ORM-6151: A First-in-Class, Anti-CD33 Antibody-Enabled GSPT1 Degrader for AML

Palacino, James; Lee, Pedro; Jeong, Hangyeol; Kim, Yeonjoon; Song, Yoojin; Permpoon, Uttapol; Wong, Wesley P.; Chen, Bai; Fishkin, Nathan; Takrouri, Khuloud; Yu, Eunjin; Yao, Yi; Skaletskaya, Anna; Chang, Ki-Hwan; Kim, Min‐Soo; Kim, ﻿Dayeong; Choi, Dong-Jin; Park, Peter U

doi:10.1182/blood-2022-168936

Cited by 6 publications

(5 citation statements)

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“…ORM-6151, a CD33-targeted DAC for patients with AML, has been developed by the same company. This DAC has demonstrated antigen-dependent in vitro cytotoxicity comparable to that of the FDA-approved anti-CD33 ADC gemtuzumab ozogamicin with superior activity, including complete eradication of all tumour cells in nine of nine animals with a single dose at 3 mg/ kg in an MV4-11 subcutaneous mouse xenograft model of AML 238,239 . Notably, even a 0.1 mg/kg single dose demonstrated effective disease control in a disseminated version of the MV4-11 xenograft model.…”

Section: Review Articlementioning

confidence: 94%

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Exploring the next generation of antibody–drug conjugates

Tsuchikama,

Anami,

et al. 2024

Nat Rev Clin Oncol

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Antibody-drug conjugates (ADCs) are a promising cancer treatment modality that enables the selective delivery of highly cytotoxic payloads to tumours. However, realizing the full potential of this platform necessitates innovative molecular designs to tackle several clinical challenges such as drug resistance, tumour heterogeneity and treatment-related adverse effects. Several emerging ADC formats exist, including bispecific ADCs, conditionally active ADCs (also known as probody-drug conjugates), immune-stimulating ADCs, protein-degrader ADCs and dual-drug ADCs, and each offers unique capabilities for tackling these various challenges. For example, probody-drug conjugates can enhance tumour specificity, whereas bispecific ADCs and dual-drug ADCs can address resistance and heterogeneity with enhanced activity. The incorporation of immune-stimulating and protein-degrader ADCs, which have distinct mechanisms of action, into existing treatment strategies could enable multimodal cancer treatment. Despite the promising outlook, the importance of patient stratification and biomarker identification cannot be overstated for these emerging ADCs, as these factors are crucial to identify patients who are most likely to derive benefit. As we continue to deepen our understanding of tumour biology and refine ADC design, we will edge closer to developing truly effective and safe ADCs for patients with treatment-refractory cancers. In this Review, we highlight advances in each ADC component (the monoclonal antibody, payload, linker and conjugation chemistry) and provide more-detailed discussions on selected examples of emerging novel ADCs of each format, enabled by engineering of one or more of these components.• To address these challenges, several novel ADC formats have been developed, including bispecific ADCs, probody-drug conjugates, immune-stimulating ADCs, protein-degrader ADCs and dual-drug ADCs.• Probody-drug conjugates are expected to have improved tumour specificity, whereas bispecific ADCs and dual-drug ADCs have the potential to combat drug resistance and tumour heterogeneity.• Integrating immune-stimulating ADCs and protein-degrader ADCs with current treatment regimens might enable multimodal treatment, potentially through several distinct mechanisms of action.• Patient stratification and biomarker identification will be crucial to maximize the clinical benefits of these emerging ADCs.Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

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Section: Review Articlementioning

confidence: 94%

“…234) and the chromatin regulatory protein SMARCA2 (also known as BRM) 235 . Two DACs designed to degrade the G1 to S phase transition 1 (GSPT1) protein are showing early signs of clinical potential [236][237][238][239] . These DACs use a highly potent CC-885-derived GSPT1-CRBN degrader as the payload.…”

Section: Review Articlementioning

confidence: 99%

Exploring the next generation of antibody–drug conjugates

Tsuchikama,

Anami,

et al. 2024

Nat Rev Clin Oncol

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“…141 Compared to the clinical candidate GSPT1 degrader 18 or the CD33-targeted drug Mylotarg (75), treatment with compound 74 in CD33-expressing cell lines resulted in a 10-1000-fold increase in therapeutic efficacy. 141 Furthermore, compound 74 exhibited picomolor activity, including strong activity against Mylotarg-resistant cell lines. However, in non-AML (CD33−) cells, the…”

Section: Antibody Neodegrader Conjugate (Andc)mentioning

confidence: 99%

“…In addition to HER2 + breast cancer, Orum Therapeutics has also investigated the AML indication using CD33‐targeted antibodies to generate the conjugate that led to the identification of ORM‐6151 ( 74 ). Compound 74 showed dose‐dependent and time‐dependent degradation of GSPT1 in MV4‐11 cells and was able to completely degrade GSPT1 within 12 h at a low concentration of 0.1 nM 141 . Compared to the clinical candidate GSPT1 degrader 18 or the CD33‐targeted drug Mylotarg ( 75 ), treatment with compound 74 in CD33‐expressing cell lines resulted in a 10‐1000‐fold increase in therapeutic efficacy 141 .…”

Section: Antibody Neodegrader Conjugate (Andc)mentioning

confidence: 99%

“…Compound 74 showed dose‐dependent and time‐dependent degradation of GSPT1 in MV4‐11 cells and was able to completely degrade GSPT1 within 12 h at a low concentration of 0.1 nM 141 . Compared to the clinical candidate GSPT1 degrader 18 or the CD33‐targeted drug Mylotarg ( 75 ), treatment with compound 74 in CD33‐expressing cell lines resulted in a 10‐1000‐fold increase in therapeutic efficacy 141 . Furthermore, compound 74 exhibited picomolor activity, including strong activity against Mylotarg‐resistant cell lines.…”

Section: Antibody Neodegrader Conjugate (Andc)mentioning

confidence: 99%

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Development and therapeutic potential of GSPT1 molecular glue degraders: A medicinal chemistry perspective

Chang,

Qu,

et al. 2024

Medicinal Research Reviews

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Unprecedented therapeutic targeting of previously undruggable proteins has now been achieved by molecular‐glue‐mediated proximity‐induced degradation. As a small GTPase, G1 to S phase transition 1 (GSPT1) interacts with eRF1, the translation termination factor, to facilitate the process of translation termination. Studied demonstrated that GSPT1 plays a vital role in the acute myeloid leukemia (AML) and MYC‐driven lung cancer. Thus, molecular glue (MG) degraders targeting GSPT1 is a novel and promising approach for treating AML and MYC‐driven cancers. In this Perspective, we briefly summarize the structural and functional aspects of GSPT1, highlighting the latest advances and challenges in MG degraders, as well as some representative patents. The structure‐activity relationships, mechanism of action and pharmacokinetic features of MG degraders are emphasized to provide a comprehensive compendium on the rational design of GSPT1 MG degraders. We hope to provide an updated overview, and design guide for strategies targeting GSPT1 for the treatment of cancer.

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