Abstract 1858: SBT6290, a systemically administered Nectin4-directed TLR8 ImmunoTAC™ product candidate, is designed for tumor-localized activation of myeloid cells

Comeau, Michael R.; Metz, Heather; Stevens, Brenda; Winship, Damion; Brevik, Jamie; Rhodehamel, Marcus; Childs, Monica; Hay, Elsa; Chang, Jenny; Fan, Liqing; Xu, Hengyu; Grey, Jonathan; Adamo, Jeffrey; Setter, Ben; Carillo, Ray R; Smith, Sean W.; Tan, Phil; DuBose, Robert; Latchman, Yvette; Baum, Peter; Odegard, Valerie

doi:10.1158/1538-7445.am2021-1858

Cited by 6 publications

(5 citation statements)

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“…[ 39 ] Although preclinical data have shown that antibody–PRR agonist conjugates might be useful to reduce the risk of immune‐related adverse reactions, in addition to enhancing targeted intracellular delivery and the therapeutic index, further studies are warranted to investigate this relatively underexplored field. [ 47,49,52,56 ]…”

Section: Discussionmentioning

confidence: 99%

“…[39] Although preclinical data have shown that antibody-PRR agonist conjugates might be useful to reduce the risk of immune-related adverse reactions, in addition to enhancing targeted intracellular delivery and the therapeutic index, further studies are warranted to investigate this relatively underexplored field. [47,49,52,56] Through decades of studies, unprecedented progress has been made in the field of cancer immunotherapy. The development of antibody-PRR agonist conjugates has brought new hope for patients with cancers, especially those with immunologically "cold" tumors.…”

Section: Discussionmentioning

confidence: 99%

“…[ 48 ] Another drug candidate, SBT6290, was developed by the same technology platform to treat patients with Nectin‐4‐expressing bladder cancer, breast cancer, and pancreatic cancer. [ 49 ] Related clinical trials will be conducted in 2022, and more data will soon be available.…”

Section: Pattern Recognition Receptor Agonists As Payloadsmentioning

confidence: 99%

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Antibody–Pattern Recognition Receptor Agonist Conjugates: A Promising Therapeutic Strategy for Cancer

Li²,

2022

Advanced Biology

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To date, 12 ADCs (gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, moxetumomab pasudotox, polatuzumab vedotin, trastuzumab deruxtecan, enfortumab vedotin, sacituzumab govitecan, belantamab mafodotin, loncastuximab tesirine-lpyl, and tisotumab vedotin-tftv) have been approved by the FDA to treat various solid tumors and hematological malignancies. [3] An ADC is typically composed of a monoclonal antibody (mAb; recognizes a specific target) linked to a potent cytotoxic molecule (payload drug). In addition, a linker is required to connect these two components and maintain ADC stability. [4] Two types of linkers, namely cleavable [5] and noncleavable linkers, [6] have been developed, and these have met different requirements of preclinical and clinical studies. Cleavable linkers are designed to remain stable in the bloodstream and selectively release the payload drug in the target cell, whereas noncleavable linkers mainly rely on lysosomal degradation to release the payload drug after ADC internalization. [7] All components of an ADC can be distinctively designed to maximize its binding affinity and therapeutic effect (Figure 1).The ADC as a complex fully exerts biological effect of the two components and selectively delivers the payload drug to target tissues through the mAb. The ADC initially binds to cell surface antigens and enters tumor cells through clathrin-mediated endocytosis. [8] It is then transported to the early endosome, and it subsequently enters the lysosome where it is degraded by proteolytic enzymes to release the payload drug into the cytoplasm. [9] Ultimately, cytotoxic drugs induce tumor cell death or apoptosis via different mechanisms, such as by damaging DNA or inhibiting microtubule synthesis. [10] This process results in minimal systemic toxic effects, but it improves the treatment window of cytotoxic drugs, and the therapeutic efficacy is enhanced accordingly. [11] Development History of Antibody-Drug ConjugatesThe history of ADC drug development occurred in three stages and provided three generations of ADCs. For first-generation ADCs, cytotoxic drugs were mainly conjugated with mouse mAbs via non-cleavable linkers. This increased the possibility of inducing antidrug antibody effects. In addition, off-target Antibody-drug conjugates (ADCs) are composed of monoclonal antibodies linked to cytotoxic payload drugs, each of which can be diversely designed in accordance with pharmacological and clinical requirements. The use of ADCs is effective for the treatment of different diseases, including cancers, and is gaining widespread attention. To date, 12 ADCs have been approved by the U.S. Food and Drug Administration for treating cancer and improving the quality of life of patients. To expand the application of ADCs and improve their treatment efficiency, various formats have recently been manufactured, including pattern recognition receptor (PRR) agonist-based ADCs. The antibody has a unique structure that enables the specific delivery of PRR agonists ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Antibody–Pattern Recognition Receptor Agonist Conjugates: A Promising Therapeutic Strategy for Cancer

Li²,

2022

Advanced Biology

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“…It consists of a HER2-targeting antibody and a TLR 7/8 agonist with a non-cleavable linker and is used to treat patients with HER2-positive solid tumors. Other ISACs targeting solid tumors include SBT6050 (Phase I, NCT04460456) and SBT6290 (Phase I/II, NCT05234606) ( 154 , 155 ). Both drugs use TLR8 agonists as payloads, with the difference that SBT6050 targets HER2 and SBT6290 targets Nectin4 (Nectin cell adhesion molecule 4, a type I membrane protein that is overexpressed in a variety of tumor cells).…”

Section: Dds Based On Coupling Technology For Cancer Immunotherapymentioning

confidence: 99%

Diverse drug delivery systems for the enhancement of cancer immunotherapy: an overview

Liu,

Cheng,

et al. 2024

Front. Immunol.

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Despite the clear benefits demonstrated by immunotherapy, there is still an inevitable off-target effect resulting in serious adverse immune reactions. In recent years, the research and development of Drug Delivery System (DDS) has received increased prominence. In decades of development, DDS has demonstrated the ability to deliver drugs in a precisely targeted manner to mitigate side effects and has the advantages of flexible control of drug release, improved pharmacokinetics, and drug distribution. Therefore, we consider that combining cancer immunotherapy with DDS can enhance the anti-tumor ability. In this paper, we provide an overview of the latest drug delivery strategies in cancer immunotherapy and briefly introduce the characteristics of DDS based on nano-carriers (liposomes, polymer nano-micelles, mesoporous silica, extracellular vesicles, etc.) and coupling technology (ADCs, PDCs and targeted protein degradation). Our aim is to show readers a variety of drug delivery platforms under different immune mechanisms, and analyze their advantages and limitations, to provide more superior and accurate targeting strategies for cancer immunotherapy.

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“… 30 , 33 These broad-spectrum effects can be either direct through Nectin4-specific mechanisms or indirect via the engagement of Fcγ receptors on the surface of myeloid cells. 34 Interestingly, Nectin4 was recently described as a novel ligand of T cell immunoreceptor with Ig and ITIM domains (TIGIT), which is an immune checkpoint protein. 51 SBT6290 apparently prevents the interaction between Nectin 4 and TIGIT, potentially contributing to T and NK cell activation.…”

Section: Introductionmentioning

confidence: 99%

Trial watch: Toll-like receptor ligands in cancer therapy

Naour

Kroemer

2023

OncoImmunology

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Accumulating evidence indicates that Toll-like receptor (TLR) agonists proficiently (re)instore cancer immunosurveillance as immunological adjuvants. So far, three TLR agonists have been approved by regulatory agencies for use in oncological applications. Additionally, these immunotherapeutics have been extensively investigated over the past few years. Multiple clinical trials are currently evaluating the combination of TLR agonists with chemotherapy, radiotherapy, or different immunotherapies. Moreover, antibodies targeting tumor-enriched surface proteins that have been conjugated to TLR agonists are being developed to stimulate anticancer immune responses specifically within the tumor microenvironment. Solid preclinical and translational results support the favorable immune-activating effects of TLR agonists. Here, we summarize recent preclinical and clinical advances in the development of TLR agonists for anticancer immunotherapy.

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Abstract 1858: SBT6290, a systemically administered Nectin4-directed TLR8 ImmunoTAC™ product candidate, is designed for tumor-localized activation of myeloid cells

Cited by 6 publications

References 0 publications

Antibody–Pattern Recognition Receptor Agonist Conjugates: A Promising Therapeutic Strategy for Cancer

Antibody–Pattern Recognition Receptor Agonist Conjugates: A Promising Therapeutic Strategy for Cancer

Diverse drug delivery systems for the enhancement of cancer immunotherapy: an overview

Trial watch: Toll-like receptor ligands in cancer therapy

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