On April 18, 2023 Orum Therapeutics, a clinical-stage private biotechnology company pioneering cell-specific targeted protein degradation (TPD² ) and targeted protein stabilization (TPS² ), reported new preclinical data for three of Orum’s therapeutic programs: ORM-5029, which is a proprietary GSPT1 degrader conjugated to HER2-targeting antibody pertuzumab; ORM-6151, which delivers GSPT1 degrader to CD33+ tumors; and its new immuno-oncology program for a Cbl-b inhibitor (Cbl-bi) conjugated to anti-PD-1 antibody pembrolizumab (Press release, Orum Therapeutics, APR 18, 2023, View Source [SID1234630289]). The data were presented in three posters at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting.

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"We are pleased to present new data supporting clinical development of two programs from our TPD² GSPT1 Degrader Platform, which was developed to improve the therapeutic window and realize the full potential of GSPT1 degraders through precision delivery to cancer cells via antibody drug conjugates"

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"We are pleased to present new data supporting clinical development of two programs from our TPD² GSPT1 Degrader Platform, which was developed to improve the therapeutic window and realize the full potential of GSPT1 degraders through precision delivery to cancer cells via antibody drug conjugates," said Peter Park, Ph.D., Chief Scientific Officer of Orum Therapeutics. "We are also excited to unveil at AACR (Free AACR Whitepaper) our new TPS² platform, which has the potential to achieve the full promise of Cbl-b inhibitors through T cell-specific delivery. With this novel approach, we show that we can limit unwanted systemic exposure, including the risk of toxicity associated with c-Cbl inhibition, prolong the activation of exhausted PD-1+ T cells, and provide resistance to negative environmental cues such as TGF-β or regulatory T cells. We believe our approach of harnessing the power of protein degraders and stabilizers with the precision of antibody targeting will improve the treatment of cancer for more patients."

Details of the data presented are as follows:

Title: A novel antibody-enabled Dual-precision Targeted Protein Stabilization (TPS²) that augments anti-tumor immune response by targeting Cbl-b inhibitor to exhausted T cells while blocking checkpoint molecule, PD-1
Presenter: Joanne Lim, Ph.D.
Abstract Number: 4436
Summary: Cbl-b inhibition results in stabilization of intracellular proteins downstream of the T cell activation pathways. Using a murine model well-established to be refractory to anti-PD-1 antibody treatment, we demonstrated that anti-PD-1-Cbl-b inhibitor approach increased effector T cell markers in the tumor and delayed tumor growth.
Presented Data:

The delivery of Cbl-b inhibitor (Cbl-bi) conjugated to anti-PD-1 antibody enhances the saturating, maximum activation of anti-PD-1 antibody by 300% in PD-1/PD-L1 blockade assay.
Anti-PD-1-Cbl-bi conjugates enhance T cell responses of mixed lymphocyte reaction in a dose-dependent manner and overcome suppressive effects of TGF-β and Treg cells compared to antibody alone in vitro.
Anti-PD-1-Cbl-bi conjugates enhance ex vivo activation of tumor-associated T cells from human cancer patients compared to antibody alone or when treated with antibody and unconjugated Cbl-bi.
Anti-PD-1-Cbl-bi conjugates delay the growth of melanoma tumors in hPD-1 transgenic mice, with corresponding increase in intratumoral transcript levels of CD3e, granzyme B, and perforin in the tumor.
Title: ORM-6151: A first-in-class CD33-antibody enabled GSPT1 degrader for AML
Presenter: James Palacino, Ph.D.
Abstract Number: 2700
Summary: ORM-6151 shows robust single-dose efficacy, both in vitro and in vivo with superiority or comparability to standard of care (SOC) agents. In addition, in vitro testing demonstrated superior tolerability to healthy bone marrow progenitor cells, suggesting better tolerability. Responses in representative TP53 wild-type and mutant AML models demonstrated comparable activity, indicating the potential for responses in a large percentage of AML patients with poor treatment options.
Presented Data:

ORM-6151 shows robust in vitro activity in p53 wild-type and mutant cell models.
In ex-vivo AML blasts, ORM-6151 demonstrates efficacy superior to CC-90009, a small-molecule GSPT1 degrader, or Mylotarg, an FDA-approved treatment for AML.
Compared to CC-90009 or Mylotarg, ORM-6151 exhibits minimal cytotoxic activity to healthy hematopoietic progenitor cells in vitro.
A single treatment of ORM-6151 at 3 mg/kg regresses MV4-11 tumors in vivo mouse model with 9/9 complete response (CR), and a single dose of 1 mg/kg produced equivalent antitumor effect as SOC doublet given at optimal repeated dose.
Title: Development of RNAscope multiplex-based assay for exploratory pharmacodynamic biomarkers assessment in breast cancer patients from Phase I clinical trial of ORM-5029, a potent GSPT1 degrader
Presenter: Shikha Saini, Ph.D.
Abstract Number: 2118
Summary: To fulfill the need to develop pharmacodynamic biomarkers as predictors of efficacy to support clinical development of ORM-5029, Orum identified a novel GSPT1 antibody for detection of depletion following treatment with ORM-5029. GSPT1 depletion and subsequent activation of the integrated stress response are both seen following in vitro or in vivo treatment with ORM-5029. Degree of pharmacodynamic (PD) change correlates with depth and duration of in vivo response. Orum is currently developing a multiplexed (IF/ISH/ISH) assay to track PD responses in patients, with an aim to better predict responses and efficacious doses.
Presented Data:

Orum identified the depletion of GSPT1 as a target-proximal pharmacodynamic biomarker in ORM-5029 treated in vitro and in vivo samples.
Loss of GSPT1 drives activation of integrated stress response and upregulation of ATF3 and DDIT3 mRNA and these responses are also seen following treatment with ORM-5029, in both in vitro BT-474 cells and in vivo HCC1568 mouse model.
PD responses correlate with degree and duration of response in an in vivo model treated with ORM-5029.
The posters are available to download through the links below:
PD-1-Cbl-bi TPS² preclinical poster: View Source
ORM-6151 preclinical poster: View Source
ORM-5029 predictive biomarker poster: View Source