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Beyond CCR8: key epitopes targeting dynamic CCR8 conformational states and a diversity of monoclonal antibodies to modulate the tumor microenvironment for the treatment of cancers

- Due to its high and relatively specific expression on tumor-infiltrating Tregs, CCR8 represents an attractive novel target to derive novel immunotherapies.
- At Domain, we successfully discovered and patent-protected a mAb library of several dozen of antibodies with distinct and differentiated binding and activity profiles.
- This collection constitutes a unique source for the development of a best-in-class well-differentiated anti- hCCR8 depleting antibody for the treatment of cancers.
- Based on promising profiles, a set of anti-CCR8 mAb leads with distinct characteristics have entered late optimization phase (humanization, enhanced cytotoxic activity (i.e., ADCC, CDC, ADCP), …). Cell line generation will be initiated in Q1-2023.

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A first-in-human trial of DT-9081 selective EP4 receptor antagonist, in patients with advanced, recurrent or metastatic solid tumors

High levels of prostaglandin E2 (PGE2) in tumors suppress anti-tumor immunity in the tumor microenvironment and contribute to tumor escape and disease progression. This effect of PGE2 is mediated through the activation of EP4R, a Gs protein coupled receptor activating cAMP signaling expressed by immune cells.
DT-9081 is a new small molecule, orally administered, highly selective antagonist of EP4R developed to overcome the immune-suppressive effects of PGE2, and to reverse the resistance to immune checkpoint blockers.
DT-9081 has demonstrated significant anti–tumor activity as monotherapy and in combination with immunotherapeutic agents in several syngenic murine cancer models (CT26 colorectal tumor model and MCA205 sarcoma model). These data are presented in poster #814:
”DT-9081, a selective EP4 receptor antagonist which synergizes with immune checkpoint inhibitors to induce complete responses in syngeneic murine
cancer models.”

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DT-9081, a selective EP4 receptor antagonist which synergizes with immune checkpoint inhibitors to induce complete responses in syngeneic murine cancer models

The response to Immune Checkpoint Inhibitors (ICI) treatment can be limited by the implementation of resistance mechanisms by the tumor to escape from the host immune system surveillance. Combination strategies with agents designed to shut down these resistance pathways are highly desirable to generate a better anti-tumor efficacy and, of course, long-lasting complete responses.
Elevated levels of Prostaglandin E2 (PGE2), an eicosanoid synthesized from arachidonic acid by the inducible cyclooxygenase-2 (COX-2), exert strong immunosuppressive effect in the tumor microenvironment. Also, upregulation of COX-2 was shown in several types of tumors. Counteracting this immunosuppressive pathway have the potential to synergize with the anti-tumor effects of ICI. As the use of nonsteroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors (Coxibs) in cancer proved to be non applicable due to safety concerns, there is a need to develop safer alternatives, especially by inhibiting downstream targets. PGE2 immunosuppressive effects are largely mediated by the EP4 receptor, expressed on multiple immune cells. The development of antagonists of the EP4 receptor is thus a promising strategy to inhibit the PGE2-induced immunosuppression in the tumor microenvironment and to restore anti-tumor immunity.
Phase Ia clinical candidate DT-9081, a selective EP4 receptor antagonist, was designed to counteract the PGE2-immunosuppressive effects in the TME and to synergize with ICI. DT-9081 in vivo efficacy, in combination with ICI in murine syngeneic models, is presented.

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Novel biased PAR2 inhibitors with best-in-class properties reduce resistance to both targeted therapy and immunotherapy in oncology models

A novel series of potent and selective PAR2 inhibitors has been developed by Domain Therapeutics. Data showing their unique features and their potency to alleviate the resistance to both targeted therapy and immunotherapy in cancer models are presented.

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Depleting anti-hCCR8 mAb Therapy #2: Selection of candidates for the development of innovative depleting anti-CCR8 therapeutic antibodies to control the immunosuppressive tumor microenvironment

Lead mAbs from Domain’s unique anti-hCCR8 collection were successfully humanized to deliver novel
antibodies having improved reactivity for HUT78 vs. chimeric ones. In addition, clear differentiating features were
observed with Domain’s humanized mAbs compared with competitors ones currently in the clinic. Amongst
these features, different epitope recognition and capacity to antagonize CCL1-induced receptor internalization
could represent key advantages. Finally, with the aim at optimizing depleting activities of Domain’s lead mAbs, Fc
variants were evaluated for Fc receptors binding and ADCC/ADCP activities. This characterization enabled the
identification of best Fc part for the final candidate selection.

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Depleting hCCR8 mAb Therapy #1: Characterization of a broad collection of anti-hCCR8 mAbs

We demonstrated that treatment with a depleting anti-mCCR8 mAb was able to translate into robust anti-tumor activity in multiple syngeneic models, with induction of potent and tumor specific long-term immunological memory. Moreover, the wide characterization of our diverse mAb library revealed distinct mAb cellular reactivity profiles, different epitope recognition modes (based on binding to different peptides with different post-translational modifications), subnanomolar antagonist activity, and insurmountable property with regards to CCR8 ligand CCL1.

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A pan group III mGluR PAM candidate ready to enter pre-IND studies

By targeting not only mGluR4 but also mGluR7 and 8, and by exhibiting an improved oral PK profile, DT095435 is positioned as a second generation compound that should succeed in reaching clinical efficacy where Foliglurax narrowly failed.

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A reliable real time pharmacological platform dedicated to the study of ICP co-receptors

This poster presents bioSens-All®️, a powerful and versatile pharmacological platform which is highly adaptable for hot topic targets such as Immune Checkpoint targets (Inhibitory & Stimulatory Immune Checkpoints).

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Use of novel ebBRET biosensors for comprehensive signaling profiling of 100 therapeutically relevant human GPCRs

Here, we describe a novel suite of enhanced bystander bioluminescence resonance energy transfer (ebBRET)-based biosensors that were used to define the signaling profiles of 100 therapeutically relevant human GPCRs in response to endogenous (or prototypical) ligands.

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A high value pharmacological platform dedicated to the real time study of Stimulatory immune checkpoint signaling pathways

We present here several innovative BRET assays dedicated to inhibitory and stimulatory ICPs (PD-1, CTLA-4, 4-1BB), and developed by us.
The ICP platform set up here shows good accuracy & robustness and represents a solid & reliable technology for ICP dedicated drug discovery.

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A pharmacological platform for the real time study of ICP signaling pathways

This poster presents the last generation of our proprietary platform bioSens-All®️ which is dedicated to the identification and characterization of immune checkpoint inhibitors.

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DT095597 a New NPFFR1 Antagonist Devoid of Addictive Properties to Fight Opioid Crisis

This poster presents the characterization of a proprietary NPFF receptor antagonist as a game-changer and a promising therapeutic strategy to fight the current opioid crisis.

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Decrypting EGFR signaling with BRET biosensors : A novel approach to study RTK mutations and the effects of inhibitors

This poster illustrates a valuable BRET-based platform used to characterize RTK candidates regarding constitutive activity, real-time kinetics or impact of RTK mutations on signalling pathways.

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“GPCR-ome” modulation upon PD1 / PDL1 axis blockade

co-authored with Explicyte, Bordeaux, France & Institut Bergonié, Bordeaux, France, this poster discloses an in-depth GPCR expression analysis from tumor microenvironment to dissect out mechanisms of resistance to immune checkpoint inhibitors.

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DT095895, a selective EP4 receptor antagonist with monotherapy efficacy in syngeneic mouse model(s) and best-in-class properties

This poster presents the complete characterization of Domain drug candidate benchmarked to EP4 antagonist molecules currently in the clinic and demonstrating a best-in-class potential.

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DT095435: A novel “pan” group III metabotropic glutamate receptor positive allosteric modulator for Parkinson’s disease

This poster presents the profiling of DT095435, our pan group III mGluR PAM development candidate, as a potential new anti-dyskinetic treatment for Parkinson's disease.

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Creation of a large-spectrum GPCR biosensor for functional in vitro safety and systems pharmacology analysis

This study served as a validation of the utility of the Gz/G15 large-spectrum biosensor for safety and systems pharmacology profiling. Moreover, our results support the use of this cell-based functional assay in high throughput receptor deorphanization and functional screening programs.

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GPCRs in oncology and immuno-oncology : The IRIC's virtual symposium 2021 [VIDEO]

Chaired by IRIC's CEO Michel Bouvier, this symposium showcases some of the latest discoveries & techniques leveraging the potential of GPCRs in oncology and immuno-oncology.
Leading experts share findings from world-class academic & private research on GPCRs in those crucial fields.

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The discovery and challenges of antibodies targeting GPCRs. [WEBINAR]

Xavier Leroy, Domain Therapeutics's CSO, Xavier Leroy and Martine Smit, Professor of Target and Systems Biochemistry at the University of Amsterdam, discuss the progress achieved in G protein-coupled receptor (GPCR) therapeutic antibody-based discovery and development.

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[Summary] The IRIC Virtual Symposium : “GPCRs In Oncology & Immuno-oncology” – Sponsored by Domain Therapeutics

A summary of the symposium that took place on June 4.
Chaired by IRIC's CEO Michel Bouvier, it showcases some of the latest discoveries & techniques leveraging the potential of GPCRs in oncology and immuno-oncology.

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