Abstract LB-061: CRD5500: A versatile small molecule STING agonist amenable to bioconjugation as an ADC

Banerjee, Monali; Basu, Sourav; Middya, Sandip; Shrivastava, Ritesh; Ghosh, Rajib; Pryde, David C.; Yadav, Dharmendra Kumar; Bhattacharya, Gopal; Soram, Thanilsana; Puniya, Kavita; Raina, Ritika; Kadam, V. K.; Garai, Sujay; Sharma, Priti; Singh, Anuj Kumar; Shinde, Vaibhav; Rawat, Nidhi; Middya, Anindita; Sinha, Arghyotri; Chandel, Sunita; Narisipuram, Ganesh; Chatterjee, Abhisek; Mane, Nagaswamy; Surya, Arjun

doi:10.1158/1538-7445.sabcs18-lb-061

Cited by 4 publications

(4 citation statements)

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“…However, natural CDNs are rapidly degraded by circulating and cell-bound enzymes, including ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), 131 calling for the development of molecules with improved stability for clinical applications. Novel STING agonists developed to circumvent the limited half-life of natural CDNs include both CDN derivatives (e.g., GSK 532) 132 and CDN-unrelated agents (e.g., TTI-10001, CRD5500 and amidobenzimidazole derivatives) 133 – 135 In vitro , GSK 532 can induce cytokine responses in human peripheral blood mononuclear cells (PBMCs) bearing various STING haplotypes, 132 which is not the case of DXMAA and all natural CDNs. 66 Intratumoral administration of GSK 532 mediated robust anticancer effects against CT26 colorectal carcinomas growing in immunocompetent syngeneic mice, culminating with the eradication of existing lesions and the establishment of protective immunity against rechallenge with the same cancer cell line.…”

Section: Sting Signaling In Preclinical Tumor Modelsmentioning

confidence: 99%

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Trial watch: STING agonists in cancer therapy

et al. 2020

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Stimulator of interferon response cGAMP interactor 1 (STING1, best known as STING) is an endoplasmic reticulum-sessile protein that serves as a signaling hub, receiving input from several pattern recognition receptors, most of which sense ectopic DNA species in the cytosol. In particular, STING ensures the production of type I interferon (IFN) in response to invading DNA viruses, bacterial pathogens, as well as DNA leaking from mitochondria or the nucleus (e.g., in cells exposed to chemotherapy or radiotherapy). As a type I IFN is critical for the initiation of anticancer immune responses, the pharmaceutical industry has generated molecules that directly activate STING for use in oncological indications. Such STING agonists are being tested in clinical trials with the rationale of activating STING in tumor cells or tumor-infiltrating immune cells (including dendritic cells) to elicit immunostimulatory effects, alone or in combination with a range of established chemotherapeutic and immunotherapeutic regimens. In this Trial Watch, we discuss preclinical evidence and accumulating clinical experience shaping the design of Phase I and Phase II trials that evaluate the safety and preliminary efficacy of STING agonists in cancer patients.

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Section: Sting Signaling In Preclinical Tumor Modelsmentioning

confidence: 99%

“…Finally, intravenous administration of an amidobenzimidazole (ABZI)-based compound to immunocompetent mice bearing syngeneic colorectal cancers resulted in complete and long-lasting disease control. 133 …”

Section: Sting Signaling In Preclinical Tumor Modelsmentioning

confidence: 99%

Trial watch: STING agonists in cancer therapy

et al. 2020

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“…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][190][191][192] (Table 3). The most advanced, XMT-2056 (STING agonist: XMT-1621, Fig.…”

Section: Immune-stimulating Antibody Conjugatesmentioning

confidence: 99%

Payload diversification: a key step in the development of antibody–drug conjugates

Conilh

Sadílková²,

Viricel³

et al. 2023

J Hematol Oncol

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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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“…Compound 27 (CRD-5500): Banerjee's team 79 discovered 27 (structure not available) as a direct STING agonist, causing the maturation of hDCs and release of innate and adaptive inflammatory cytokines. Pre-clinical data showed that 27 effectively reduced tumor mass via intravenous and intratumoral injections, and the anti-tumor activity can be further amplified when combined with check point inhibitor therapy.…”

Section: Small Molecule Immunomodulators Targeting the Innate Immune ...mentioning

confidence: 99%