Abstract:BACKGROUND
Innate immune signaling mediated through STING (Stimulator of Interferon Genes) generates a Type I interferon (Type 1 IFN) signal that increases T cell infiltration into cold or non-inflamed tumors leading to significant regression (Woo et al., 2015). Comprehensive data from one of our STING agonists was presented at the AACR Tumor Immunology meeting in 2017. Here we describe CRD5500, a versatile next generation compound that can be dosed either by intra-tumoral route, systemically (I… Show more
“…, TAK-500), and Curadev ( i.e. , CRD5500) . On the basis of recent reports leveraging ADC technology for the delivery of other innate immune agonists, such targeting strategies appear well poised to be a major advancement in the field.…”
Section: Summary Perspectives and
Future Directionsmentioning
confidence: 99%
“…While no published reports are available, antibody drug conjugates (ADCs) for targeted STING agonist delivery are being developed by several companies, including Mersana (i.e., XMT-2056), 541,542 Takeda (i.e., TAK-500), 210 and Curadev (i.e., CRD5500). 543 On the basis of recent reports leveraging ADC technology for the delivery of other innate immune agonists, 398 such targeting strategies appear well poised to be a major advancement in the field. However, this also raises the important and unknown question as to which cell type(s) in the tumor should STING agonists be targeted.…”
Section: Summary Perspectives and Futurementioning
The stimulator of interferon genes (STING) cellular signaling pathway is a promising target for cancer immunotherapy. Activation of the intracellular STING protein triggers the production of a multifaceted array of immunostimulatory molecules, which, in the proper context, can drive dendritic cell maturation, antitumor macrophage polarization, T cell priming and activation, natural killer cell activation, vascular reprogramming, and/or cancer cell death, resulting in immune-mediated tumor elimination and generation of antitumor immune memory. Accordingly, there is a significant amount of ongoing preclinical and clinical research toward further understanding the role of the STING pathway in cancer immune surveillance as well as the development of modulators of the pathway as a strategy to stimulate antitumor immunity. Yet, the efficacy of STING pathway agonists is limited by many drug delivery and pharmacological challenges. Depending on the class of STING agonist and the desired administration route, these may include poor drug stability, immunocellular toxicity, immune-related adverse events, limited tumor or lymph node targeting and/or retention, low cellular uptake and intracellular delivery, and a complex dependence on the magnitude and kinetics of STING signaling. This review provides a concise summary of the STING pathway, highlighting recent biological developments, immunological consequences, and implications for drug delivery. This review also offers a critical analysis of an expanding arsenal of chemical strategies that are being employed to enhance the efficacy, safety, and/or clinical utility of STING pathway agonists and lastly draws attention to several opportunities for therapeutic advancements.
“…, TAK-500), and Curadev ( i.e. , CRD5500) . On the basis of recent reports leveraging ADC technology for the delivery of other innate immune agonists, such targeting strategies appear well poised to be a major advancement in the field.…”
Section: Summary Perspectives and
Future Directionsmentioning
confidence: 99%
“…While no published reports are available, antibody drug conjugates (ADCs) for targeted STING agonist delivery are being developed by several companies, including Mersana (i.e., XMT-2056), 541,542 Takeda (i.e., TAK-500), 210 and Curadev (i.e., CRD5500). 543 On the basis of recent reports leveraging ADC technology for the delivery of other innate immune agonists, 398 such targeting strategies appear well poised to be a major advancement in the field. However, this also raises the important and unknown question as to which cell type(s) in the tumor should STING agonists be targeted.…”
Section: Summary Perspectives and Futurementioning
The stimulator of interferon genes (STING) cellular signaling pathway is a promising target for cancer immunotherapy. Activation of the intracellular STING protein triggers the production of a multifaceted array of immunostimulatory molecules, which, in the proper context, can drive dendritic cell maturation, antitumor macrophage polarization, T cell priming and activation, natural killer cell activation, vascular reprogramming, and/or cancer cell death, resulting in immune-mediated tumor elimination and generation of antitumor immune memory. Accordingly, there is a significant amount of ongoing preclinical and clinical research toward further understanding the role of the STING pathway in cancer immune surveillance as well as the development of modulators of the pathway as a strategy to stimulate antitumor immunity. Yet, the efficacy of STING pathway agonists is limited by many drug delivery and pharmacological challenges. Depending on the class of STING agonist and the desired administration route, these may include poor drug stability, immunocellular toxicity, immune-related adverse events, limited tumor or lymph node targeting and/or retention, low cellular uptake and intracellular delivery, and a complex dependence on the magnitude and kinetics of STING signaling. This review provides a concise summary of the STING pathway, highlighting recent biological developments, immunological consequences, and implications for drug delivery. This review also offers a critical analysis of an expanding arsenal of chemical strategies that are being employed to enhance the efficacy, safety, and/or clinical utility of STING pathway agonists and lastly draws attention to several opportunities for therapeutic advancements.
“…The fact that CRD-5500 can be dosed via multiple routes makes it a favorable agent for future clinical development. Pre-clinical data show that both intravenous and intratumoral injections of CRD-5500 induce tumor regression in murine CT26 colon carcinoma models engineered to express human STING, and this anti-tumor effect is further amplified when CRD-5500 is combined with check point inhibitor therapy [ 92 ].…”
Section: Sting Agonists In Pre-clinical Evaluationsmentioning
The interrogation of intrinsic and adaptive resistance to cancer immunotherapy has identified lack of antigen presentation and type I interferon signaling as biomarkers of non-T-cell-inflamed tumors and clinical progression. A myriad of pre-clinical studies have implicated the cGAS/stimulator of interferon genes (STING) pathway, a cytosolic DNA-sensing pathway that drives activation of type I interferons and other inflammatory cytokines, in the host immune response against tumors. The STING pathway is also increasingly understood to have other anti-tumor functions such as modulation of the vasculature and augmentation of adaptive immunity via the support of tertiary lymphoid structure development. Many natural and synthetic STING agonists have entered clinical development with the first generation of intra-tumor delivered cyclic dinucleotides demonstrating safety but only modest systemic activity. The development of more potent and selective STING agonists as well as novel delivery systems that would allow for sustained inflammation in the tumor microenvironment could potentially augment response rates to current immunotherapy approaches and overcome acquired resistance. In this review, we will focus on the latest developments in STING-targeted therapies and provide an update on the clinical development and application of STING agonists administered alone, or in combination with immune checkpoint blockade or other approaches.
“…3 ). In addition, three STING-conjugated ADCs are being developed at the preclinical stage: CDR-550, XMT-2056 and more recently a FcγR-targeting immune-stimulating ADC conjugated to the STING agonist XMT-1621 [ 189 – 192 ] (Table 3 ). The most advanced, XMT-2056 (STING agonist: XMT-1621, Fig.…”
Section: Payloads That Have Reached Clinical Trials: Promises and Fai...mentioning
Antibody–drug conjugates (ADCs) is a fast moving class of targeted biotherapeutics that currently combines the selectivity of monoclonal antibodies with the potency of a payload consisting of cytotoxic agents. For many years microtubule targeting and DNA-intercalating agents were at the forefront of ADC development. The recent approval and clinical success of trastuzumab deruxtecan (Enhertu®) and sacituzumab govitecan (Trodelvy®), two topoisomerase 1 inhibitor-based ADCs, has shown the potential of conjugating unconventional payloads with differentiated mechanisms of action. Among future developments in the ADC field, payload diversification is expected to play a key role as illustrated by a growing number of preclinical and clinical stage unconventional payload-conjugated ADCs. This review presents a comprehensive overview of validated, forgotten and newly developed payloads with different mechanisms of action.
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