Abstract IA022: DYP688, a first-in-class PMEL17-targeted antibody drug conjugate delivering a Gq/11-specific inhibitor for the treatment of metastatic uveal melanoma
Bibliographic record
Abstract
Abstract Activating mutations in GNAQ/GNA11, encoding the G protein α subunits Gq and G11, are the most frequent genetic alterations in uveal melanoma (UVM) and considered to be critical for the initiation and maintenance of this malignancy. Despite inhibitors of Gq and G11 exhibiting promising preclinical anti-uveal melanoma activity, their therapeutic potential is limited by on-target toxicities associated with the ubiquitous expression and critical biological processes mediated by these G proteins. Here we report the discovery of a novel Gq/11 inhibitor-based antibody-drug-conjugate (ADC), DYP688, that selectively targets UVM cells, while sparing normal Gq/11-dependent cells. This conjugate consists of the highly potent and selective Gq/11 inhibitor SDZ475 (FR900359) conjugated to an antibody targeting PMEL17, a lineage gene having significant differential expression in melanoma. DYP688 potently inhibits Gq/11 oncogenic signaling, resulting in selective antiproliferative activity and apoptosis in PMEL17-positive, GNAQ/11-mutant UVM cells. In vivo, DYP688 exhibits marked and durable tumor regression in GNAQ/11-mutant UVM models, including patient-derived xenograft and liver metastasis models. Finally, we show that DYP688 features favorable preclinical pharmacokinetic and safety profiles, supportive of clinical evaluation. A phase 1 clinical trial with DYP688 is currently ongoing to assess the safety, tolerability and preliminary anti-tumor activity in patients with metastatic UVM and other GNAQ/11-mutant melanomas (clinicaltrials.gov identifier NCT05415072). Citation Format: Josephzore Wk, Joseph A. D'Alessio, Padmaja Yerramilli-Rao, John Blankenship, Kathrin Buntin, Matthew Burger, Zhuoliang Chen, Young Shin Cho, John Davis, Nicolas Ebel, Jochen Eisfeld, Anne Haberkorn, Dominik Hainzl, Keith Hoffmaster, Matthias Napp, Dominik Pistorius, Vivek Rauniyar, Aimee Reynolds, Vincent Romanet, Christian Schnell, Katherine Seiss, William R. Tschantz, Susanne Wieland-Berghausen, Laurin Wimmer, Kuno Wuersch, Alan Zhang, Eusebio Manchado. DYP688, a first-in-class PMEL17-targeted antibody drug conjugate delivering a Gq/11-specific inhibitor for the treatment of metastatic uveal melanoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA022.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".