometabolism and immune checkpoint evasion, the development of new therapeutic approaches targeting the energy metabolism of cancer or immune cells greatly improve the efficacy of immunotherapy in different cancer models. Herein, we highlight the changes in metabolic pathways that regulate the differentiation of pro- and antitumor immune cells and how TME-induced metabolic stress impedes their antitumor activity. Finally, we propose some drug strategies to target these pathways in the context of cancer immunotherapy.

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Exploitation of Elevated Extracellular ATP to Specifically Direct Antibody to Tumor Microenvironment

Cited by 43 publications

References 46 publications

Design of a Trispecific Checkpoint Inhibitor and Natural Killer Cell Engager Based on a 2 + 1 Common Light Chain Antibody Architecture

Design of a Trispecific Checkpoint Inhibitor and Natural Killer Cell Engager Based on a 2 + 1 Common Light Chain Antibody Architecture

Recent Advances in the Molecular Design and Applications of Multispecific Biotherapeutics

Targeting Metabolism to Control Immune Responses in Cancer and Improve Checkpoint Blockade Immunotherapy

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